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an antibiotic (trade name Nebcin) that is especially effective against Gram-negative bacteria (同)Nebcin

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/04/30 16:17:41」(JST)

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Tobramycin is an aminoglycoside antibiotic derived from Streptomyces tenebrarius and used to treat various types of bacterial infections, particularly Gram-negative infections. It is especially effective against species of Pseudomonas.^[1]

Mechanism of action

Tobramycin works by binding to a site on the bacterial 30S and 50S ribosome, preventing formation of the 70S complex. As a result, mRNA cannot be translated into protein, and cell death ensues. According to Kotra, Haddad and collaborators "aminoglycosides, including Tobramycin, are multifunctional hydrophilic sugars that possess several amino and hydroxy functionalities. The amine moieties are mostly protonated in biological media; hence, these antibiotics can be considered polycationic species for the purpose of understanding their biological interactions. Since they are polycationic, they show a binding affinity for nucleic acids. Specifically, aminoglycosides possess high affinities for certain portions of RNAs, especially the prokaryotic rRNA. In addition, aminoglycosides bind to the hammerhead ribozyme, tRNA(Phe), the Rev response element (RRE) transcriptional activation region in human immunodeficiency virus (HIV), the ribozyme from hepatitis delta virus, and group I self-splicing introns.[4]"

Administration and indications

Like all aminoglycosides, tobramycin does not pass the gastro-intestinal tract, so for systemic use it can only be given intravenously or intramuscularly. Ophthalmic (tobramycin only, Tobrex, or combined with dexamethasone, sold as TobraDex) and nebulised formulations both have low systemic absorption. The formulation for injection is branded Nebcin. The nebulised formulation (brand name Tobi) is indicated in the treatment of exacerbations of chronic infection with Pseudomonas aeruginosa in patients diagnosed with cystic fibrosis. A proprietary formulation of micronized, nebulized tobramycin has been tested as a treatment for bacterial sinusitis.^[2] Tobrex is a 0.3% tobramycin sterile ophthalmic solution is produced by Bausch & Lomb Pharmaceuticals. Benzalkonium chloride 0.01% is added as a preservative. It is available by prescription only in the United States and Canada. In certain countries, such as Italy, it is available over the counter. Tobrex and TobraDex are indicated in the treatment of superficial infections of the eye, such as bacterial conjunctivitis. Tobramycin (injection) is also indicated for various severe or life-threatening gram-negative infections: meningitis in neonates, brucellosis, pelvic inflammatory disease, Yersinia pestis infection (plague).^{[citation needed]} Tobramycin is preferred over gentamicin for Pseudomonas aeruginosa pneumonia due to better lung penetration.^{[citation needed]}.

Side effects

Like other aminoglycosides, tobramycin is ototoxic: it can cause hearing loss, or a loss of equilibrioception, or both in genetically susceptible individuals. These individuals carry a normally harmless genetic mutation that allows aminoglycosides such as tobramycin to affect cochlear cells. Aminoglycoside-induced ototoxicity is generally irreversible.

As with all amino glycosides, tobramycin is also nephrotoxic, it can damage or destroy the tissue of the kidneys [3]. This effect can be particularly worrisome when multiple doses accumulate over the course of a treatment or when the kidney concentrates urine by increasing tubular reabsorption during sleep. Adequate hydration may help prevent excess nephrotoxicity and subsequent loss of renal function. For these reasons parenteral tobramycin needs to be carefully dosed by body weight, and its serum concentration monitored. Tobramycin is thus said to be a drug with a narrow therapeutic index.

Spectrum of susceptibility

Tobramycin has a narrow spectrum of activity and is active against Gram-negative bacteria. Clinically, tobramycin is frequently used to eliminate Pseudomonas aeruginosa in cystic fibrosis patients. The following represents MIC susceptibility data for a few strains of Pseudomonas aeruginosa:

Pseudomonas aeruginosa - <0.25 µg/mL - 92 µg/mL [ref?]
Pseudomonas aeruginosa (non-mucoid) - 0.5 µg/mL - >512 µg/mL [ref?]
Pseudomonas aeruginosa (ATCC 27853) - 0.5 µg/mL - 2 µg/mL^[3]

It's not active against gram positive Bacteria except for Staphylococcus aureus.

References

^ "Tobramycin" (PDF). Toku-E. 2010-01-12. Retrieved 2012-06-11.
^ "Nebulized Tobramycin in treating bacterial Sinusitis" (Press release). July 22, 2008. Retrieved 2009-12-06.
^ http://www.toku-e.com/Assets/MIC/Tobramycin.pdf

3. Davis, Bernard D. "Mechanism of bactericidal action of aminoglycosides." Microbiological reviews 51.3 (1987): 341.

4. Kotra, Lakshmi P., Jalal Haddad, and Shahriar Mobashery. "Aminoglycosides: perspectives on mechanisms of action and resistance and strategies to counter resistance." Antimicrobial agents and chemotherapy 44.12 (2000): 3249-3256.

