Tobramycin

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Sicherheit

  P201：Vor Gebrauch besondere Anweisungen einholen.

  P202：Vor Gebrauch alle Sicherheitshinweise lesen und verstehen.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

  P308+P313：BEI Exposition oder falls betroffen: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

  P405：Unter Verschluss aufbewahren.

  P501：Inhalt/Behälter ... (Entsorgungsvorschriften vom Hersteller anzugeben) zuführen.

Tobramycin Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.

• S-Sätze Betriebsanweisung:

  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
  S37/39:Bei der Arbeit geeignete Schutzhandschuhe und Schutzbrille/Gesichtsschutz tragen.

• Beschreibung

  Tobramycin is one component (factor 6) of a mixture produced by fermentation of Streptomyces tenebrari us. Lacking the C-3′ hydroxyl group, it is not a substrate for APH(3′)-1 and APH(3′)-II and so has an intrinsically broader spectrum than kanamycin. It is a substrate, however, for adenylation at C-2′ by ANT (2′) and acetylation at C-3 by AAC(3)-I and AAC(3)-II and at C-2′ by AAC(2′).

• Chemische Eigenschaften

  White or almost white powder.

• Originator

  Brulamycin,Biogal S.A.,Hungary

• Verwenden

  Antihypertensive

• Verwenden

  antibacterial, inhibits protein synthesis

• Verwenden

  Single factor antibiotic comprising about 10% of nebramycin, the aminoglycosidic antibiotic complex produced by Streptomyces tenebrarius. Antibacterial

• Verwenden

  Tobramycin is an aminoglycoside antibiotic.

• Definition

  ChEBI: A amino cyclitol glycoside that is kanamycin B lacking the 3-hydroxy substituent from the 2,6-diaminoglucose ring.

• Indications

  Tobramycin is highly active with respect to Gram-negative microorganisms (blue-pus bacillus and gastric bacilli, rabbit fever, serratia, providencia, enterobacteria, proteus, salmonella, shigella), as well as Gram-positive microorganisms (staphylococci, including those resistant to penicillin and some cephalosporins), and a few strains of streptococci.
  It is used for severe bacterial infections: peritonitis, sepsis, meningitis, osteomyelitis, endocarditis, pneumonia, pleural empyema, pulmonary abscess, purulent skin infections and soft tissue infections, and infections of the urinary tract caused by microorganisms that are sensitive to the drug. Synonyms of this drug are nebicine, obracine, and others.

