macrolides

マクロライド系抗菌薬

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/10/21 20:20:32」(JST)

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The macrolides are a group of drugs (typically antibiotics) whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Macrolides belong to the polyketide class of natural products.

Erythromycin. The macrolide ring is the lactone (cyclic ester) at upper-left.

Clarithromycin

Roxithromycin

Members

Antibiotic macrolides

US FDA-approved :

• Azithromycin - unique; does not inhibit CYP3A4
• Clarithromycin
• Erythromycin
• Fidaxomicin
• Telithromycin

Non-US FDA-approved:

• Carbomycin A
• Josamycin
• Kitasamycin
• Midecamycin/midecamycin acetate
• Oleandomycin
• Solithromycin
• Spiramycin - approved in the EU, and in other countries
• Troleandomycin - used in Italy and Turkey
• Tylosin/tylocine - used in animals
• Roxithromycin

Ketolides

Ketolides are a class of antibiotics that are structurally related to the macrolides. They are used to treat respiratory tract infections caused by macrolide-resistant bacteria. Ketolides are especially effective, as they have two ribosomal binding sites; the newer fluoroketolides have three ribosomal interaction sites.

Ketolides include:

• Telithromycin
• Cethromycin
• Solithromycin - the first fluoroketolide (not yet approved)

Non-antibiotic macrolides

The drugs tacrolimus, pimecrolimus, and sirolimus, which are used as immunosuppressants or immunomodulators, are also macrolides. They have similar activity to cyclosporin.

Antifungal drugs

Polyene antimycotics, such as amphotericin B, nystatin etc., are a subgroup of macrolides.

Toxic macrolides

A variety of toxic macrolides produced by bacteria have been isolated and characterized, such as the mycolactones.

Uses

Antibiotic macrolides are used to treat infections caused by Gram-positive (e.g., Streptococcus pneumoniae) and limited Gram-negative (e.g., Bordetella pertussis, Haemophilus influenzae) bacteria, and some respiratory tract and soft-tissue infections. The antimicrobial spectrum of macrolides is slightly wider than that of penicillin, and, therefore, macrolides are a common substitute for patients with a penicillin allergy. Beta-hemolytic streptococci, pneumococci, staphylococci, and enterococci are usually susceptible to macrolides. Unlike penicillin, macrolides have been shown to be effective against Legionella pneumophila, mycoplasma, mycobacteria, some rickettsia, and chlamydia.

Macrolides are not to be used on non-ruminant herbivores, such as horses and rabbits. They rapidly produce a reaction causing fatal digestive disturbance. It can be used in horses less than one year old, but care must be taken that other horses (such as a foal's mother) do not come in contact with the macrolide treatment.

Mechanism of action

Antibacterial

Macrolides are protein synthesis inhibitors. The mechanism of action of macrolides is inhibition of bacterial protein biosynthesis, and they are thought to do this by preventing peptidyltransferase from adding the growing peptide attached to tRNA to the next amino acid (similarly to chloramphenicol) as well as inhibiting ribosomal translation. Another potential mechanism is premature dissociation of the peptidyl-tRNA from the ribosome.

Macrolide antibiotics do so by binding reversibly to the P site on the subunit 50S of the bacterial ribosome. This action is considered to be bacteriostatic. Macrolides are actively concentrated within leukocytes, and are, therefore, transported into the site of infection.

Immunomodulation

Diffuse panbronchiolitis

The macrolide antibiotics erythromycin, clarithromycin, and roxithromycin have proven to be an effective long-term treatment for the idiopathic, Asian-prevalent lung disease diffuse panbronchiolitis (DPB). The successful results of macrolides in DPB stems from controlling symptoms through immunomodulation (adjusting the immune response), with the added benefit of low-dose requirements.

With macrolide therapy in DPB, great reduction in bronchiolar inflammation and damage is achieved through suppression of not only neutrophil granulocyte proliferation but also lymphocyte activity and obstructive secretions in airways. The antimicrobial and antibiotic effects of macrolides, however, are not believed to be involved in their beneficial effects toward treating DPB. This is evident, as the treatment dosage is much too low to fight infection, and in DPB cases with the occurrence of the macrolide-resistant bacterium Pseudomonas aeruginosa, macrolide therapy still produces substantial anti-inflammatory results.

Resistance

The primary means of bacterial resistance to macrolides occurs by post-transcriptional methylation of the 23S bacterial ribosomal RNA. This acquired resistance can be either plasmid-mediated or chromosomal, i.e., through mutation, and results in cross-resistance to macrolides, lincosamides, and streptogramins (an MLS-resistant phenotype).

Two other types of acquired resistance rarely seen include the production of drug-inactivating enzymes (esterases or kinases), as well as the production of active ATP-dependent efflux proteins that transport the drug outside of the cell.

