トブラマイシン

Pharmaceuticals -> Antibiotics

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Antibiotics

White to off-white powder

Crystals

freely soluble

Freely soluble in water (1 in 1.5 parts)

Very slightly soluble in ethanol (1 in 2000 parts). Practically insoluble in chloroform, ether

5.37e+01 g/L

Breast Feeding; Lactation; Milk, Human; Anti-Infective Agents; Antibacterial Agents; Aminoglycosides

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Ophthalmological preparations > Anti-infective agents

Hazardous decomposition products formed under fire conditions - Carbon oxides, nitrogen oxides (NOx).

When heated to decomposition it emits toxic fumes of /nitrogen oxides/.

Stable under recommended storage conditions.

... Hygroscopic powder.

This chemical does not meet GHS hazard criteria for 6.7% (1 of 15) of reports.

Danger

H315 (46.7%): Causes skin irritation [Warning Skin corrosion/irritation]

P203, P260, P261, P264, P264+P265, P270, P271, P272, P273, P280, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P332+P317, P333+P317, P337+P317, P362+P364, P391, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 15 reports by companies from 13 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tobramycin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tobramycin sulfate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Tobramycin sulfate/

KAHLMETER G; GENTAMICIN AND TOBRAMYCIN. CLINICAL PHARMACOKINETICS AND NEPHROTOXICITY. ASPECTS ON ASSAY TECHNIQUES; SCAND J INFECT DIS (SUPPL) 18: 40PP (1979). REVIEW WITH 149 REFERENCES ON PHARMACOKINETICS & NEPHROTOXICITY OF GENTAMICIN & TOBRAMYCIN.

Skin Irrit. 2 (46.7%)

Acute Tox. 3 (16.7%)

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company; Contaminated packaging: Dispose of as unused product.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains.

Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed.

Appropriate engineering controls: General industrial hygiene practice.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place.

Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Concomitant and/or sequential use of an aminoglycoside and other systemic, oral, or topical drugs that have neurotoxic, ototoxic, or nephrotoxic effects (e.g., other aminoglycosides, acyclovir, amphotericin B, bacitracin, capreomycin, certain cephalosporins, colistin, cisplatin, methoxyflurane, polymyxin B, vancomycin) may result in additive toxicity and should be avoided, if possible. /Aminoglycosides/

Because of the possibility of an increased risk of ototoxicity due to additive effects or altered serum and tissue aminoglycoside concentrations, aminoglycosides should not be given concomitantly with potent diuretics such as ethacrynic acid, furosemide, urea, or mannitol. It has been suggested that concomitant use of certain anti-emetics that suppress nausea and vomiting of vestibular origin and vertigo (e.g., dimenhydrinate, meclizine) may mask symptoms of aminoglycoside-associated vestibular ototoxicity. /Aminoglycosides/

Concurrent use of an aminoglycoside with general anesthetics or neuromuscular blocking agents (e.g., succinylcholine, rocuronium, tubocurarine) may potentiate neuromuscular blockade and cause respiratory paralysis. ... Aminoglycosides should be used with caution in patients receiving anesthetics or neuromuscular blocking agents, and patients should be closely observed for signs of respiratory depression. /Aminoglycosides/

In vitro studies indicate that the antibacterial activity of aminoglycosides and beta-lactam antibiotics may be additive or synergistic against some organisms including Enterobacteriaceae, Pseudomonas aeruginosa, enterococci, and viridans streptococci. The synergistic effect of aminoglycosides and beta-lactams is used to therapeutic advantage, especially in the treatment of infections caused by enterococci or Ps. aeruginosa. Although the exact mechanism of this synergistic effect has not been determined, it appears that by inhibiting bacterial cell-wall synthesis the penicillin allows more effective ingress of the aminoglycoside to the ribosomal binding site. Synergism between aminoglycosides and extended-spectrum penicillins generally is unpredictable and antagonism has been reported rarely in vitro when these penicillins were used in conjunction with amikacin, gentamicin, or tobramycin. Therefore, some clinicians suggest that when concomitant therapy is indicated it may be advisable to use appropriate in vitro studies to demonstrate synergism against the isolated organism. Concomitant administration of an extended-spectrum penicillin and an aminoglycoside has resulted in decreased serum aminoglycoside concentrations and elimination half life, especially in patients with renal impairment. Therefore, serum aminoglycoside concentrations should be monitored in patients receiving concomitant therapy, especially when very high doses of an extended-spectrum penicillin are used or when the patient has impaired renal function. /Aminoglycosides/

For more Interactions (Complete) data for Tobramycin (10 total), please visit the HSDB record page.

