Tobradex Mechanism of Action

tobramycin + dexamethasone




Full Prescribing Info
Pharmacotherapeutic group: Anti-inflammatory agents and anti-infectives in combination; corticosteroids and anti-infectives in combination. ATC code: S01CA01.
Pharmacology: Pharmacodynamics: Mechanism of action: Topical corticosteroids exert an anti-inflammatory action and have been used for the treatment for anterior inflammation since the 1950s. Aspects of the inflammatory process such as edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, deposition of collagen, scar formation, and fibroblastic proliferation are suppressed. Topical corticosteroids are effective in acute inflammatory conditions of the conjunctiva, sclera, cornea, lids, iris, and anterior segment of the globe as well as in ocular allergic conditions.
Dexamethasone is one of the most potent corticosteroids; it is 5 to 14 times more potent than prednisolone and 25 to 75 times more potent than cortisone and hydrocortisone. Of paramount importance with regard to local therapy is the fact that dexamethasone is over 2,000 times more soluble than hydrocortisone or prednisolone. The exact mechanism of anti-inflammatory action of dexamethasone is unknown. It inhibits multiple inflammatory cytokines and produces multiple glucocorticoid and mineralocorticoid effects.
Dexamethasone is a potent corticoid. Corticoids suppress the inflammatory response to a variety of agents and they can delay or slow healing. Since corticoids may inhibit the body's defense mechanism against infection, a concomitant antimicrobial drug may be used when this inhibition is considered to be clinically significant. Tobramycin is an antibacterial drug. It inhibits the growth of bacteria by inhibiting protein synthesis.
Mechanism of resistance: Resistance to tobramycin occurs by several different mechanisms including (1) alterations of the ribosomal subunit within the bacterial cell; (2) interference with the transport of tobramycin into the cell, and (3) inactivation of tobramycin by an array of adenylylating, phosphorylating, and acetylating enzymes. Genetic information for production of inactivating enzymes may be carried on the bacterial chromosome or on plasmids. Cross resistance to other aminoglycosides may occur.
Breakpoints: The breakpoints and the in vitro spectrum as mentioned as follows are based on systemic use. These breakpoints might not be applicable on topical ocular use of the medicinal product as higher concentrations are obtained locally and the local physical/chemical circumstances can influence the activity of the product on the site of administration. In accordance with EUCAST, the following breakpoints are defined for tobramycin: Enterobacteriaceae S ≤2 mg/L, R >4 mg/L; Pseudomonas spp. S ≤4 mg/L, R >4 mg/L; Acinetobacter spp. S ≤4 mg/L, R >4 mg/L; Staphylococcus spp. S ≤1 mg/L, R >1 mg/L; Not species-related S ≤2 mg/L, R >4 mg/L.
Clinical efficacy against specific pathogens: The information listed as follows gives only an approximate guidance on probabilities whether microorganisms will be susceptible to tobramycin in Tobradex. Bacterial species that have been recovered from external ocular infections of the eye such as observed in conjunctivitis are presented here.
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of tobramycin in at least some types of infections is questionable.
COMMONLY SUSCEPTIBLE SPECIES: Aerobic Gram-positive microorganisms: Bacillus megaterium, Bacillus pumilus, Corynebacterium macginleyi, Corynebacterium pseudodiphtheriticum, Kocuria kristinae, Staphylococcus aureus (methicillin susceptible - MSSA), Staphylococcus epidermidis (coagulase-positive and -negative), Staphylococcus haemolyticus (methicillin susceptible - MSSH), Streptococci (inlcuding some of the group A beta-hemolytic species, some nonhemolytic species, and some Streptococcus pneumoniae).
Aerobic Gram-negative microorganisms: Acinetobacter calcoaceticus, Acinetobacter junii, Acinetobacter ursingii, Citrobacter koseri, Enterobacter aerogenes, Escherichia coli, H. aegyptius, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Moraxella catarrhalis, Moraxella lacunata, Moraxella oslonensis, Some Neisseria species, Proteus mirabilis, Most Proteus vulgaris strains, Pseudomonas aeruginosa, Serratia liquifaciens.
Anti-bacterial activity against other relevant pathogens: SPECIES FOR WHICH ACQUIRED RESISTANCE MIGHT BE A PROBLEM: Acinetobacter baumanii, Bacillus cereus, Bacillus thuringiensis, Kocuria rhizophila, Staphylococcus aureus (methicillin resistant - MRSA), Staphylococcus haemolyticus (methicillin resistant - MRSH); Staphylococcus, other coagulase-negative spp.; Serratia marcescens.
INHERENTLY RESISTANT ORGANISMS: Aerobic Gram-positive microorganisms: Enterococcus faecalis, Streptococcus mitis, Streptococcus pneumoniae, Streptococcus sanguis, Chryseobacterium indologenes.
