Tobrel0.3%

Tobrel is an aminoglycoside antibiotic active against susceptible aerobic gram-negative bacteria, most notably Pseudomonas aeruginosa. In Bangladesh, Tobrel is marketed mainly as an ophthalmic solution/ointment and as a nebuliser (inhalation) solution; injectable (systemic) Tobrel is used internationally for serious infections but is primarily a hospital-procured product rather than a common retail item locally.

Established / FDA-approved indications

• Ophthalmic (eye drops/ointment): Treatment of superficial bacterial infections of the eye and its adnexa (e.g., bacterial conjunctivitis, keratitis, blepharitis) caused by susceptible organisms such as Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, Haemophilus influenzae, and Escherichia coli.
• Inhalation (nebuliser solution): Management of chronic pulmonary infection due to Pseudomonas aeruginosa in patients with cystic fibrosis, approved for patients 6 years of age and older.
• Systemic (intravenous/intramuscular injection): Treatment of serious infections caused by susceptible strains of gram-negative bacteria, including septicaemia, complicated urinary tract infection, lower respiratory tract infection, meningitis, intra-abdominal infection, and skin/bone/soft-tissue infection, generally as part of a combination regimen for severe or life-threatening infection.

Guideline-supported / adjunct use

• Often combined with a beta-lactam antibiotic for empirical or documented gram-negative sepsis, febrile neutropenia, or endocarditis due to susceptible organisms, in line with hospital antibiotic stewardship protocols.

Tobrel is not effective against most gram-positive anaerobes or viral/fungal eye infections and should be reserved for infections proven or strongly suspected to be caused by susceptible bacteria.

Depending on the marketed formulation, Tobramycin preparations available in Bangladesh contain:

• Ophthalmic solution: Tobramycin 0.3% (3 mg/ml), as tobramycin sulfate
• Ophthalmic ointment: Tobramycin 0.3% (3 mg/g), as tobramycin sulfate
• Nebuliser solution: Tobramycin 300 mg/5 ml in a single-use ampoule, as tobramycin sulfate

Internationally, injectable Tobramycin is also supplied as tobramycin sulfate solution for intravenous/intramuscular injection (commonly 40 mg/ml, or a paediatric-strength 10 mg/ml).

Tobrel is an aminoglycoside antibiotic derived from Streptomyces tenebrarius. It is bactericidal against a wide range of aerobic gram-negative bacteria, with particularly strong activity against Pseudomonas aeruginosa, and some activity against Staphylococcus aureus. Tobrel is used topically in the eye for localized bacterial infections, by inhalation for chronic pulmonary Pseudomonas infection in cystic fibrosis, and, in hospital settings, by injection for serious systemic gram-negative infections. Because systemic absorption and toxicity risk differ greatly between these routes, the serious precautions relevant to injectable Tobrel (nephrotoxicity, ototoxicity) apply to a much lesser degree with topical ophthalmic use.

Tobrel belongs to the aminoglycoside antibiotic class - used as an ophthalmic anti-infective, an inhaled antipseudomonal agent for cystic fibrosis, and (parenterally) a systemic antibacterial for serious gram-negative infections.

Tobramycin exerts bactericidal activity by binding irreversibly to the 30S (and to a lesser extent 50S) ribosomal subunit of susceptible bacteria. This disrupts translation of messenger RNA, causing misreading of the genetic code and production of nonfunctional proteins, and also increases bacterial cell membrane permeability, ultimately leading to cell death. Uptake into bacterial cells is an oxygen-dependent active transport process, which explains reduced activity of Tobramycin in anaerobic environments such as abscesses.

Tobramycin is most active against aerobic gram-negative bacilli, especially Pseudomonas aeruginosa, and has some activity against Staphylococcus aureus; it is not active against anaerobes, most streptococci, or fungi.

Ophthalmic solution/ointment: wash hands, tilt the head back, instil into the lower conjunctival sac without touching the tip to the eye or any surface, then close the eye gently for 1-2 minutes; wait several minutes between different eye medications. Nebuliser solution: administered only by oral inhalation using an approved hand-held nebuliser device connected to a compressor - never inject or swallow the nebuliser solution. Systemic Tobrel: administered by slow intravenous infusion (over 30-60 minutes) or by deep intramuscular injection in a hospital/clinical setting; not intended for self-administration at home.

Concurrent or sequential use of Tobrel (particularly the systemic/inhaled forms) with other nephrotoxic or ototoxic drugs increases the risk of kidney and hearing/balance damage; this includes other aminoglycosides, amphotericin B, vancomycin, cisplatin, and potent loop diuretics such as furosemide and ethacrynic acid, which can also independently cause ototoxicity. Concomitant use with neuromuscular blocking agents or general anaesthetics may potentiate neuromuscular blockade and cause prolonged respiratory depression. Use with other antipseudomonal or nebulised antibiotics should be spaced apart and combined only under medical supervision. Ophthalmic Tobrel has minimal systemic absorption, so clinically significant systemic drug interactions are unlikely with routine topical eye use.

Ophthalmic use

• Local burning, stinging, or itching after instillation
• Conjunctival redness/hyperaemia
• Eyelid swelling or itching (hypersensitivity)
• Transient blurred vision

Inhalation (nebuliser) use

• Voice alteration (hoarseness)
• Tinnitus (usually reversible)
• Cough, bronchospasm/wheeze
• Taste disturbance

Systemic (injectable) use

• Nephrotoxicity (rising serum creatinine, reduced urine output)
• Ototoxicity - auditory (hearing loss, which may be irreversible) and/or vestibular (dizziness, vertigo, unsteadiness)
• Neuromuscular blockade (muscle weakness, respiratory difficulty) in predisposed patients
• Injection-site pain or phlebitis
• Rash or other hypersensitivity reactions

The risk and severity of systemic toxicities are much lower with topical ophthalmic Tobrel and generally low with inhaled Tobrel, and are mainly a concern with systemic/injectable Tobrel.

