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. The majority of antibiotics in this class, including tobramycin, are bactericidal. They work synergistically with beta-lactams to penetrate the cell walls of aerobic gram-negative bacteria. Aminoglycosides are then actively transported across the bacterial cell membrane to bind and inactivate the initiation complex of translation. Tobramycin has been prescribed to treat various conditions, from superficial infections to deep infections.
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 aeruginosa, Escherichia coli, Proteus, Klebsiella, Enterobacter, Serratia, Providencia, 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 for the management of cystic fibrosis in individuals six years of age or older with Pseudomonas aeruginosa. Ophthalmic tobramycin is FDA approved for the treatment of 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.
Tobramycin binds to the 16s ribosomal RNA of the bacterial 30s ribosomal unit and inhibits the initiation step of translation. 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.
Tobramycin is typically administered by various routes, but like other aminoglycosides, it has poor oral absorption. The efflux P-glycoprotein pump located in the brush border of the intestines causes this resistance, so oral administration is typically avoided. Administration is usually via intravenous or intramuscular injection. Dosing can be in combination with beta-lactams, such as penicillins or cephalosporins, to penetrate the outer walls of gram-negative bacteria. Tobramycin can be used to treat ocular infections in the form of a 0.3% ophthalmic solution or 0.3% ophthalmic ointment. Intramuscular injection, intravenous infusion, and intraventricular (off-label) administration have been used to treat serious bacterial infections. Tobramycin administration via oral inhalation is available for the treatment of cystic fibrosis-associated pneumonia.
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. 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.
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). Bacteria with biofilm have greater resistance to aminoglycosides. Another mechanism of resistance is related to the reversible down-regulation of drug uptake into the bacteria. Some strains of Pseudomonas aeruginosa has developed aminoglycoside resistance through enzyme modification and decreasing outer membrane permeability for the drug.
Contraindications include patients with hypersensitivity to tobramycin or any other aminoglycoside antibiotics. 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.
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. 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. The drug is excreted mainly by the kidneys, so it is essential to monitor renal function. 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. Tobramycin can cross the placenta, concentrating in the kidney and urine of the fetus. The theory is that tobramycin could potentially cause nephrotoxic events in the fetus, but this requires further investigation.
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 occurs from the loss of hair cells in the inner ear. The damage to cranial nerve VIII (vestibulocochlear nerve) could cause hearing or balance dysfunctions. Once-daily administration of tobramycin is thought to help reduce the risk of ototoxicity. This adverse effect is often irreversible.
Nephrotoxicity, unlike the ototoxicity, is a reversible adverse reaction. 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. Similar to preventing ototoxicity, nephrotoxicity is avoidable by longer dosing intervals. Tobramycin can cause both direct nephrotoxicity, which is dose-related, as well as 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. The toxic changes caused by tobramycin are observable in the proximal tubule. Vacuolation and myeloid bodies in the tubular epithelial cell lysosomes are present under electron microscopy with the usage of the medication. Granular casts, microscopic hematuria, and proteinuria are also often present. Close monitoring of kidney function is crucial to minimize nephrotoxic effects. Maintaining adequate hydration can also decrease the likelihood of nephrotoxic events. Studies show that antioxidant administration, most notably deferoxamine, can alleviate the toxic events produced in the kidneys.
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 to reduce the dosage. 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.
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 prokaryotes, it can cause serious adverse events in patients. It is important 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 members of the healthcare team, including physicians, 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.