Azithromycin has been used to treat strep throat (Group A streptococcal (GAS) infection caused by Streptococcus pyogenes) in penicillin-sensitive patients, however macrolide-resistant strains of GAS are not uncommon. Cephalosporin is another option for these patients.

Side-effects

A 2008 British Medical Journal article highlights that the combination of some macrolides and statins (used for lowering cholesterol) is not advisable and can lead to debilitating myopathy. This is because some macrolides (clarithromycin and erythromycin, not azithromycin) are potent inhibitors of the cytochrome P450 system, particularly of CYP3A4. Macrolides, mainly erythromycin and clarithromycin, also have a class effect of QT prolongation, which can lead to torsades de pointes. Macrolides exhibit enterohepatic recycling; that is, the drug is absorbed in the gut and sent to the liver, only to be excreted into the duodenum in bile from the liver. This can lead to a build-up of the product in the system, thereby causing nausea. In infants the use of erythromycin has been associated with pyloric stenosis.

Some macrolides are also known to cause cholestasis.

Bibliography

• Ōmura, S. (2002). Macrolide antibiotics: chemistry, biology, and practice (2nd ed.). Boston: Academic Press. ISBN 0-12-526451-8. 

References

External links

• Structure Activity Relationships "Antibacterial Agents; Structure Activity Relationships", André Bryskier MD; beginning at pp143

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. アジスロマイシン、クラリスロマイシン、およびテリスロマイシン azithromycin clarithromycin and telithromycin
• 2. マクロライド系剤、アミノグリコシド、テトラサイクリン、クリンダマイシン、およびメトロニダゾールに対する過敏反応 hypersensitivity reactions to macrolides aminoglycosides tetracyclines clindamycin and metronidazole
• 3. マクロライド系抗菌薬、アザライド系抗菌薬、リンコサミン系抗菌薬、ケトライド系抗菌薬に対する肺炎レンサ球菌の耐性 resistance of streptococcus pneumoniae to the macrolides azalides lincosamides and ketolides
• 4. 嚢胞性線維症：肺疾患治療の概要 cystic fibrosis overview of the treatment of lung disease
• 5. 成人における市中肺炎の治療に関する抗菌薬の研究 antibiotic studies for the treatment of community acquired pneumonia in adults

English Journal

• Overcoming acquired resistance to letrozole by targeting the PI3K/AKT/mTOR pathway in breast cancer cell clones.

• Cavazzoni A, Bonelli MA, Fumarola C, La Monica S, Airoud K, Bertoni R, Alfieri RR, Galetti M, Tramonti S, Galvani E, Harris AL, Martin LA, Andreis D, Bottini A, Generali D, Petronini PG.SourceDepartment of Experimental Medicine, Unit of Experimental Oncology, University of Parma, Italy.
• Cancer letters.Cancer Lett.2012 Oct 1;323(1):77-87. Epub 2012 Apr 3.
• Development of resistance to endocrine therapy is a clinical issue in estrogen receptor (ER)-positive breast cancer. Here we show that persistent activation of AKT/mTOR signaling is crucial to the acquisition of letrozole resistance in cell clones generated from MCF-7/AROM-1 aromatase-expressing bre
• PMID 22484466

• Fluorescently labeled macrolides as a tool for monitoring cellular and tissue distribution of azithromycin.

• Matijašić M, Munić Kos V, Nujić K, Cužić S, Padovan J, Kragol G, Alihodžić S, Mildner B, Verbanac D, Eraković Haber V.SourceGlaxoSmithKline Research Centre Zagreb Ltd., Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia.
• Pharmacological research : the official journal of the Italian Pharmacological Society.Pharmacol Res.2012 Oct;66(4):332-42. Epub 2012 Jun 26.
• Exceptional therapeutic effects of macrolides in treating various infections and inflammatory conditions can be significantly contributed to their unique pharmacokinetic properties. Macrolides accumulate in cells and tissues, with concentrations usually 10 to more than 100 times higher of those meas
• PMID 22749903

Japanese Journal

• Anti-inflammatory effects of garenoxacin on IL-8 production and ERK1/2 activation induced by lipopolysaccharides in A549 and THP-1 cells.

