Tobramycin

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Continuing Education Activity

Tobramycin is an antibiotic used to manage and treat systemic and ocular infections. It is a type of aminoglycoside. This activity describes the indications, action, and toxicities of tobramycin as a valuable agent in treating various infections. In addition, this activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team.

Objectives:

  • Identify the mechanism of action of tobramycin.
  • Describe the potential adverse effects of tobramycin.
  • Identify appropriate monitoring for patients receiving therapy with tobramycin.
  • Summarize interprofessional team strategies for improving care coordination and communication to safely use tobramycin and improve patient outcomes.

Indications

Tobramycin belongs to the class of broad-spectrum antibiotics known as aminoglycosides. Streptomycin was the first aminoglycoside invented in 1944, which led to the success of others in its category.[1] The majority of antibiotics in this class, including tobramycin, are bactericidal.[2] They work synergistically with beta-lactams to penetrate the cell walls of aerobic gram-negative bacteria.[3] Aminoglycosides are then actively transported across the bacterial cell membrane to bind and inactivate the initiation complex of translation.[1] Tobramycin has been prescribed to treat various conditions, from superficial infections to deep infections.[4]

Indications

  • The FDA has approved systemic administration (intramuscular or intravenous) of tobramycin for the treatment of various reinfections caused by susceptible organisms, mainly gram-negative bacteria and Staphylococcus aureus (penicillinase and non­ penicillinase-producing strains). Gram-negative bacteria include Pseudomonas aeruginosaEscherichia coliProteusKlebsiellaEnterobacterSerratiaProvidencia, and Citrobacter species. The nature of infections caused by these organisms that are treatable with tobramycin could range from septicemia, lower respiratory tract infections, central nervous system (CNS) infections like meningitis, intra-abdominal infections, skin and subcutaneous tissue infections including osteomyelitis, complicated urinary tract infections. 
  • Inhaled tobramycin is FDA approved to manage cystic fibrosis in individuals six years of age or older with Pseudomonas aeruginosa.[5] 
  • Ophthalmic tobramycin is FDA approved to treat external ocular infections by susceptible organisms in adults and children.
  • Off-label use of tobramycin includes intraventricular administration in the management of intraventricular catheter-associated central nervous system infections.[6]

Mechanism of Action

Tobramycin binds to the 16s ribosomal RNA of the bacterial 30s ribosomal unit and inhibits the initiation step of translation.[2] By binding to the A-site, tobramycin induces mistranslation and causes misreading of the codon by the transfer RNA, thus causing incorrect delivery of aminoacyl units. Incorrectly synthesized proteins build up inside the cell, disrupting the cell membrane and various cellular processes, designating tobramycin as a bactericidal agent.[1][7][8]

Pharmacokinetics

Tobramycin is absorbed rapidly following intramuscular injection. Peak serum concentrations of tobramycin reach between 30 to 90 minutes following intramuscular administration. Tobramycin dose of 1 mg/kg of body weight results in 4 mcg/mL peak serum concentrations. Therapeutic levels of tobramycin are generally considered between 4 to 6 mcg/mL. Tobramycin injected by intravenous infusion over one-hour results in similar serum concentrations to intramuscular administration. It gets poorly absorbed from the gastrointestinal tract. Tobramycin gets excreted via kidneys through glomerular filtration. The serum half-life of tobramycin is about 2 hours in an adult and prolonged in neonates to about 4.5 to 8.7 hours.[9]

Administration

Tobramycin is administered by various routes, but it has poor oral absorption like other aminoglycosides. The efflux P-glycoprotein pump located in the brush border of the intestines causes this resistance, so oral administration is typically avoided.[10] The administration is usually via intravenous or intramuscular injection.[11] Dosing can be in combination with beta-lactams, such as penicillins or cephalosporins to penetrate the outer walls of gram-negative bacteria.[11] 