With antibiotic resistance becoming more and more 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]
|||Mingeot-Leclercq MP,Glupczynski Y,Tulkens PM, Aminoglycosides: activity and resistance. Antimicrobial agents and chemotherapy. 1999 Apr; [PubMed PMID: 10103173]|
|||Kotra LP,Haddad J,Mobashery S, Aminoglycosides: perspectives on mechanisms of action and resistance and strategies to counter resistance. Antimicrobial agents and chemotherapy. 2000 Dec; [PubMed PMID: 11083623]|
|||Periti P, [Tobramycin--clinical pharmacology and chemotherapy]. Journal of chemotherapy (Florence, Italy). 1996 Jan; [PubMed PMID: 8948764]|
|||Wilhelmus KR,Gilbert ML,Osato MS, Tobramycin in ophthalmology. Survey of ophthalmology. 1987 Sep-Oct; [PubMed PMID: 3317953]|
|||Hagerman JK,Knechtel SA,Klepser ME, Tobramycin solution for inhalation in cystic fibrosis patients: a review of the literature. Expert opinion on pharmacotherapy. 2007 Mar; [PubMed PMID: 17309341]|
|||Tunkel AR,Hasbun R,Bhimraj A,Byers K,Kaplan SL,Michael Scheld W,van de Beek D,Bleck TP,Garton HJ,Zunt JR, 2017 Infectious Diseases Society of America's Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2017 Feb 14; [PubMed PMID: 28203777]|
|||Davis BD, Mechanism of bactericidal action of aminoglycosides. Microbiological reviews. 1987 Sep; [PubMed PMID: 3312985]|
|||Davis BD,Chen LL,Tai PC, Misread protein creates membrane channels: an essential step in the bactericidal action of aminoglycosides. Proceedings of the National Academy of Sciences of the United States of America. 1986 Aug; [PubMed PMID: 2426712]|
|||Banerjee SK,Jagannath C,Hunter RL,Dasgupta A, Bioavailability of tobramycin after oral delivery in FVB mice using CRL-1605 copolymer, an inhibitor of P-glycoprotein. Life sciences. 2000 Sep 8; [PubMed PMID: 11072877]|
|||Tobramycin . 2012 [PubMed PMID: 31643824]|
|||Kernt K,Martinez MA,Bertin D,Stroman D,Cupp G,Martínez C,Tirado M,Guasch J, A clinical comparison of two formulations of tobramycin 0.3% eyedrops in the treatment of acute bacterial conjunctivitis. European journal of ophthalmology. 2005 Sep-Oct; [PubMed PMID: 16167284]|
|||Wu AY,Gervasio KA,Gergoudis KN,Wei C,Oestreicher JH,Harvey JT, Conservative therapy for chalazia: is it really effective? Acta ophthalmologica. 2018 Jun; [PubMed PMID: 29338124]|
|||Aminimanizani A,Beringer PM,Kang J,Tsang L,Jelliffe RW,Shapiro BJ, Distribution and elimination of tobramycin administered in single or multiple daily doses in adult patients with cystic fibrosis. The Journal of antimicrobial chemotherapy. 2002 Oct; [PubMed PMID: 12356801]|
|||Tunkel AR,Hartman BJ,Kaplan SL,Kaufman BA,Roos KL,Scheld WM,Whitley RJ, Practice guidelines for the management of bacterial meningitis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2004 Nov 1; [PubMed PMID: 15494903]|
|||Aminoglycosides 2012; [PubMed PMID: 31643557]|
|||Barclay ML,Begg EJ,Chambers ST,Thornley PE,Pattemore PK,Grimwood K, Adaptive resistance to tobramycin in Pseudomonas aeruginosa lung infection in cystic fibrosis. The Journal of antimicrobial chemotherapy. 1996 Jun; [PubMed PMID: 8836818]|
|||Vázquez-Espinosa E,Girón RM,Gómez-Punter RM,García-Castillo E,Valenzuela C,Cisneros C,Zamora E,García-Pérez FJ,Ancochea J, Long-term safety and efficacy of tobramycin in the management of cystic fibrosis. Therapeutics and clinical risk management. 2015; [PubMed PMID: 25792839]|
|||Pedersen SS,Jensen T,Osterhammel D,Osterhammel P, Cumulative and acute toxicity of repeated high-dose tobramycin treatment in cystic fibrosis. Antimicrobial agents and chemotherapy. 1987 Apr; [PubMed PMID: 3606063]|
|||Israel KS,Welles JS,Black HR, Aspects of the pharmacology and toxicology of tobramycin in animals and humans. The Journal of infectious diseases. 1976 Aug; [PubMed PMID: 787452]|
|||Bernard B,Garcia-Cazares SJ,Ballard CA,Thrupp LD,Mathies AW,Wehrle PF, Tobramycin: maternal-fetal pharmacology. Antimicrobial agents and chemotherapy. 1977 Apr; [PubMed PMID: 856021]|
|||Prazma J,Postma DS,Pecorak JB,Fischer ND, Ototoxicity of tobramycin sulfate. The Laryngoscope. 1976 Feb; [PubMed PMID: 1053373]|
|||Smith CR,Lipsky JJ,Lietman PS, Relationship between aminoglycoside-induced nephrotoxicity and auditory toxicity. Antimicrobial agents and chemotherapy. 1979 Jun; [PubMed PMID: 475363]|
|||Coca A,Blade J,Martinez A,Segura F,Soriano E,Ribas-Mundo M, Tobramycin nephrotoxicity. A prospective clinical study. Postgraduate medical journal. 1979 Nov; [PubMed PMID: 523366]|
|||Mingeot-Leclercq MP,Tulkens PM, Aminoglycosides: nephrotoxicity. Antimicrobial agents and chemotherapy. 1999 May; [PubMed PMID: 10223907]|
|||Elsais A,Popperud TH,Melien Ø,Kerty E, [Drugs that may trigger or exacerbate myasthenia gravis]. Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke. 2013 Feb 5; [PubMed PMID: 23381166]|
|||Hussain N,Hussain F,Haque D,Chittivelu S, A diagnosis of late-onset Myasthenia gravis unmasked by topical antibiotics. Journal of community hospital internal medicine perspectives. 2018; [PubMed PMID: 30181833]|