Intravenous and intramuscular therapy with tobramycin is usually associated with no increase in rates of serum aminotransferase or bilirubin elevations. Only isolated case reports of acute liver injury with jaundice have been associated with aminoglycoside therapy including tobramycin, not all of which are very convincing. The hepatic injury is typically mixed but can evolve into a cholestatic hepatitis. The latency to onset is rapid, occurring within 1 to 3 weeks and is typically associated with skin rash, fever and sometimes eosinophilia. Recovery typically occurs within 1 to 2 months and chronic injury has not been described. Aminoglycosides are not mentioned in large case series of drug induced liver disease and acute liver failure; thus, hepatic injury due to tobramycin is rare if it occurs at all.

The overall structure of rRNA is conserved across different species; however, aminoglycosides exhibit a significantly higher affinity, approximately 10-fold, for the rRNA of prokaryotes compared to eukaryotes. This increased binding affinity is not significant enough to explain the adverse effect profile of tobramycin. The most common adverse effects are dizziness, headache, confusion, nausea, and skin rash. Serious adverse drug reactions of tobramycin include ototoxicity, neuropathy, and nephrotoxicity. Rare cases of liver injury have been reported with the use of tobramycin.

IDENTIFICATION AND USE: Tobramycin is aminoglycoside antibiotic. HUMAN EXPOSURE AND TOXICITY: Serious allergic reactions including anaphylaxis and dermatologic reactions including exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson Syndrome have been reported rarely in patients on tobramycin therapy. Although rare, fatalities have been reported. Adverse effects on both the vestibular and auditory branches of the eighth nerve have been noted, especially in patients receiving high doses or prolonged therapy, in those given previous courses of therapy with an ototoxin, and in cases of dehydration. Symptoms include dizziness, vertigo, tinnitus, roaring in the ears, and hearing loss. Hearing loss is usually irreversible and is manifested initially by diminution of high-tone acuity. Renal function changes, as shown by rising BUN, NPN, and serum creatinine and by oliguria, cylindruria, and increased proteinuria, have been reported, especially in patients with a history of renal impairment who are treated for longer periods or with higher doses than those recommended. Adverse renal effects can occur in patients with initially normal renal function. Clostridium difficile associated diarrhea has been reported with use of nearly all antibacterial agents, including Tobramycin for Injection, USP, and may range in severity from mild diarrhea to fatal colitis. ANIMAL STUDIES: Tobramycin applied as 5% eyedrops to rabbit eyes caused only mild conjunctival erythema. However, 0.3% tobramycin eyedrops interfered with healing of rabbit corneal endothelium. The mean number of dose days required to produce vestibulotoxic effects, demonstrated by impaired righting reflex or locomotor ataxia, was from 41 to 61 in cats dosed with tobramycin. Histologic examination of the cochleae revealed degeneration of the hair cells and supporting sensory structures in the majority of cats dosed with tobramycin at 40 and 80 mg/kg. Renal toxicity was observed in pregnant rats and their fetuses after maternal administration of high doses of tobramycin, 30 or 60 mg/kg/day fo 10 days, during organogenesis. The dose-related fetal renal toxicity consisted of granularity and swelling of proximal tubule cells, poor glomerular differentiation, and increased glomerular density.

FDA-boxed warnings for tobramycin are ototoxicity, nephrotoxicity, and neuromuscular blockage. These adverse reactions limit the use of this class of broad-spectrum bactericidal antibiotics.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of December 8, 2016: http://actor.epa.gov/dashboard/]

/SIGNS AND SYMPTOMS/ Clinically apparent signs and symptoms of an overdose of tobramycin ophthalmic solution (punctate keratitis, erythema, increased lacrimation, edema and lid itching) may be similar to adverse reaction effects seen in some patients.

/SIGNS AND SYMPTOMS/ Serious allergic reactions including anaphylaxis and dermatologic reactions including exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson Syndrome have been reported rarely in patients on tobramycin therapy. Although rare, fatalities have been reported.