• Hara Shintaro,Ishimatsu Yuji,Mukae Hiroshi,Sakamoto Noriho,Kakugawa Tomoyuki,Fujita Hanako,Hara Atsuko,Kohno Shigeru
• European Journal of Pharmacology 668(1-2), 264-270, 2011-10-01
• … The anti-inflammatory properties of macrolides have been applied to the treatment of inflammatory airway diseases. …
• NAID 120003324084

• マクロライド耐性肺炎球菌に対するマクロライドの効果 (特集 注目される抗菌薬・抗菌薬療法)

• 森永 芳智,柳原 克紀
• 呼吸器内科 20(1), 41-47, 2011-07
• NAID 40018973017

• 薬物療法 喀痰調整薬・マクロライド (COPDの治療・管理update) -- (安定期の管理)

• 山谷 睦雄
• 日本胸部臨床 70(-), S62-69, 2011
• NAID 40018966285

Related Pictures

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★リンクテーブル★

リンク元	「抗菌薬」「マクロライド系抗菌薬」
関連記事	「macrolide」

「抗菌薬」

　　[★]

英

antibacterial drug, antibacterial

関

抗生剤、薬理学、抗菌薬一覧、抗細菌薬

first aid step 1 2006 p.165

定義

• 細菌/微生物に静菌作用、殺菌作用を示す物質。結果として、人において病原性を除去する目的で使用される。
• このうち、微生物によって産生される物質を抗生物質と呼ぶ

作用機序による分類

• 細胞壁合成阻害：βラクタム系抗菌薬(ペニシリン系抗菌薬、セフェム系抗菌薬、モノバクタム系抗菌薬、カルバペネム系抗菌薬)
• 核酸合成阻害　：ニューキノロン系抗菌薬、メトロニダゾール
• タンパク質合成阻害

• 30S：アミノグリコシド系抗菌薬、テトラサイクリン系抗菌薬
• 50S：マクロライド系抗菌薬、クリンダマイシン、クロラムフェニコール、ストレプトグラミン系抗菌薬、オキソゾリニドン系抗菌薬(リゾネリド)

• 代謝拮抗：サルファ剤(サルファメソキサゾール、トリメトプリム)

first aid step 1 2006 p.165

	Mechanism of action	Drugs
1	Block cell wall synthesis by inhibition of peptidoglycan cross-linking	penicillin, ampicillin, ticarcillin, piperacillin, imipenem, aztreonam, cephalosporins
2	Block peptidoglycan synthesis	bacitracin, vancomycin, cycloserine
3	Disrupt bacterial/fungal cell membranes	polymyxins
4	Disrupt fungal cell membranes	amphotericin B, nystatin, fluconazole/azoles
5	Block nucleotide synthesis	sulfonamides, trimethoprim
6	Block DNA topoisomerases	quinolones
7	Block mRNA synthesis	rifampin
8	Block protein synthesis at 50S ribosomal subunit	chloramphenicol, erythromycin/macrolides, lincomycin, clindamycin, streptogramins (quinupristin, dalfopristin), linezolid
9	Block protein synthesis at 30S ribosomal subunit	aminoglycosides, tetracyclines, spectinomycin 　ATuSi　→　あつし

薬物動態

• 濃度依存性：アミノグリコシド系抗菌薬、ニューロキノロン系抗菌薬
• 時間依存性：βラクタム系抗菌薬

治療期間

小児

尾内一信 ; 第 39 回日本小児感染症学会教育講演 2 小児感染症の抗菌薬療法 -耐性菌時代の適正使用-

感染臓器・臨床診断	原因菌	投与期間（抗菌薬）
髄膜炎	インフルエンザ菌	7-10日
	肺炎球菌	10-14日
	髄膜炎菌	7-10日
	GBS，腸内細菌，リステリア	21日
中耳炎	＜2 歳	10日
	2 歳≦	5-7日
咽頭炎	A 群連鎖球菌	10日(ペニシリン系薬)
		5日(セフェム系薬)
肺炎	肺炎球菌，インフルエンザ菌	解熱後3-4日
	黄色ブドウ球菌	3-4週間
	マイコプラズマ，クラミジア	10-21日
腎臓、膀胱炎、腎盂腎炎	大腸菌，プロテウス，腸球菌	3日
		14日
骨髄炎	黄色ブドウ球菌	21日
	連鎖球菌，インフルエンザ菌	14日

主要な感染症の抗菌薬投与期間

感染レジマニュ p.27

骨	骨髄炎		4-6週
耳鼻咽喉	中耳炎		5-7日
	副鼻腔炎		5-14日
	A群溶連菌咽頭炎		10日
肺	肺炎	肺炎球菌	7-10日 or 解熱後3日間
		インフルエンザ菌	10-14日
		マイコプラズマ	14日(7-10日)
		レジオネラ	21日
	肺化膿症		28-42日
心臓	感染性心内膜炎	α連鎖球菌	2-4週
		黄色ブドウ球菌	4-6週
消化管	腸炎	赤痢菌	3日
		チフス	14日(5-7日)
		パラチフス
	腹膜炎	特発性	5日
		二次性	10-14日
胆肝膵	肝膿瘍	細菌性	4-8週
		アメーバ性	10日
尿路	膀胱炎		3日
	急性腎盂腎炎		14日(7-10日)
	急性腎盂腎炎・再発		6週
	慢性前立腺炎		1-3ヶ月
髄腔	髄膜炎	インフルエンザ菌	7-10日
		髄膜炎菌
		肺炎球菌	10-14日
		リステリア	21日
敗血症	敗血症	コアグラーゼ陰性ブドウ球菌	5-7日
		黄色ブドウ球菌	28日(14日)
		グラム陰性桿菌	14日(7-14日)
		カンジダ	血液培養陰性化後, 14日