  • Clinicians can use tobramycin to treat ocular infections in the form of a 0.3% ophthalmic solution or 0.3% ophthalmic ointment.[12][13] 
  • Tobramycin administration via oral inhalation is available for the treatment of cystic fibrosis-associated pneumonia.[5]
  • Intramuscular injection, intravenous infusion, and intraventricular (off-label) administration have been used to treat serious bacterial infections.[12][14][15] 

Adult Dosing

Tobramycin is dosed 3 mg/kg/day in divided doses every 8 hours for serious infections. If the infections are life-threatening, the dose can be increased to 5 mg/kg/day in equally divided doses every 6 to 8 hours and reduced to 3 mg/kg/day as clinically appropriate. However, dosage should not exceed 5 mg/kg/day unless serum levels are monitored to prevent potential toxicity due to excessive serum levels.

Intravenous Administration

Tobramycin for intravenous administration is diluted with (0.9% sodium chloride injection or 5% dextrose injection) 50-100 mL for adult doses. It is usually infused over 20 to 60 minutes. Less than 20 minutes of infusion periods are not recommended as peak serum levels can exceed 12 mcg/mL resulting in supratherapeutic concentrations. Tobramycin injection should not be premixed with other drugs, and it should be administered separately according to the recommended dose and route.

Inhalation Solution

Tobramycin 300 mg / 5 solution is administered by oral inhalation for 15-minute, using a nebulizer in patients with cystic fibrosis. The recommended dose of tobramycin inhalation solution for pediatric patients six years of age and older and adults is one single-dose ampule (300 mg) inhaled twice daily for 28 days. Dosage need not be adjusted by weight. Tobramycin inhalation solution after 28 days of treatment should be stopped for the next 28 days and then resume for the next 28 days. The doses should be inhaled as close to 12 hours apart as possible; they should not be taken less than 6 hours apart.  

Tobramycin should not be diluted or mixed with any other medicine or dornase alfa in the nebulizer. Tobramycin inhalation solution is not for subcutaneous, intravenous, or intrathecal administration. Caution, when Tobramycin injection is administered to premature or neonatal infants as their renal immaturity, can result in prolongation of serum half-life of medicine.

Pregnancy Implications

Tobramycin is an FDA pregnancy category D medicine. Aminoglycosides may cause fetal harm when given to a pregnant woman. Aminoglycoside antibiotics can cross the placenta, and irreversible bilateral congenital deafness in children is reported with maternal administration of streptomycin during pregnancy. Serious adverse effects to pregnant women, fetuses, or newborns are not reported with maternal use of other aminoglycosides. Use with caution only if potential benefits overweight potential risks.

Patients with Impaired Renal Function

If possible, serum tobramycin concentrations should be monitored during therapy to adjust the dose. Tobramycin loading dose of 1 mg/kg is followed by subsequent dosage adjustments based on the patient's serum creatinine or creatinine clearance. The half-life of tobramycin increases as the creatinine clearance of the patient decreases. Therefore, either normal doses are given at prolonged intervals, or reduced doses are administered at 8-hour intervals are recommended as guides to be used when the serum concentration of tobramycin cannot be measured directly. Consider monitoring patients' clinical and laboratory parameters for better therapeutic efficacy. These methods are not used when the patient is on dialysis.

Adverse Effects

The overall structure of rRNA is conserved among all species, but aminoglycosides have a 10-fold higher affinity to the rRNA of prokaryotes compared to that of eukaryotes. This affinity is not large enough of a binding affinity, explaining the side effect profile of tobramycin.[2] The most common side effects are dizziness, headache, confusion, nausea, and skin rash. Serious adverse drug reactions of tobramycin include ototoxicity, neuropathy, and nephrotoxicity. Reports exist of rare side effects of liver injury with tobramycin use.[16]