Aerobic Gram-negative microorganisms: Haemophilus influenzae, Stenotrophomonas maltophilia.
Anaerobic Bacteria: Propionibacterium acnes.
Bacterial susceptibility studies demonstrate that in some cases, microorganisms resistant to gentamicin retain susceptibility to tobramycin.
PK/PD relationship: A specific PK/PD relationship has not been established for Tobradex. Dexamethasone has demonstrated dose-independent pharmacokinetics in published animal studies.
Published in vitro and in vivo studies have shown that tobramycin features a prolonged post-antibiotic effect, which effectively suppresses bacterial growth despite low serum concentrations.
Systemic administration studies of tobramycin have reported higher maximum concentrations with once daily compared to multiple daily dosing regimens. However, the weight of current evidence suggests that once daily systemic dosing is equally as efficacious as multiple-daily dosing. Tobramycin exhibits a concentration-dependent antimicrobial kill and greater efficacy with increasing levels of antibiotic above the MIC or minimum bactericidal concentration (MBC).
Data from clinical studies: Pharmacodynamic clinical trials of cumulative safety data from clinical studies are presented in Adverse Reactions.
Geriatric patients: No overall clinical differences in safety or efficacy have been observed between the elderly and other adult populations.
Pharmacokinetics: Absorption: Tobramycin is poorly absorbed across the cornea and conjunctiva when administered by topical ocular route. A peak concentration of 3 micrograms/mL in aqueous humor after 2 hours was attained followed by a rapid decline after topical administration of 0.3% tobramycin. However, Tobradex delivers 542 ± 425 micrograms/mL tobramycin in human tears at 2 minutes after ocular dosing, a concentration that generally exceeds the MIC of the most resistant isolates (MICs >64 micrograms/mL).
Peak dexamethasone concentrations in aqueous humor after administration of Tobradex were attained approximately at 2 hours with a mean value 32 ng/mL.
Systemic absorption of tobramycin after Tobradex administration was poor with plasma concentrations generally below the limit of quantitation.
Plasma concentrations of dexamethasone was observed but were very low with all values less than 1 ng/mL after Tobradex administration.
The bioavailability of oral dexamethasone ranged from 70 to 80% in normal subjects and patients.
Distribution: For tobramycin, systemic volume of distribution is 0.26 L/kg in man. Human plasma protein binding of tobramycin is low at less than 10%.
For dexamethasone, the volume of distribution at steady state was 0.58 L/kg after intravenous administration. The plasma protein binding of dexamethasone is 77%.
Biotransformation: Tobramycin is not metabolized while dexamethasone is principally metabolized to 6betahydroxydexamethasone along with the minor metabolite, 6beta-hydroxy-20- diydrodexamethasone.
Elimination: Tobramycin is excreted rapidly and extensively in the urine via glomerular filtration, and primarily as unchanged drug. Systemic tobramycin clearance was 1.43 ± 0.34 mL/min/kg for normal weight patients after intravenous administration and its systemic clearance decreased proportionally to renal function. The half-life for tobramycin is approximately 2 hours.
With dexamethasone after intravenous administration, the systemic clearance was 0.125 L/hr/kg with 2.6% of the dose recovered as unchanged parent drug while 70% of the dose was recovered as metabolites. The half-life has been reported as 3 to 4 hours but was found to be slightly longer in males. This observed difference was not attributed to changes in dexamethasone systemic clearance but to differences in volume of distribution and body weight.
Linearity/non-linearity: Ocular or systemic exposure with increasing dosing concentrations of tobramycin after topical ocular administration of tobramycin has not been tested. Therefore, the linearity of exposure with topical ocular dose could not be established. Mean Cmax for dexamethasone at a topical ocular dose concentration of 0.033% with 0.3% tobramycin appeared lower than with Tobradex with a value of approximately 25 ng/mL but this decrease was not proportional to dose.
Hepatic and renal impaired: The pharmacokinetics of tobramycin or dexamethasone with Tobradex administration has not been studied in these patient populations.
Effect of age on pharmacokinetics: There is no change in tobramycin pharmacokinetics in older patients when compared to younger adults. No correlation between age and plasma concentrations of dexamethasone was observed after oral administration of dexamethasone as well.
Toxicology: Preclinical safety data: Non-clinical data revealed no special hazard for humans from topical ocular exposure to tobramycin or dexamethasone based on conventional repeated-dose topical ocular toxicity studies, genotoxicity or carcinogenicity studies. Effects in non-clinical reproductive and developmental studies with tobramycin and dexamethasone were observed only at exposures considered sufficiently in excess of the maximum human ocular dosage indicating little relevance to clinical use for low-dose short-term courses of therapy.
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