ソース不明

• シャント感染：黄色ブドウ球菌：頭蓋内デバイスの感染の場合、髄液培養陰性+10日間

妊婦に避けるべき抗菌薬

• Antibiotics to avoid in pregnancy
• Sulfonamides––kernicterus.
• Aminoglycosides––ototoxicity.
• Fluoroquinolones––cartilage damage.
• Erythromycin––acute cholestatic hepatitis in mom

(and clarithromycin––embryotoxic).

• Metronidazole––mutagenesis.
• Tetracyclines––discolored teeth, inhibition of bone growth.
• Ribavirin (antiviral)––teratogenic.
• Griseofulvin (antifungal)––teratogenic.
• Chloramphenicol––“gray baby.”
• SAFE Moms Take Really Good Care.

使っても良い

YN.H-24

• βラクタム系
• エリスロマイシン、アジスロマイシン

参考

• 抗菌薬インターネットブック

まとまっていてよい

http://www.antibiotic-books.jp

「マクロライド系抗菌薬」

　　[★]

英

macrolide antibiotic macrolide antibiotics, macrolides, MLs

同

マクロライド系抗生物質　←厳密には違うが、多くの人が間違って使っている

関

抗菌薬

特徴

• 抗菌スペクトルが広い
• 静菌的に作用
• 大きな環状構造を有する。14員環-16員環
• タンパク質合成阻害薬
• 抗生物質としての作用の他に、抗炎症作用を有するらしい

炎症の抑制 ex.びまん性汎細気管支炎

構造

• http://www.sigmaaldrich.com/life-science/life-science-catalog/product-catalog.html?TablePage=14572877
• Macrolide antibiotics contain a many-membered lactone ring (14-membered rings for erythromycin and clarithromycin and a 15-membered ring for azithromycin) to which are attached one or more deoxy sugars. Clarithromycin differs from erythromycin only by methylation of the hydroxyl group at the 6 position, and azithromycin differs by the addition of a methyl-substituted nitrogen atom into the lactone ring. These structural modifications improve acid stability and tissue penetration and broaden the spectrum of activity.(GOO. chapter 46)

作用機序

• 50Sリボソームに結合してタンパク質合成を阻害

• inhibit bacterial protein synthesis by reacting with the 50s ribosomal subunit and preventing the release of the uncharged tRNA.

動態

• 経口で吸収される

抗菌スペクトル

• ペニシリンより広い抗菌スペクトル
• グラム陽性球菌、グラム陰性球菌、グラム陰性桿菌、スピロヘータ、一部のリケッチア、ウイルス

適応

• マイコプラズマ肺炎、クラミジア感染症、カンピロバクター腸炎、レジオネラ症
• びまん性汎細気管支炎：14員環マクロライドのみ
• URIs, pneumonias, STD

• グラム陽性球菌(ペニシリンアレルギー), Mycoplasma, Legionella, Chlamydia, Neisseria

副作用

• 肝障害
• 消化器障害
• QT延長、心室性不整脈

悪心、嘔吐、消化器の蠕動を促進

• 薬物相互作用

テオフィリン

喘息の治療薬。CYP3A4で代謝される。中毒域と治療域がちかいので注意する

マクロライド系抗菌薬

14員環

• エリスロマイシン erythromycin
• クラリスロマイシン clarithromycin
• ロキシスロマイシン roxithromycin

15員環

• アジスロマイシン azithromycin

16員環

• ジョサマイシン josamycin
• ロキタマイシン rokitamycin

14員環 (ケトライド系抗菌薬)

• テリスロマイシン telithromycin　→　厳密にはケトライド系

有効性 (SMB.147)

○：殺菌的、△静菌的

• ○グラム陽性菌
• ○マイコプラズマ
• ○クラミジア
• ○トレポネーマ
• ○リケッチア
• △ブドウ球菌
• △腸球菌
• ○?連鎖球菌

「macrolide」

　　[★] マクロライド、大環状化合物、(薬剤)マクロライド系薬、マクロライド系抗生物質、マクロライド系抗菌薬、マクロライド系の

関

macrocyclic compound、macrolide antibiotic、MLSB耐性