Resistance

Resistance to aminoglycosides occurs, as it does with any group of antibiotics; however, the occurrence of resistance is far less comparatively. There are different explanations for this finding, such as aminoglycosides are not prescribed as readily as other classes of antibiotics like beta-lactams. Resistance to aminoglycosides includes modification of the target site. Three classes of enzymes that modify and decrease the efficacy of tobramycin include aminoglycoside phosphotransferases (APHs), nucleotidyltransferases (ANTs), and acetyltransferases (AACs).[2] Bacteria with biofilm have greater resistance to aminoglycosides.[17] Another mechanism of resistance is related to the reversible down-regulation of drug uptake into the bacteria.[17] Some strains of Pseudomonas aeruginosa have developed aminoglycoside resistance through enzyme modification and decreasing outer membrane permeability for the drug.[18]

Drug Interactions

Concurrent use of other nephrotoxic and neurotoxic antibiotics, especially other aminoglycosides (e.g., streptomycin, amikacin, kanamycin, neomycin, paromomycin, and gentamicin), cephaloridine, polymyxin B, viomycin, colistin, vancomycin, and cisplatin should be avoided. Concurrent use of aminoglycosides with potent diuretics, such as furosemide and ethacrynic acid, should be avoided. Some diuretics can cause ototoxicity, and intravenously administered diuretics increase aminoglycoside's toxicity.

Contraindications

Contraindications include patients with hypersensitivity to tobramycin or any other aminoglycoside antibiotics. In addition, caution is necessary for patients with old age, prone to dehydration, and pre-existing conditions like renal failure, neuromuscular conditions like myasthenia gravis, and Parkinson disease.

Clostridium difficile associated diarrhea (CDAD) is reported with tobramycin injection and may range from mild diarrhea to fatal colitis. Careful patient medical history is essential as CDAD is reported to occur over two months after administering antibiotics. If CDAD is suspected or confirmed, ongoing tobramycin use may need to be discontinued. Appropriate electrolyte and fluid management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be performed as clinically indicated.

Monitoring

Monitoring drug frequency and dosing are essential in tobramycin administration to decrease the chances of toxic side effects. Researchers have observed that a longer dosing interval may reduce the risk of ototoxicity and nephrotoxicity.[3] The dosing and frequency of administration require adjustment based on the patient’s renal function because the medication is retained longer in patients with renal abnormalities or renal failure.[16] The drug is excreted mainly by the kidneys, so it is essential to monitor renal function.[19]  Tobramycin can cross the placenta, concentrating in the kidney and urine of the fetus.[9] The theory is that tobramycin could potentially cause nephrotoxic events in the fetus, but this requires further investigation.[20] 

Serum sodium, calcium, and magnesium should be monitored while on treatment. Peak and trough tobramycin serum levels should be monitored periodically usually after the first 2 to 3 doses, so the dose can be adjusted if needed and monitored at every 3-to 4-day intervals during therapy. Prolonged serum concentrations higher than 12 mcg/mL should be avoided. Rising trough concentrations above 2 mcg/mL might indicate tissue accumulation. Monitor serum levels closely in patients with advanced age and known renal impairment.

Toxicity

A few serious toxicities that could happen with tobramycin include ototoxicity, nephrotoxicity, and neurotoxicity. These adverse reactions put limitations on the use of this class of broad-spectrum bactericidal antibiotics.

Ototoxicity

Ototoxicity occurs from the loss of hair cells in the inner ear.[21] The damage to cranial nerve VIII (vestibulocochlear nerve) could cause hearing or balance dysfunctions.[22] Once-daily administration of tobramycin is thought to help reduce the risk of ototoxicity.[3] This adverse effect is often irreversible.

