Tobrex Mechanism of Action





Firma Chun Cheong
Full Prescribing Info
Pharmacotherapeutic group: ophthalmologicals; anti-infectives. ATC code: S01A A12.
Pharmacology: Pharmacodynamics: Mechanism of action: Tobramycin is a potent, broad-spectrum, fast-working bactericidal aminoglycoside antibiotic. It exerts its primary effect on bacterial cells by inhibiting polypeptide assembly and synthesis on the ribosome.
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 TOBREX. 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 accolens, Corynebacterium bovis, Corynebacterium macginleyi, Corynebacterium pseudodiphtheriticum, Kocuria kristinae, Staphylococcus aureus (methicillin susceptible - MSSA), Staphylococcus epidermidis (coagulase-positive and -negative), Staphylococcus haemolyticus (methicillin susceptible - MSSH), Streptococci (including some of the group A beta-hemolytic species, some nonhemolytic species, and some Streptococcus pneumonia).
Aerobic Gram-negative microorganisms: Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Acinetobacter junii, Acinetobacter ursingii, Citrobacter koseri, H. aegyptius, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Moraxella catarrhalis, Moraxella oslonensis, Moraxella lacunata, 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 haemolyticus (methicillin resistant - MRSH); Staphylococcus, other coagulase-negative spp.; Serratia marcescens.
INHERENTLY RESISTANT ORGANISMS: Aerobic Gram-positive microorganisms: Enterococci faecalis, Staphylococcus aureus (methicillin resistant - MRSA), Streptococcus mitis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus sanguis.
Aerobic Gram-negative microorganisms: Haemophilus influenzae, Stenotrophomonas maltophilia, Chryseobacterium indologenes, Burkholderia cepacia.
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 TOBREX. 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 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.
Elderly population: No overall clinical differences in safety or efficacy have been observed between the elderly and other adult populations.
Paediatric population: Over 600 paediatric patients were enrolled in 10 clinical studies with tobramycin eye drops or eye ointment for the treatment of bacterial conjunctivitis, blepharitis, or blepharoconjunctivitis. These patients ranged in age from 1 year to 18 years. Overall, the safety profile in paediatric patients was comparable to that of adult patients. For children younger than age 1, no recommendation on a posology can be made due to a lack of data.
Pharmacokinetics: Absorption: Tobramycin is poorly absorbed across rabbit cornea and conjunctiva and minimal amounts are absorbed into the eye after topical administration of tobramycin.
Additionally, systemic absorption of tobramycin is poor clinically after topical ocular administration of tobramycin products with similar concentration to TOBREX (0.3%).
The high concentration of tobramycin in TOBREX delivers tobramycin at the site of infection (ocular surface) at a concentration generally much higher than the MIC of the most resistant isolates (MICs > 64 µg/ml; tobramycin concentration in human eye after a single dose of TOBREX is 848 ± 674 µg/ml, 1 minute after dosing).
Tobramycin concentration in healthy human tears remains over MIC90 (16 µg/ml as described for ocular isolates) at least up to 44 minutes post dosing of a treatment with TOBREX.
Distribution: The volume of distribution is 0.26 l/kg in man. Human plasma protein binding of tobramycin is low at less than 10%.
Biotransformation: Tobramycin is excreted in the urine primarily as unchanged drug.
Elimination: Tobramycin is excreted rapidly and extensively in the urine via glomerular filtration, primarily as unchanged drug.
The plasma half‑life is approximately two hours. The reported systemic clearance in adult subjects with normal renal function ranged from of 0.05 - 0.1 L/hr/kg and decreased with decreased renal function.
Linearity/non-linearity: Ocular or systemic absorption with increasing dosing concentrations after topical ocular administration has not been tested. Therefore, the linearity of exposure with ocular dose could not be established.
Use in hepatic and renal impairment: TOBREX eye drops and eye ointment have not been studied in these patient populations. However, due to low systemic absorption of tobramycin after topical administration of this product, dose adjustment is not necessary.
Use in paediatrics: TOBREX may be used in paediatric patients (1 year of age and older) at the same dose as in adults. However, limited information is available in paediatric patients younger than 1 year of age.
Toxicology: Preclinical safety data: Tobramycin is very poorly absorbed from the gastrointestinal tract. High parenterally administered doses of tobramycin have been reported to cause renal toxicity in rats and dogs, and ototoxicity in cats.
Preclinical studies have shown high systemic doses of tobramycin were administered using the intra-peritoneal (IP) route at 30 and 60 mg/kg to rats during periods of major organogenesis; which caused increases in glomerular density and the loss of cortical area within the kidney in the fetuses and in newborn rats. Similarly in other laboratory animals, aminoglycoside antibiotics are considered to be ototoxic. Prolonged systemic treatment of tobramycin in cats administered using the subcutaneous route at 20, 40 and 80 mg/kg/day for 30 weeks resulted in dose-dependent degeneration of hair cells and supporting sensory structures in the ear. However, the human ear is now perceived as being anatomically more protected and thereby, less vulnerable to aminoglycoside-induced injury than with the animal models.
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