• Manufacturing Process

  Two thousand parts by volume of an aqueous culture medium (pH 7.2) comprising 0.5% of glycerol, 0.5% of polypeptone, 0.5% of yeast extract and 0.3% of meat extract is inoculated with Escherichia coli R11 (IFO-13560). The medium is incubated at 37°C under aeration for 18 h. The culture broth is subjected to centrifuge to recover 4.4 parts of wet cells. The cells are suspended into 17.6 parts by volume of 0.05 M phosphate buffer (pH 7.0). The suspension is subjected to ultrasonic oscillation (Kaijo Denki Co., Ltd.; TA-4201, 4280-type, 2A) to disintegrate the cells, followed by removing the debris (insoluble materials) by centrifugation, whereby 17 parts by volume of crude enzyme solution is obtained.
  To 17 parts by volume of the crude enzyme solution are added 5 parts of kanamycin B, 50 parts by volume of 0.5 M phosphate buffer (pH 7.0), 100 parts by volume of 1 M adenosine triphosphate solution, 50 parts by volume of 0.1 M magnesium acetate solution and 50 parts by volume of 0.1 M 2- mercaptoethanol, which is filled up to 500 parts by volume with distilled water. The mixture is subjected to enzymic reaction at 37°C for 20 h. The reaction mixture is heated at 80°C for 5 min to cease the reaction, followed by centrifugation. The supernatant is run onto a column of 100 parts by volume of cation-exchange resin [Amberlite IRC-50, NH4 +-form]. The
  column is washed with water, and then eluted with 1 N-aqueous ammonia to give fractions which contain kanamycin B-3'-phosphate. The fractions are collected and concentrated under reduced pressure, and then the concentrate is run onto a column of 100 parts by volume of cation-exchange resin [carboxy-methyl Sephadex C-25, NH4 +-form]. The column is washed with water, and eluted with 0.2 N-aqueous ammonia to give fractions which contain kanamycin B-3'-phosphate. The fractions are collected, concentrated and lyophilized, whereby 4.5 parts of kanamycin B-3'-phosphate. A solution of one part of kanamycin B-3'-phosphate, 10 parts by volume of bis(trimethylsilyl)acetamide, 2 parts by volume of trimethylchlorosilane and 0.4 part of triphenylphosphine is heated at 115°C for 30 h. After cooling, the reaction mixture is concentrated under reduced pressure, and to the concentrate is added 100 parts by volume of methanol and 50 parts by volume of water, and then the mixture is stirred for 1 h. Methanol is removed by distillation, and ethyl acetate-soluble portion is removed. The water layer is run onto a column of 60 parts by volume of cation-exchange resin [Amberlite CG-50, NH4 +-form]. The column is washed with 200 parts by volume of water, and fractionated by linear gradient method with 600 parts by volume of water and 600 parts by volume of 0.5 N-aqueous ammonia, each fraction being 10 parts by weight. Upon concentration of some fractions 0.61 part of 2',3'- epimino-2'-deamino-3'-deoxykanamycin B is obtained. In 40 parts by volume of water is dissolved 0.6 part of 2',3'-epimino-2'- deamino-3'-deoxykanamycin B, and in the presence of 9 parts by volume of Raney nickel the mixture is stirred while introducing hydrogen gas at a pressure of 100 kg/cm2 at 60°C for 6 h. After the reaction Raney nickel is separated by filtration. The Raney nickel is washed well with 300 parts by volume of 1 N-aqueous ammonia and the washing is added to the filtrate. The whole is concentrated to about 100 parts by volume. The precipitated insolubles are removed by filtration, and the pH of the supernatant is adjusted to about 5.0 with hydrochloric acid. The mixture is run onto a column of 50 ml of cation-exchange resin [Amberlite CG-50, NH4 +-form]. The column is washed with 150 parts by volume of water, and fractionated by linear gradient method with 1400 parts by volume of water and 1400 parts by volume of 0.3 N-aqueous ammonia, each fraction being 14 parts by weight. From No. 146 to 162 fractions 0.30 part of 3'-deoxykanamycin B (Tobramycin) is obtained.

• Therapeutic Function

  Antibiotic

• Antimicrobial activity

  In-vitro activity against Ps. aeruginosa is usually somewhat greater than that of gentamicin; against other organisms activity is similar or a little lower. Other Pseudomonas species are generally resistant, as are streptococci and most anaerobic bacteria. Other organisms usually susceptible in vitro include Acinetobacter, Legionella and Yersinia spp. Alkaligenes, Flavobacterium spp. and Mycobacterium spp. are resistant. It exhibits bactericidal activity at concentrations close to the MIC and bactericidal synergy typical of aminoglycosides in combination with penicillins or cephalosporins.

• Acquired resistance

  It is inactivated by many aminoglycoside-modifying enzymes that inactivate gentamicin. However, AAC(3′)-I does not confer tobramycin resistance and AAC(3′)-II confers a lower degree of tobramycin resistance than of gentamicin resistance. Conversely, ANT(4′) confers tobramycin but not gentamicin resistance, as do some types of AAC(6′). Overproduction of APH(3′), conferring a low degree of resistance to tobramycin (MIC 8 mg/L), but not gentamicin (MIC 2 mg/L), was ascribed to ‘trapping’ rather than phosphorylation.
  Resistance rates are generally similar to those of gentamicin, although they may vary locally because of the prevalence of particular enzyme types.

• Biologische Aktivität

  Pharmacologically, tobramycin is quite similar to gentamicin. The drug is somewhat more active against Ps. aeruginosa than gentamicin. Tobramycin also acts synergistically with penicillin, but to a lesser degree than gentamicin.