/SIGNS AND SYMPTOMS/ Adverse effects on both the vestibular and auditory branches of the eighth nerve have been noted, especially in patients receiving high doses or prolonged therapy, in those given previous courses of therapy with an ototoxin, and in cases of dehydration. Symptoms include dizziness, vertigo, tinnitus, roaring in the ears, and hearing loss. Hearing loss is usually irreversible and is manifested initially by diminution of high-tone acuity. Tobramycin and gentamicin sulfates closely parallel each other in regard to ototoxic potential.

/SIGNS AND SYMPTOMS/ Renal function changes, as shown by rising BUN, NPN, and serum creatinine and by oliguria, cylindruria, and increased proteinuria, have been reported, especially in patients with a history of renal impairment who are treated for longer periods or with higher doses than those recommended. Adverse renal effects can occur in patients with initially normal renal function.

For more Human Toxicity Excerpts (Complete) data for Tobramycin (11 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

Tobramycin

DILI Positive

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Acute Exposure/ .../Tobramycin/ applied as 5% eyedrops to rabbit eyes caused only mild conjunctival erythema... However, 0.3% tobramycin eyedrops interfered with healing of rabbit corneal endothelium.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In this study, mixed-breed cats (four/group) were given daily sc injections of netilmicin (20, 40, and 80 mg/kg), gentamicin (20 and 40 mg/kg), or tobramycin (20, 40, and 80 mg/kg) for up to 30 weeks or until ototoxicity was observed. The animals were examined throughout the study for effects on cochlear and vestibular function. Hematologic, serum chemical, and drug-serum (24-hr postdose) assays were performed at approximate monthly intervals during the dosing period. The cochleae, kidneys, and liver were examined microscopically. The mean number of dose days required to produce vestibulotoxic effects, demonstrated by impaired righting reflex or locomotor ataxia, was from 41 to 61 in cats dosed with tobramycin (40 and 80 mg/kg) or gentamicin. No vestibular dysfunction was observed in any of the netilmicin 20-mg/kg-dosed cats, in two cats each of the tobramycin 20-mg/kg and netilmicin 40-mg/kg groups, and in one netilmicin 80-mg/kg-dosed animal. Histologic examination of the cochleae revealed degeneration of the hair cells and supporting sensory structures in the majority of cats dosed with gentamicin at 20 and 40 mg/kg and tobramycin at 40 and 80 mg/kg. Less than 50% of the tissues from cats of the tobramycin 20-mg/kg and netilmicin 40- and 80-mg/kg-dosed groups had similar degenerative cochlear changes. No cochlear damage was noted in any of the cats given netilmicin at 20 mg/kg. Results of the clinical laboratory determinations were generally unremarkable. Proximal tubular degeneration was the principal finding observed in the kidneys of the animals. Under the conditions of this study, at least a twofold (vestibular) to fourfold (cochlear) relative safety margin for ototoxicity was established in favor of netilmicin over tobramycin and gentamicin.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ /The purpose of this study was/ to investigate the possible differences in cochleotoxic effects in rabbits between twice-daily administration of topical gentamicin and tobramycin throughout the perforated tympanic membrane with the use of distortion-product otoacoustic emissions (DPOAEs). Twenty female rabbits were studied prospectively daily for 21 days. The rabbits' ears were divided into two groups: right and left ear groups. Twice-daily for 21 days after paracentesis, 0.3% gentamicin was administered topically in the left ears, and 0.3% tobramycin was administered topically in the right ears. For 21 days, the cochlear activity of the right and left ears of all rabbits was examined every 7 days using DPOAEs. The numerical values of the distortion product (DP) intensity recorded on days 7, 14 and 21 of drug administration were compared between the two groups. Cochlear activity was reduced earlier in the gentamicin group in the 2-4 kHz frequencies compared to the tobramycin group in the second DPOAE measurement (day 7 of the experiment). In two rabbits in the gentamicin group, the third DPOAE measurement showed that cochlear activity was reduced in all frequencies. In six rabbits in the tobramycin group, the third DPOAE measurement showed that cochlear activity was reduced in all frequencies. There was no statistical significance between the two groups except day 7 in the 2 and 3 kHz frequencies (p<0.05). We concluded that low frequencies (2 and 3 kHz) are more sensitive to the administration of topical gentamicin than to topical tobramycin. Early cessation of tobramycin drops may be minimally cochlear toxic compared to gentamicin within the first 7 days when these drugs are misused in treating chronic otitis media.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ /The purpose of the research was/ to study the possible age-dependent ototoxic effects of tobramycin a subacute toxicity study was performed. To young adult (3 months) and old (27-30 months) female Wag-Rij rats 0, 10, 40, and 160 mg tobramycin sulfate/kg was administered subcutaneously in two doses a day. After 14 days all animals were autopsied. The cochlea was fixed by perfusion through the opened oval window and prepared for scanning electron microscopy. The rat cochlea consists of two turns. In all animals of the young control group the row of inner hair cells (IHC) as well as the three rows of outer hair cells (OHC) of the organ of Corti were fully intact. IHC as well as OHC are provided with three rows of stereocilia, from inside to outside with increasing length. The stereocilia of OHC are arranged in a characteristic W-configuration. In the young low dose group effects were focally seen in only 1 of 10 rats, consisting of shortened, disoriented or partly disappeared stereocilia of IHC and OHC in the basal turn. In the young mid dose group 4 of 10 animals had focally shortened, disoriented, and less stereocilia in the first row of OHC in the basal turn, and once of IHC and OHC in the apical turn. Seven of 8 animals of the young high dose group showed effects consisting of focal loss or shortening of stereocilia of IHC and OHC of the apical turn (3x), of OHC in the basal turn (3x), and once of stereocilia of IHC only. In the old control group the stereocilia of IHC were fully intact. However, many OHC, independent of row or turn, had no stereocilia at all. The percentages of OHC without stereocilia in the three rows of the apical and basal turns were 44-10-50 and 40-20-50, respectively. In the old low, mid, and high dose group the percentages of OHC without stereocilia were nearly identical to those of the old control group. In the old low and high dose group a reduced number of stereocilia per IHC occurred in half of the number of animals, while in the mid dose group the IHC were fully intact. In young adult animals the number of mildly affected cochleae increased as well as the extent of the lesion increased with increasing dose of tobramycin. The lesions of IHC and OHC, consisting of a decrease in number or shortening of stereocilia, were restricted mainly to (the last part of) the basal turn. As old control rats showed already a large number of OHC without stereocilia, the possible ototoxic effects of tobramycin were not detected against this "background" of stereociliary loss, consistent with aging. The damage in old rats was certainly not greater than in young adult rats. In conclusion, old rats were not more sensitive to the possible ototoxic effects of tobramycin than young adult rats.