External links

Tobramycin bound to proteins in the Protein Data Bank

UpToDate Contents

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1. 嚢胞性線維症：肺疾患に対する抗菌薬療法 cystic fibrosis antibiotic therapy for lung disease
2. アミノグリコシド（非経口）の用量および投与 dosing and administration of parenteral aminoglycosides
3. アミノグリコシド aminoglycosides
4. 腸球菌における抗菌薬耐性の機構 mechanisms of antibiotic resistance in enterococci
5. 成人における非結核性抗酸菌による骨髄炎の治療 treatment of osteomyelitis due to nontuberculous mycobacteria in adults

English Journal

Antimicrobial resistance, integron carriage, and gyrA and gyrB mutations in Pseudomonas aeruginosa isolated from dogs with otitis externa and pyoderma in Brazil.

Arais LR1, Barbosa AV1, Carvalho CA1, Cerqueira AM1.
Veterinary dermatology.Vet Dermatol.2016 Apr;27(2):113-e31. doi: 10.1111/vde.12290. Epub 2016 Feb 1.
BACKGROUND: Pseudomonas aeruginosa is associated with otitis and pyoderma in dogs and is frequently resistant to several antimicrobial drugs. Resistance genes can be carried by integrons with quinolone resistance mainly due to mutations in DNA topoisomerases II and IV.OBJECTIVE: To evaluate the anti
PMID 26833540

Impact of the Topical Ophthalmic Corticosteroid Loteprednol Etabonate on Intraocular Pressure.

Sheppard JD1, Comstock TL2, Cavet ME3.
Advances in therapy.Adv Ther.2016 Mar 17. [Epub ahead of print]
Corticosteroids are a mainstay therapeutic option for the treatment of ocular inflammation. However, safety remains a concern for clinicians, particularly with long-term use. Though highly effective at suppressing inflammatory and allergic responses, topical ophthalmic corticosteroids carry an inher
PMID 26984315

Design of Ionizable Lipids To Overcome the Limiting Step of Endosomal Escape: Application in the Intracellular Delivery of mRNA, DNA, and siRNA.

Habrant D1, Peuziat P2,3, Colombani T2,3, Dallet L4, Gehin J1, Goudeau E1, Evrard B1, Lambert O4, Haudebourg T2,3, Pitard B1,2,3.
Journal of medicinal chemistry.J Med Chem.2016 Mar 17. [Epub ahead of print]
The intracellular delivery of nucleic acid molecules is a complex process involving several distinct steps; among these the endosomal escape appeared to be of particular importance for an efficient protein production (or inhibition) into host cells. In the present study, a new series of ionizable ve
PMID 26943260

Japanese Journal

症例報告ドルナーゼアルファとトブラマイシンの吸入療法が著効した嚢胞性線維症の幼児例

村上至孝,宮田豊寿,石黒洋
日本小児呼吸器学会雑誌 = Japanese journal of pediatric pulmonology 26(1), 28-34, 2015
NAID 40020527015

Successful Colistin Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infection Using a Rapid Method for Determination of Colistin in Plasma: Usefulness of Therapeutic Drug Monitoring

Yamada Takehiro,Ishiguro Nobuhisa,Oku Kenji [他],Higuchi Issei,Nakagawa Ikuma,Noguchi Atsushi,Yasuda Shinsuke,Fukumoto Tatsuya,Iwasaki Sumio,Akizawa Kouji,Furugen Ayako,Yamaguchi Hiroaki,Iseki Ken
Biological and Pharmaceutical Bulletin 38(9), 1430-1433, 2015
… She was initially treated with imipenem–cilastatin, tobramycin, and aztreonam; …
NAID 130005096999

Successful Colistin Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infection Using a Rapid Method for Determination of Colistin in Plasma: Usefulness of Therapeutic Drug Monitoring

Yamada Takehiro,Ishiguro Nobuhisa,Oku Kenji,Higuchi Issei,Nakagawa Ikuma,Noguchi Atsushi,Yasuda Shinsuke,Fukumoto Tatsuya,Iwasaki Sumio,Akizawa Kouji,Furugen Ayako,Yamaguchi Hiroaki,Iseki Ken
Biological and Pharmaceutical Bulletin advpub(0), 2015
… She was initially treated with imipenem-cilastatin, tobramycin, and aztreonam; …
NAID 130005087349