• Pharmakokinetik

  C_max 80 mg intramuscular: 3–4 mg/L after 30 min
  1 mg/kg intravenous: 6–7 mg/L after 30 min
  5 mg/kg: >10 mg/L after 1 h
  Plasma half-life: 1.5–3 h
  Volume of distribution: c. 0.25 L/kg
  Plasma protein binding: <30%
  The pharmacokinetic behavior after systemic administration closely resembles that of gentamicin. In patients treated for prolonged periods with 2.5 mg/kg intravenously every 12 h, average peak steady-state values were 6.5 mg/L after 30 weeks and 7.1 mg/L after 40 weeks. Continuous intravenous infusion of 6.6 mg/h and 30 mg/h produced steady-state concentrations of 1 and 3.5–4.5 mg/L, respectively. Higher concentrations (10–12 mg/L) have been obtained by bolus injection over about 3 min. Peak concentrations of around 50 mg/L have been reported in cystic fibrosis patients given 9 mg/kg once daily. Ten minutes after a 300 mg dose of tobramycin solution for inhalation, mean concentration of drug in the sputum of cystic fibrosis patients was 1.2 mg/g and ranged from 0.04 to 1.4 mg/g. The systemic availability of nebulized drug is very variable (6–27%). In general, the concentration found in the sputum of cystic fibrosis patients is high when administered by inhalation, but varies widely depending on individual airway pathology and nebulizer efficiency.
  In the neonate, peak plasma concentrations of 4–6 mg/L have been found 0.5–1 h after doses of 2 mg/kg. Mean plasma elimination half-lives of 4.6–8.7 h were inversely proportional to the birth weight and creatinine clearance. The half-life was found to be initially extremely variable (3–17 h) in infants weighing 2.5 kg at birth, but considerably more stable (4–8 h) at the end of therapy 6–9 days later.
  β-Lactam inactivation
  In common with other aminoglycosides, tobramycin interacts with certain β-lactam agents, but is said to be stable in the presence of ceftazidime, imipenem and aztreonam. Of the penicillins tested, piperacillin caused least inactivation in vitro.
  Distribution
  The volume of distribution slightly exceeds the extracellular water volume; it increases in patients with ascites, and is relatively smaller in morbidly obese patients. In tracheostomized or intubated patients given a loading dose of 1 mg/kg and then intravenous infusions every 8 h of 2–3.5 mg/kg, average concentrations in the bronchial secretions were 0.7 mg/L with a mean secretion:serum ratio of 0.18. In patients with cystic fibrosis receiving 10 mg/kg of the drug per day, the bronchial secretions may contain 2 mg/L or more.
  Concentrations are low in peritoneal fluid but can rise to 60% of the plasma concentration in peritonitis and in synovial fluid. Tobramycin crosses the placenta, and concentrations of 0.5 mg/L have been found in the fetal serum when the mother was receiving a dose of 2 mg/kg. Penetration into the CSF resembles that of gentamicin.
  Excretion
  It is eliminated in the glomerular filtrate and is unaffected by probenecid. Renal clearance is 90 mL/min. About 60% of the administered dose is recovered from the urine over the first 10 h, producing urinary concentrations after a dose of 80 mg of 90–500 mg/L over the first 3 h. The nature of the extrarenal disposal of the remaining 40% of the drug has not been established. The total body clearance is increased in patients with cystic fibrosis and the plasma half-life is shorter, which may necessitate higher dosage (15 mg/kg per day) for optimum blood concentrations. Renal clearance is increased in younger burn patients. In patients with impaired renal function, urinary concentrations of the drug are depressed and the plasma half-life prolonged in proportion to the rise in serum creatinine, reaching 6–8 h at a creatinine concentration of 350 μmol/L. Dosage in patients with impaired renal function may be based on the procedures used for gentamicin since behavior of the two drugs is virtually identical. About 70% of t

• Clinical Use

  Severe infections caused by susceptible micro-organisms Ps. aeruginosa infections, including chronic pulmonary infections in cystic fibrosis (administration by injection or nebulizer)
  For practical purposes use is identical to that of gentamicin, except possibly for Pseudomonas infection, where it has somewhat greater activity against gentamicin-susceptible and some gentamicin-resistant strains. Its value as a substitute for gentamicin in the speculative treatment of severe undiagnosed infection is offset by its lower activity against other organisms that may be implicated.
  It has been used extensively to treat Ps. aeruginosa infections in patients with cystic fibrosis.

