Optob Eye drops

Indications

• Bacterial infections (systemic use)
• Septicaemia
• Meningitis and other CNS infections
• Urinary tract infections
• Acute pyelonephritis or prostatitis
• Pneumonia in hospital patients
• Chronic pulmonary Pseudomonas aeruginosa infection in patients with cystic fibrosis

Mechanism of action

Tobramycin binds to the bacterial 30S ribosomal subunit, disrupting protein synthesis. This binding causes misreading of mRNA, leading to the production of non-functional proteins. Additionally, tobramycin increases the permeability of the bacterial cell membrane, facilitating further entry of the drug. This dual action results in both immediate and delayed bactericidal effects.

Pharmacodynamics

Tobramycin has a broad spectrum of activity against a variety of Gram-negative bacteria including Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, as well as some Gram-positive organisms such as Staphylococcus spp. It is particularly effective in treating infections associated with cystic fibrosis and serious hospital-acquired infections. Due to its mechanism of action, tobramycin is also associated with potential toxic effects, especially in renal and auditory systems.

Pharmacokinetics

Tobramycin is poorly absorbed from the gastrointestinal tract, necessitating parenteral administration for systemic effects. It is distributed widely in body fluids, including synovial and peritoneal fluids, and it crosses the placenta. The drug is primarily excreted unchanged in the urine, and its half-life is approximately 2 hours in normal renal function, extending in cases of renal impairment. Monitoring of serum tobramycin levels is essential to avoid toxicity, particularly nephrotoxicity and ototoxicity.

Contra-indications

• History of hypersensitivity to tobramycin or other aminoglycosides
• Severe renal impairment
• Pre-existing auditory or vestibular disorders

Adverse effects

• Ototoxicity
• Nephrotoxicity
• Electrolyte imbalance
• Diarrhoea
• Nausea
• Vomiting
• Confusion
• Paraesthesia
• Malaise
• Respiratory disorders
• Abdominal pain
• Drowsiness
• Ear disorders
• Asthenia
• Sputum discolouration
• Hypertension

Interactions

• Increased risk of nephrotoxicity with other nephrotoxic agents
• Potentially decreased exposure with miconazole
• Enhanced neuromuscular blockade when used with neuromuscular blockers

Precautions

• Monitor renal function before and during treatment
• Auditory and vestibular function should be monitored during treatment
• Caution in patients with pre-existing neuromuscular disorders
• Use with caution in hepatic impairment

Pregnancy

There is a risk of auditory or vestibular nerve damage in the infant when aminoglycosides are used in the second and third trimesters of pregnancy.

Breast-feeding

Tobramycin is excreted in breast milk; caution is advised when administering to breastfeeding mothers.

Storage

Store in a cool, dry place away from direct sunlight. Protect from moisture.

Formulations

• Injectable solution (e.g., 300 mg/5 mL)
• Nebulised solution (e.g., 170 mg every 12 hours for 28 days)
• Ophthalmic ointment (e.g., applied 3 times a day for 5 days)
• Oral solution (e.g., 125 mg/5 mL)

Mechanism of action

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-acetyl

Pharmacodynamics

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.