For more Non-Human Toxicity Excerpts (Complete) data for Tobramycin (9 total), please visit the HSDB record page.

Renal function changes, as shown by rising blood urea nitrogen (BUN), non-protein nitrogen (NPN), and serum creatinine and by oliguria, cylindruria, and increased proteinuria, have been reported, especially in patients with a history of renal impairment ... .

Tobramycin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Dose reduction is required for patients with impaired renal function. Elderly patients may have reduced renal function that may not be evident in the results of routine screening tests, such as blood urea nitrogen (BUN) or serum creatinine. A creatinine clearance determination may be more useful. Monitoring of renal function during treatment with aminoglycosides is particularly important in the elderly.

Aminoglycosides should be used with caution in patients with muscular disorders, such as myasthenia gravis or parkinsonism, since these drugs may aggravate muscle weakness because of their potential curare-like effect on neuromuscular function. /Aminoglycosides/

Elderly patients may be at a higher risk of developing nephrotoxicity and ototoxicity while receiving tobramycin.

For more Populations at Special Risk (Complete) data for Tobramycin (6 total), please visit the HSDB record page.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

LD50 Guinea pig sc 676 mg/kg

LD50 Mouse im 440 mg/kg

LD50 Mouse iv 72,500 ug/kg

LD50 Mouse sc 367 mg/kg

For more Non-Human Toxicity Values (Complete) data for Tobramycin (8 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tobramycin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tobramycin sulfate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Tobramycin sulfate/