• Nebenwirkungen

  Ototoxicity
  The effect is predominantly on the auditory branch of the eighth nerve; vestibular function is seldom affected. Experimental evidence suggests that comparable effects on cochlear electrophysiology and histology require doses about twice those of gentamicin. In patients, electrocochleography has shown an immediate and dramatic reduction of cochlear activity when the serum tobramycin concentration exceeded 8–10 mg/L, but there were no associated symptoms and function recovered fully as the drug was eliminated. Clinical ototoxicity is rare and most likely to be seen in patients with renal impairment, or treated concurrently or sequentially with other potentially ototoxic agents.
  Nephrotoxicity
  Renal impairment with proteinuria, excretion of granular casts, oliguria and rise of serum creatinine have been noted in 1–2% of patients. Some evidence of nephrotoxicity has been found in about 10% of patients, depending on the sensitivity of the tests employed. In patients treated with a 120 mg loading dose and 80 mg every 8 h, renal enzyme excretion increased and there was a small but significant reduction in chrome-EDTA clearance even when the clinical condition improved. It has been suggested that intermittent dosage with large but infrequent plasma peaks may be less toxic than, and as efficacious as, continuous dosing. Tobramycin appears to be less nephrotoxic than gentamicin in critically ill patients.
  The likelihood of toxicity is thought to increase with preexisting renal impairment and higher or more prolonged dosage, but in a comparison of patients treated with 8 mg/kg per day for Pseudomonas endocarditis with those treated with 3 mg/kg per day for Gram-negative sepsis there was no evidence of renal impairment in either group. Although there was audiological evidence of high-frequency loss in some patients receiving the higher dosage, there was no sustained loss of conversational hearing. There seems to be no significant effect of age: in patients aged 20–39 years the mean elimination half-life of the drug at the end of treatment was 2.3 h while in those aged 60–79 years it was 2.4 h. Evidence of renal toxicity may be found in 20% of severely ill patients.
  Other reactions
  Other toxic manifestations are rare. Local reactions sometimes occur at the site of injection. Rashes and eosinophilia in the absence of other allergic manifestations are seen. Voice alterations and tinnitus were rare in cystic fibrosis patients receiving tobramycin by inhalation. Increased transaminase levels may occur in the absence of other evidence of hepatic derangement.

• Synthese

  Tobramycin, O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→6)-O-[2,6-amino- 2,3,6-trideoxy-α-D-ribo-glucopyranosyl-(1→4)]-2-deoxy-D-streptamine (3.4.7), is isolated from a culture liquid of the vital activity of the actinomycete S. tenebrarius.

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Antibacterials: increased risk of nephrotoxicity with colistimethate or polymyxins and possibly cephalosporins; increased risk of ototoxicity and nephrotoxicity with capreomycin or vancomycin.
  Ciclosporin: increased risk of nephrotoxicity.
  Cytotoxics: increased risk of nephrotoxicity and possibly of ototoxicity with platinum compounds.
  Diuretics: increased risk of ototoxicity with loop diuretics.
  Muscle relaxants: enhanced effect of nondepolarising muscle relaxants and suxamethonium.
  Parasympathomimetics: antagonism of effect of neostigmine and pyridostigmine.
  Tacrolimus: increased risk of nephrotoxicity.

• Stoffwechsel

  Tobramycin is almost completely eliminated by the kidneys and the drug is eliminated unchanged almost entirely by glomerular filtration.

• Lager

  +4°C

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