| Identification | Back Directory | [Name]
Tobramycin | [CAS]
32986-56-4 | [Synonyms]
nf6
tobra
tobrex
nebcin
obracin
nebicina
tobralex
Tobracin
Tobramax
obramycin
distobram
gernebcin
TOBRAMYCIN
NSC 180514
Tobramaxin
Tobramycine
tobradistin
nebramycin6
nebramycinvi
Tobramycetin
Tobramycin Base
deoxykanamycinb
1-epitobramycin
nebramycinfactor6
3’-deoxykanamycinb
Tobramycin (350 mg)
TobraMycin Base API
Tobramycin, Free Base
TobramycinSulphate49842-07-1/Base
-d-glycopyranosyl]-2-deoxystreptamine
Tobramycin (350 mg)L0E077970ug/mg(an)
Tobramycin (base and/or unspecified salts)
Tobramycin, Antibiotic for Culture Media Use Only
lpha-d-ribohexopyranosyl-(1-4)]-2-deoxy-d-streptamine
6-trideoxy-alpha-d-ribo-hexopyranosyl-(1-4))-2-deoxy-
d-6-trideoxy-alpha-d-ribohexopyranosyl-(1-6))-2-deoxy
d-6-tyrideoxy-alpha-d-ribohexopyranosyl-(1-6))-2-deoxy
O-3-Amino-3-deoxy-alpha-D-glucopyranosyl-(1-6)-O-(2,6-
TOBRAMYCIN (RE-EXPORT OF REJECTED MATERIAL RETURN TO VENDOR)
4-[2,6-diamino-2,3,6-trideoxy-alpha-d-glycopyranosyl]-6-[3-amino-3-deoxy-alpha
streptamine,o-3-amino-3-deoxy-alpha-d-glucopyranosyl-(1-4)-o-(2,6-diamino-2,3,
o-3-amino-3-deoxy-alpha-d-glucopyranosyl-(1-6)-o-[2,6-diamino-2,3,6-trideoxy-a
O-3-Amino-3-deoxy-a-D-glucopyranosyl-(14)-O-[2,6-diamino-2,3,6-trideoxy-a-D-ribo-hexopyranosyl-(16)]-2-deoxystreptamine
O-3-Amino-3-deoxy-a-D-glucopyranosyl-(1-6)-O-[2,6-diamino-2,3,6-trideoxy-a-D-ribo-hexopyranosyl-(1-4)]-2-deoxy-D-streptamine
o-[3-amino-3-deoxy-α-d-glucopyranosyl-(1→6)]-o-[2,6-diamino-2,3,6-trideoxy-α-d-ribohexopyranosyl-(1→4)]-2-deoxy-d-streptamine
O-3-Amino-3-deoxy-α-D-glucopyranosyl-(1-6)-O-[2,6-diamino-2,3,6-trideoxy-a -D-ribo-hexopyranosyl-(1-4)]-2-deoxy-D-streptamine
O-[3-Amino-3-deoxy-α-D-glucopyranosyl-(1→6)]-O-[2,6-diamino-2,3,6-trideoxy-α-D-ribohexopyranosyl-(1→4)]-2-deoxy-D-streptamine
O-[3-Amino-3-deoxy-a-D-glucopyranosyl-(1[R]6)]-O-[2,6-diamino-2,3,6-trideoxy-a-D-ribohexopyranosyl-(1[R]4)]-2-deoxy-D-streptamine
D-Streptamine, O-3-amino-3-deoxy-a-D-glucopyranosyl-(16)-O-[2,6-diamino-2,3,6-trideoxy-a-D-ribo-hexopyranosyl-(14)]-2-deoxy- (9CI)
O-3-Amino-3-deoxy-alpha-D-glucopyranosyl-(1-4)-O-(2,6-diamino-2,3,6-trideoxy-alpha-D-ribohexopyranosyl-(1-4))-2-deoxy-D-streptamine
Streptamine, O-3-amino-3-deoxy-a-D-glucopyranosyl-(14)-O-[2,6-diamino-2,3,6-trideoxy-a-D-ribo-hexopyranosyl-(16)]-2-deoxy-, D- (8CI)
O-[3-Amino-3-deoxy-alpha-D-glucopyranosyl-(1→6)]-O-[2,6-diamino-2,3,6-trideoxy-alpha-D-ribohexopyranosyl-(1→4)]-2-deoxy-D-streptamine
O-[3-AMINO-3-DEOXY-ALPHA-D-GLUCOPYRANOSYL-(1->6)]-O-[2,6-DIAMINO-2,3,6-TRIDEOXY-ALPHA-D-RIBOHEXOPYRANOSYL-(1->4)]-2-DEOXY-D-STREPTAMINE
Tobramycin,O-[3-Amino-3-deoxy-α-D-glucopyranosyl-(1→6)]-O-[2,6-diamino-2,3,6-trideoxy-α-D-ribohexopyranosyl-(1→4)]-2-deoxy-D-streptamine