Nephrotoxicity

Nephrotoxicity, unlike ototoxicity, is a reversible adverse reaction.[22] In a double-blind study completed at Johns Hopkins University School of Medicine, researchers noted that the aminoglycoside-induced ototoxicity and nephrotoxicity occurred independently of each other.[22] Similar to preventing ototoxicity, nephrotoxicity is avoidable by longer dosing intervals.[3] Tobramycin can cause both direct nephrotoxicity, which is dose-related and a hypersensitivity reaction. Tobramycin activates the renin-angiotensin-aldosterone system and causes permanent vasoconstriction in the kidneys, causing an oliguric state with minimal urine output.[23] The toxic changes caused by tobramycin are observable in the proximal tubule.[23] Vacuolation and myeloid bodies in the tubular epithelial cell lysosomes are present under electron microscopy when using the medication.[23] Granular casts, microscopic hematuria, and proteinuria are also often present.[23] Close monitoring of kidney function is crucial to minimize nephrotoxic effects.[19] Maintaining adequate hydration can also decrease the likelihood of nephrotoxic events.[24] Studies show that antioxidant administration, most notably deferoxamine,  can alleviate the toxic events produced in the kidneys.[24]

Neurotoxicity

Tobramycin causes neuromuscular blockade by interfering with acetylcholine release. Patients with diseases affecting the neuromuscular junction, such as myasthenia gravis (MG), should not take aminoglycosides. This group of antibiotics can trigger or exacerbate symptoms of MG. If a patient with MG is taking tobramycin and starts to deteriorate, it is best to discontinue tobramycin or reduce the dosage.[25] Aminoglycosides are also known to cause the drug-induced myasthenic syndrome, which is a reversible disorder in patients who otherwise did not have neuromuscular transmission defects. The symptoms with the drug-induced myasthenic syndrome will occur soon after the drug starts but will cease upon stopping the medication.[26] 

Overdose

Patients overdosed on tobramycin with normal renal function should be hydrated adequately to preserve urine output of 3-5 mL/kg/hr. Fluid and electrolyte balance, creatinine clearance, and tobramycin serum concentrations should be monitored closely until the serum tobramycin concentration falls below 2 mcg/mL. Patients in whom the tobramycin elimination half-life is more than 2 hours or whose renal function is impaired may require aggressive therapy, and hemodialysis may be beneficial.

Enhancing Healthcare Team Outcomes

Tobramycin is a powerful and effective aminoglycoside, approved for complicated infections with various indications. Because of having a weak binding affinity to the rRNA of eukaryotes, it can cause serious adverse events in patients.[2] It is essential to monitor the patient for side effects and intervene promptly. Educating the patient about these possible effects and close monitoring can help avoid detrimental outcomes. All interprofessional healthcare team members, including clinicians, nursing staff, and pharmacists, should play an active role in coordinating the care to minimize and early detection of adverse events. Taking preventative measures to avoid the toxic side effect profile is crucial. Assessing a patient’s renal function, keeping a patient well-hydrated, and considering antioxidants will help prevent injury kidney. The ordering clinician should consult the pharmacy department for dosing, interactions, and appropriateness of coverage. Nursing will administer the drug, watch for adverse events, and monitor treatment effectiveness, informing the clinicians of any issues that arise. These examples of interprofessional coordination show how such an approach will improve patient outcomes and limit adverse events. [Level5]

With antibiotic resistance becoming increasingly prominent, it is also essential that the healthcare team only prescribes tobramycin when necessary. This approach will allow tobramycin to continue working well and effectively in the community. With too many prescriptions written, bacteria can become resistant over time. That is why involving a board-certified infectious disease pharmacist who can access the latest antibiogram data should be on the case. As an interprofessional team, it is also important to avoid prescribing tobramycin in patients with neuromuscular junction disorders because of its ability to decrease acetylcholine. With the team approach helping in factoring risks versus benefits for a patient, tobramycin could be a valuable asset in treating difficult systemic infections. [Level 5]


Article Details

Article Author

Gizem Reyhanoglu

Article Editor:

Anil Kumar Reddy Reddivari

Updated:

6/23/2022 2:38:33 PM

PubMed Link:

Tobramycin

References

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