Tobrel, like other aminoglycosides, crosses the placenta and has been associated with a risk of fetal ototoxicity when given systemically during pregnancy. Systemic Tobrel should be used in pregnancy only if clearly needed and if the potential benefit justifies the potential risk to the fetus, and only under close physician supervision. Inhaled Tobrel is generally not recommended in pregnancy unless a physician determines the benefit outweighs the risk. Ophthalmic Tobrel results in minimal systemic absorption but should still be used in pregnancy only if considered necessary by the treating physician. Tobrel passes into breast milk in small amounts; a physician should be consulted before use while breastfeeding, particularly for systemic or inhaled therapy.

Nephrotoxicity and ototoxicity: Systemic (and to a lesser extent, inhaled) Tobrel can cause dose- and duration-related kidney damage and damage to the auditory and/or vestibular branches of the eighth cranial nerve; hearing loss from Tobrel can be irreversible. Renal function and, where possible, serum Tobrel concentrations (peak/trough) should be monitored during systemic therapy, especially in patients with pre-existing renal impairment, the elderly, dehydrated patients, or those on prolonged therapy. Avoid concurrent or sequential use with other nephrotoxic or ototoxic drugs where possible (see Interactions).

Neuromuscular blockade: Tobrel can cause or worsen neuromuscular blockade; use with caution in patients with myasthenia gravis, Parkinson's disease, or other conditions featuring muscle weakness, and in patients receiving anaesthetics or neuromuscular blocking agents, since respiratory paralysis has been reported.

Formulation-specific risk: The above systemic risks apply mainly to injectable and, to a lesser extent, inhaled Tobrel. Ophthalmic Tobrel carries a much lower systemic risk because ocular absorption is minimal, though prolonged or excessive topical use should still be avoided.

Superinfection: Prolonged use of any formulation of Tobrel may result in overgrowth of non-susceptible organisms, including fungi; discontinue and reassess if this occurs.

Antibiotic stewardship: Use Tobrel exactly as prescribed by your physician; do not stop, extend, skip doses, or share this medicine with others without medical advice.

Overdose or excessive dosing of systemic or inhaled Tobrel may increase the risk of nephrotoxicity, ototoxicity, and neuromuscular blockade (including respiratory depression); accidental ingestion of ophthalmic or nebuliser solution is unlikely to cause serious systemic toxicity but should still be treated with caution. In case of a known or suspected overdose of Tobrel, seek immediate medical attention or contact a poison control centre/emergency services; do not attempt specific home treatment. In hospital settings, management of significant systemic overdose may include supportive care, monitoring of renal function and serum drug levels, and haemodialysis in severe renal impairment, as directed by a physician.

Ophthalmic solution/ointment: store at room temperature (below 30°C), away from light and moisture; keep the container tightly closed and discard per the labelled in-use period after opening. Nebuliser solution: store refrigerated at 2-8°C, protected from light; if refrigeration is unavailable, it may be kept at room temperature for a limited period as specified on the product label, and should be discarded if it becomes cloudy or discoloured. Keep all forms of Tobrel out of reach of children.

Renal impairment: Systemic Tobrel requires dose or interval adjustment based on creatinine clearance, with monitoring of renal function and serum drug levels; use inhaled Tobrel with caution in patients with significant renal disease.

Elderly: May have reduced renal function; use systemic/inhaled Tobrel cautiously with renal function monitoring.

Hepatic impairment: No specific dose adjustment is established for Tobrel; it is primarily renally eliminated.

Pregnancy and lactation: See Pregnancy & Lactation section above.

Cystic fibrosis patients: Inhaled Tobrel is specifically studied and approved in this population 6 years of age and older with Pseudomonas aeruginosa infection; not established below this age or outside the studied lung-function range.

Ophthalmic Tobrel is typically used for 7-10 days for acute bacterial eye infection, or as directed; treatment beyond this should be reassessed by a physician. Inhaled Tobrel is used in repeating cycles of 28 days on-treatment followed by 28 days off-treatment for chronic suppressive therapy in cystic fibrosis. Systemic Tobrel is generally given for the shortest effective duration (commonly 7-10 days, occasionally longer for specific serious infections such as endocarditis) with close monitoring, since prolonged systemic therapy increases toxicity risk.

Aminoglycoside antibiotics (the class to which Tobramycin belongs)

Tobramycin binds to the 30S ribosomal subunit of susceptible bacteria, causing misreading of mRNA and inhibition of protein synthesis, and also disrupts bacterial cell membrane integrity, resulting in a bactericidal effect against susceptible aerobic gram-negative organisms, particularly Pseudomonas aeruginosa.

D

Ophthalmic: Safety and efficacy of Tobrel eye drops/ointment in children under 1 year of age have not been established; used with caution in infants and young children under medical supervision.

Inhalation: Tobrel nebuliser solution is approved for cystic fibrosis patients 6 years of age and older with Pseudomonas aeruginosa infection; safety and efficacy below age 6 have not been established.

Systemic: Tobrel injection may be used in neonates and older children with weight-based dosing as directed by a physician (see Dosage & Administration), with close monitoring for nephrotoxicity and ototoxicity given the increased vulnerability of paediatric patients.