>D-Streptamine, O-3-amino-3-deoxy-.alpha.-D-glucopyranosyl-(1?6)-O-2,6-diamino-2,3,6-trideoxy-.alpha.-D-ribo-hexopyranosyl-(1?4)-2-deoxy-
(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-hydroxy-oxan-2-yl]oxy-2-hydroxy-cyclohexyl]oxy-6-(hydroxymethyl)oxane-3,5-diol | [EINECS(EC#)]
251-322-5 | [Molecular Formula]
C18H37N5O9 | [MDL Number]
MFCD00077885 | [MOL File]
32986-56-4.mol | [Molecular Weight]
467.51 |
| Chemical Properties | Back Directory | [Appearance]
White Powder | [Melting point ]
178 °C | [alpha ]
D20 +129° (c = 1 in water) | [Boiling point ]
570.01°C (rough estimate) | [density ]
1.3458 (rough estimate) | [refractive index ]
143 ° (C=4, H2O) | [storage temp. ]
2-8°C
| [solubility ]
H2O: 50 mg/mL, clear, faintly yellow
| [form ]
White to off-white solid | [pka]
pKa 6.7 (Uncertain);8.3 (Uncertain);9.9 (Uncertain) | [color ]
white to off-white | [Water Solubility ]
Soluble in water | [Merck ]
14,9490 | [BRN ]
1357507 | [Stability:]
Hygroscopic |
| Hazard Information | Back Directory | [Chemical Properties]
White Powder | [Uses]
antibacterial, inhibits protein synthesis | [Uses]
Antihypertensive | [Uses]
Single factor antibiotic comprising about 10% of nebramycin, the aminoglycosidic antibiotic complex produced by Streptomyces tenebrarius. Antibacterial | [Uses]
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. | [Description]
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′). | [Originator]
Brulamycin,Biogal S.A.,Hungary | [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. | [Biological Activity]
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. | [Pharmacokinetics]
Cmax 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
the drug is removed by hemodialysis over 12 h, but the efficiency
of different dialyzers varies markedly. | [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. | [Side effects]
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. | [Synthesis]
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. | [Drug interactions]
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. | [Metabolism]
Tobramycin is almost completely eliminated by the kidneys and the drug is eliminated unchanged almost entirely by glomerular filtration. | [storage]
+4°C |
| Safety Data | Back Directory | [Hazard Codes ]
Xi | [Risk Statements ]
36/37/38 | [Safety Statements ]
26-37/39 | [WGK Germany ]
2
| [RTECS ]
WK2100000
| [F ]
3-10 | [HS Code ]
29419090 | [Hazardous Substances Data]
32986-56-4(Hazardous Substances Data) | [Reaction]
- Catalyst for Suzuki-Miyaura Couplings of Heteroatom-Substituted Heteroaryl Chlorides
- Catalyst for the Negishi Approach to 1,5-Disubstituted 3-Amino-1H-1,2,4-triazoles.
| [Toxicity]
LD50 in mice, rats (mg/kg): 441, 969 s.c. (Welles) |
|
|