J01GB01

J - Antiinfectives for systemic use

S - Sensory organs

QS - Sensory organs

QJ - Antiinfectives for systemic use

Tobramycin is an aminoglycoside antibiotic derived from the actinomycete _Streptomyces tenebrarius_. It has a broad spectrum of activity against Gram-negative bacteria, including _Enterobacteriaceae_, _Escherichia coli_, _Klebsiella pneumoniae_, _Morganella morganii_, _Moraxella lacunata_, _Proteus_ spp., _Haemophilus_ spp., _Acinetobacter_ spp., _Neisseria_ spp., and, importantly, _Pseudomonas aeruginosa_. Aminoglycosides also generally retain activity against the biothreat agents _Yersinia pestis_ and _Francisella tularensis_. In addition, aminoglycosides are active against some Gram-positive bacteria such as _Staphylococcus_ spp., including methicillin-resistant (MRSA) and vancomycin-resistant strains, _Streptococcus_ spp., and _Mycobacterium_ spp. Like other aminoglycosides, tobramycin is taken up and retained by proximal tubule and cochlear cells in the kidney and ear, respectively, and hence carries a risk of nephrotoxicity and ototoxicity. There is also a risk of neuromuscular block, which may be more pronounced in patients with preexisting neuromuscular disorders such as myasthenia gravis or Parkinson's disease. Aminoglycosides can cross the placenta, resulting in total, irreversible, bilateral congenital deafness in babies born to mothers who were administered an aminoglycoside during pregnancy. Due to the low systemic absorption of inhaled and topical tobramycin formulations, these effects are more pronounced with injected tobramycin than with other formulations. However, all formulations carry a risk of hypersensitivity reactions, including potentially fatal cutaneous reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

Tobramycin is a 4,6-disubstituted 2-deoxystreptamine (DOS) ring-containing aminoglycoside antibiotic with activity against various Gram-negative and some Gram-positive bacteria. The mechanism of action of tobramycin has not been unambiguously elucidated, and some insights into its mechanism rely on results using similar aminoglycosides. In general, like other aminoglycosides, tobramycin is bactericidal and exhibits both immediate and delayed killing, which are attributed to different mechanisms, as outlined below. Aminoglycosides are polycationic at physiological pH, such that they readily bind to bacterial membranes ("ionic binding"); this includes binding to lipopolysaccharide and phospholipids within the outer membrane of Gram-negative bacteria and to teichoic acid and phospholipids within the cell membrane of Gram-positive bacteria. This binding displaces divalent cations and increases membrane permeability, which allows aminoglycoside entry. Additional aminoglycoside entry ("energy-dependent phase I") into the cytoplasm requires the proton-motive force, allowing access of the aminoglycoside to its primary intracellular target of the bacterial 30S ribosome. Mistranslated proteins produced as a result of aminoglycoside binding to the ribosome (see below) integrate into and disrupt the cell membrane, which allows more of the aminoglycoside into the cell ("energy-dependent phase II"). Hence, tobramycin and other aminoglycosides have both immediate bactericidal effects through membrane disruption and delayed bactericidal effects through impaired protein synthesis; observed experimental data and mathematical modelling support this two-mechanism model. Inhibition of protein synthesis was the first recognized effect of aminoglycoside antibiotics. Structural and cell biological studies suggest that aminoglycosides bind to the 16S rRNA in helix 44 (h44), near the A site of the 30S ribosomal subunit, altering interactions between h44 and h45. This binding also displaces two important residues, A1492 and A1493, from h44, mimicking normal conformational changes that occur with successful codon-anticodon pairing in the A site. Overall, aminoglycoside binding has several negative effects, including inhibiting translation initiation and elongation and ribosome recycling. Recent evidence suggests that the latter effect is due to a cryptic second binding site situated in h69 of the 23S rRNA of the 50S ribosomal subunit. Also, by stabilizing a conformation that mimics correct codon-anticodon pairing, aminoglycosides promote error-prone translation; mistranslated proteins can incorporate into the cell membrane, inducing the damage discussed above. Although direct mutation of the 16S rRNA is a rare resistance mechanism, due to the gene being present in numerous copies, posttranscriptional 16S rRNA modification by 16S rRNA methyltransferases (16S-RMTases) at the N7 position of G1405 or the N1 position of A1408 are common resistance mechanisms in aminoglycoside-resistant bacteria. These mutants also further support the proposed mechanism of action of aminoglycosides. Direct modification of the aminoglycoside itself through acetylation, adenylation, and phosphorylation by aminoglycoside-modifying enzymes (AMEs) are also commonly encountered resistance mutations. Finally, due to the requirement for active transport of aminoglycosides across bacterial membranes, they are not active against obligately anaerobic bacteria.