Related Pictures

★リンクテーブル★

リンク元	「アミノグリコシド系抗菌薬」「トブラマイシン」「TOB」

「アミノグリコシド系抗菌薬」

Tobramycin
Systematic (IUPAC) name
	(2S,3R,4S,5S,6R)-4-amino-2-{[(1S,2S,3R,4S,6R)-4,6-diamino-3-{[(2R,3R,5S,6R)-3-amino-6-(aminomethyl)-5-hydroxyoxan-2-yl]oxy}-2-hydroxycyclohexyl]oxy}-6-(hydroxymethyl)oxane-3,5-diol
Clinical data
Trade names	Tobrex
AHFS/Drugs.com	monograph
MedlinePlus	a682660
Pregnancy; category	D (Injection, Inhalation); B (Ophthalmic) (US);
Routes of; administration	IV, IM, inhalation, ophthalmic
Pharmacokinetic data
Protein binding	< 30%
Identifiers
CAS Registry Number	32986-56-4
ATC code	J01GB01 S01AA12
PubChem	CID 36294
DrugBank	DB00684
ChemSpider	33377
UNII	VZ8RRZ51VK
KEGG	D00063
ChEBI	CHEBI:28864
ChEMBL	CHEMBL1747
Chemical data
Formula	C18H37N5O9
Molecular mass	467.515 g/mol
	SMILES C1[C@@H]([C@H]([C@@H]([C@H]([C@@H]1N)O[C@@H]2[C@@H]([C@H]([C@@H]([C@H](O2)CO)O)N)O)O)O[C@@H]3[C@@H](C[C@@H]([C@H](O3)CN)O)N)N;
	InChI InChI=1S/C18H37N5O9/c19-3-9-8(25)2-7(22)17(29-9)31-15-5(20)1-6(21)16(14(15)28)32-18-13(27)11(23)12(26)10(4-24)30-18/h5-18,24-28H,1-4,19-23H2/t5-,6+,7+,8-,9+,10+,11-,12+,13+,14-,15+,16-,17+,18+/m0/s1 ; Key:NLVFBUXFDBBNBW-PBSUHMDJSA-N ;
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　　[★]

英: aminoglycoside antibiotic
関: 抗菌薬、アミノグリコシド系薬、アミノグリコシド

GOO. chapter.45

タンパク質合成阻害による抗菌薬は静菌的なのもが多いが、アミノグリコシド系抗菌薬は「殺菌的」に作用

構造

amino sugars linked to an aminocyclitol ring by glycosidic bonds (GOO.1155)
名前の通りアミノ基-NH₂を多数有しているため正電荷を帯びる

→経口吸収不良

→脳脊髄液に移行しにくい。

→腎排泄されやすい

動態

内服不可能→外来患者に使いにくい
細胞膜(内膜)の通過は膜電位ポテンシャルに依存している。ここが律速段階となる。　→　細胞内移行性悪

阻害、拮抗要素：二価陽イオン、高浸透圧、pHの低下、嫌気的条件

膿瘍など嫌気的条件、酸性の高浸透圧尿など細菌の膜電位ポテンシャルが低下する場合に薬効低下

作用機序

30Sリボソームに作用してタンパク質合成を阻害

1. 翻訳開始を阻害
2. 翻訳を停止させる
3. 誤ったアミノ酸を取り込ませる

異常蛋白が細胞膜に挿入され、膜の透過性を変えてさらにアミノグリコシド系抗菌薬の取り込みを促す

薬理作用

薬効は迅速。濃度依存的。
post-antibiotic effectがある。

抗菌薬の血漿濃度がminnimum inhibitory concentration以下になっても殺菌活性が残存。殺菌活性の残存時間は濃度依存的

抗菌スペクトル

広い

副作用

腎障害：近位尿細管の壊死変性。用量依存的
耳毒性：CN VIII障害。内耳の有毛細胞を破壊。用量依存的
神経・筋遮断作用：(稀であるが)神経筋遮断作用(およびこれによる無呼吸)を呈する。遮断作用はネオマイシンが一番強く、カナマイシン、アミカシン、ゲンタマイシン、トブラマイシンがこれに続く。通常、胸腔内、腹腔に大量投与した時に生じるが、静脈内、筋肉内、あるいは経口投与でも起こりうる。大抵の発作(神経筋接合部が遮断される発作)は麻酔薬やその他の神経筋接合部遮断薬の投与で生じる(←どういう意味？)。重症筋無力症の患者はアミノグリコシド系抗菌薬による神経筋接合部遮断作用を受けやすい。(GOO.1164)