Aminoglycosides are usually bacterial in action. Although the exact mechanism of action has not been fully elucidated, the drugs appear to inhibit protein synthesis in susceptible bacteria by irreversibly binding to 30S ribosomal subunits. /Aminoglycosides/

... Aminoglycosides are aminocyclitols that kill bacteria by inhibiting protein synthesis as they bind to the 16S rRNA and by disrupting the integrity of bacterial cell membrane. Aminoglycoside resistance mechanisms include: (a) the deactivation of aminoglycosides by N-acetylation, adenylylation or O-phosphorylation, (b) the reduction of the intracellular concentration of aminoglycosides by changes in outer membrane permeability, decreased inner membrane transport, active efflux, and drug trapping, (c) the alteration of the 30S ribosomal subunit target by mutation, and (d) methylation of the aminoglycoside binding site. ... /Aminoglycosides/

Tobramycin has an apparent serum terminal half-life of ~3 hours following a single 112 mg inhaled dose in cystic fibrosis patients.

Total body clearance of tobramycin is approximately 20% higher in patients with cystic fibrosis than in patients without the disease; however, renal clearance is similar.

When tobramycin is administered by oral inhalation using a nebulizer, any drug that is not absorbed systemically probably is eliminated principally in expectorated sputum.

... Terminal elimination half-lives of greater than 100 hours have been reported in adults with normal renal function following repeated IM or IV administration of the drug.

The plasma elimination half-life of tobramycin following parenteral administration usually is 2-3 hours in adults with normal renal function and has ranged from 50-70 hours in adults with impaired renal function. The serum elimination half-life of tobramycin is reported to average 4.6 hours in full-term infants weighing more than 2.5 kg and 8.7 hours in infants weighing less than 1.5 kg. In one study in neonates 2-7 days of age, elimination half-life ranged from 5.68-13.6 hours in those weighing less than 2 kg and 3.54-6.73 hours in those weighing 2 kg or more.

Tobramycin is not appreciably metabolized.

Aminoglycosides are not metabolized and are excreted unchanged in the urine primarily by glomerular filtration. /Aminoglycosides/

VZ8RRZ51VK

TOBRAMYCIN

Established Pharmacologic Class [EPC] - Aminoglycoside Antibacterial

Chemical Structure [CS] - Aminoglycosides

Tobramycin is an Aminoglycoside Antibacterial.

TOBRAMYCIN

Tobramycin administered by inhalation in cystic fibrosis patients showed greater variability in sputum as compared to serum. After a single 112 mg dose, the serum Cmax was 1.02 ± 0.53 μg/mL, which was reached in one hour (Tmax), while the sputum Cmax was 1048 ± 1080 μg/g. Comparatively, for a 300 mg dose, the serum Cmax was 1.04 ± 0.58 μg/mL, which was also reached within one hour, while the sputum Cmax was 737 ± 1028 μg/g. The systemic exposure (AUC0-12) was also similar between the two doses, at 4.6 ± 2.0 μg∙h/mL for the 112 mg dose and 4.8 ± 2.5 μg∙h/mL for the 300 mg dose. When tobramycin was administered over a four-week cycle at 112 mg twice daily, the Cmax measured one hour after dosing ranged from 1.48 ± 0.69 μg/mL to 1.99 ± 0.59 μg/mL.

Tobramycin is primarily excreted unchanged in the urine.

Inhalation tobramycin had an apparent volume of distribution in the central compartment of 85.1 L for a typical cystic fibrosis patient.

Inhaled tobramycin has an apparent serum clearance of 14.5 L/h in cystic fibrosis patients aged 6-58 years.

Tobramycin is poorly absorbed from the GI tract.

Tobramycin is rapidly absorbed following IM administration. Following IM administration of a single dose of tobramycin of 1 mg/kg in adults with normal renal function, peak serum tobramycin concentrations average 4-6 ug/mL and are attained within 30-90 minutes; at 6-8 hours after the dose, serum concentrations are 1 ug/mL or less. When the same dose is administered by IV infusion over 30-60 minutes, similar plasma concentrations of the drug are attained.

MEDICATION (VET)

MEDICATION

Anti-Bacterial Agents

Use (kg; approx.) in Germany (2009): >100

An antibiotic entity separated from an antibiotic complex produced by Streptomyces tenebrarius.

Aminoglycoside antibiotic; component of the nebramycin complex produced by Streptomyces tenebrarius.

Table: Tobramycin Sulfate Preparations [Table#4515]

Table: Tobramycin Sulfate in Sodium Chloride Preparations [Table#4516]

Oral inhalation: Solution, for nebulization only: 300 mg/5 mL, Tobi (Chiron)

Ophthalmic: Suspension: 0.3% with Loteprednol Etabonate 0.5%, Zylet (Bausch & Lomb)

For more Formulations/Preparations (Complete) data for Tobramycin (6 total), please visit the HSDB record page.