Continuing Education Activity

While aminoglycosides are an older class of medication, they continue to be clinically valuable. Aminoglycosides have a broad spectrum of activity covering aerobic organisms, including gram-negative bacteria and mycobacteria. There are several drugs within the aminoglycoside class, including gentamicin, tobramycin, amikacin, neomycin, plazomicin, and streptomycin, and FDA-approved indications vary between the for these individual aminoglycosides. This activity reviews the indications, contraindications, mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent to members of the interprofessional team who wish to prescribe aminoglycosides.

Objectives:

• Describe the mechanism of action of the aminoglycosides.
• Outline the indications for different aminoglycosides.
• Summarize the adverse effects and monitoring requirements of aminoglycosides.
• Explain the importance of antimicrobial stewardship and how it affects antimicrobial selection as it pertains to improving care coordination among the interprofessional team when initiating aminoglycoside therapy.

Indications

Although not a new class of antimicrobials, aminoglycosides have continued to prove their clinical value in fighting infections. Aminoglycosides have a broad spectrum of activity covering aerobic organisms, including gram-negative bacteria and mycobacteria. Because there are several drugs within the aminoglycoside class, including gentamicin, tobramycin, amikacin, neomycin, plazomicin, paromomycin, and streptomycin, FDA approved indications vary between the different individual aminoglycosides.  

In general, indications for aminoglycosides include both empirical or directed treatment. Since this drug class has demonstrated effectiveness in multi-drug resistant Gram-negative pathogens, aminoglycosides are indicated for empiric therapy in patients with severe illness; this includes empiric treatment for patients with infective endocarditis, sepsis, complicated intraabdominal infections, and complicated genitourinary infections. Typically, in these settings, aminoglycosides should not be used for more than two days, due to toxicity to the patient. 

For directed treatment, aminoglycoside use for longer than 48 hours is acceptable. They are part of directed combination treatment for brucellosis, listeriosis, CNS nocardiosis, and Pseudomonas aeruginosa infection. Aminoglycosides monotherapy is for tularemia, resistant mycobacteria, bacteremia caused by Campylobacter spp. and Yersinia spp., and drug-resistant gram-negative pathogens. The Infectious Diseases Society of America Guidelines should be referenced to see if an aminoglycoside is the correct agent to use for a particular patient.[1][2]

Mechanism of Action

Aminoglycosides have bactericidal activity in which they bind to the bacteria ribosomal 30S subunit. Specifically, they are believed to bind to the A-site (aminoacyl) on the 16S rRNA, a component of the ribosomal 30S subunit. Through this binding, the genetic code gets misread, and the translation is disrupted, leading to the bacteria being unable to carry out protein synthesis.[3][4]

Administration

Depending on the aminoglycoside chosen, the administration can be oral, parenteral, inhalation, intraperitoneal, or intraventricular. Administration of these agents is most commonly parenteral; gentamicin, amikacin, and tobramycin are the most frequently used aminoglycosides administered via the parenteral route.[1] Tobramycin may be inhaled using a nebulizer for cystic fibrosis patients experiencing pulmonary exacerbation from infection.[5]  Aminoglycosides taken orally are paromomycin and neomycin because they are not able to be absorbed systemically; these two aminoglycosides demonstrate intraluminal activity in the bowel.  In addition, gentamicin is an aminoglycoside that can be administered intraperitoneally and intraventricularly. Intraperitoneal administration of gentamicin is useful in peritoneal dialysis patients who develop peritonitis.[6] Gentamicin administration intraventricularly has proved helpful in central nervous system infections.[7]

Adverse Effects

The main noted adverse effects of aminoglycosides are ototoxicity, nephrotoxicity, and neuromuscular blockade.  Therefore, patients should be educated to look out for warning signs of these adverse effects before the initiation of aminoglycoside therapy.[1]

Aminoglycoside-induced ototoxicity has been reported to occur in 2 to 45% of adults.  The ototoxicity can be vestibular and/or cochlear and is typically dose-dependent. Gentamicin, streptomycin, and tobramycin more commonly cause vestibular damage, while amikacin and kanamycin (discontinued use in the USA) result in more cochlear damage.[8] Studies have found that aminoglycosides seem to create reactive oxygen species within the inner ear; this, in turn, causes damage to the vestibular and cochlear sensory cells along with cochlear neurons. Often the vestibular loss is salvageable while hearing loss is irreversible.[9][10]

Nephrotoxicity due to aminoglycosides may appear in up to 10 to 25% of patients.  In patients receiving aminoglycoside therapy, renal tubular toxicity decreased blood flow to the kidneys, and reduced GFR most commonly causes the nephrotoxicity seen. Renal effects with aminoglycosides generally are reversible. Furthermore, there are risk factors associated with the development of aminoglycoside-induced nephrotoxicity, including dehydration, pregnancy, and hepatic dysfunction. Taking other medications concurrently with aminoglycosides that can cause nephrotoxicity, such as NSAIDs, cyclosporine, and diuretics, also puts a patient at risk for renal problems.  It is important to monitor patient renal function when taking aminoglycosides.[11][12]

Aminoglycosides have also demonstrated correlations with neuromuscular blockade. Although this is less common than ototoxicity and nephrotoxicity, patients with diseases affecting the neuromuscular junction and patients using medications prolonging neuromuscular blockade, most notably calcium channel blockers, should be cautious when using aminoglycosides.[13][14]

Contraindications

Aminoglycosides should be avoided in patients with myasthenia gravis because of the risk of prolonged neuromuscular blockade.

Monitoring

Therapeutic drug monitoring is necessary with aminoglycosides to optimize patient outcomes and limit toxicity. However, there is no universal agreement on the method of monitoring. Therapeutic drug monitoring has been shown to reduce hospital stay duration and toxicities.  Studies also suggest that therapeutic drug monitoring reduces mortality. It is important to note that monitoring clearance should be considered in critically ill, burn, and obese patients due to their abnormal distribution volume.[15]

For toxicity purposes, renal function and cochlear function require monitoring. Serial audiometry may be considered to prevent irreversible hearing loss. Additionally, monitoring serum creatinine must be done to assess for nephrotoxicity in patients requiring aminoglycoside therapy.[9][11]

Toxicity

There is no antidote for the toxicities of aminoglycosides. However, agents with protective effects on the ear and kidney may help prevent aminoglycoside-induced toxicity.  In particular, N-acetylcysteine demonstrates promising protective effects on patients using aminoglycosides.[16]

Enhancing Healthcare Team Outcomes

Evaluating the need for aminoglycoside therapy requires a holistic approach by an interprofessional team of professional individuals, including but not limited to physicians, specialists, nurses, pharmacists, laboratory technologists, audiometric technicians, and social workers, to achieve optimal outcomes. [Level V]

Physicians and pharmacists have a critical role in determining the need for empiric treatment or directed treatment with an aminoglycoside.  Both healthcare professionals need to utilize communication and their expertise to determine if and which aminoglycoside is necessary, what is the correct dosing, and what is the optimal duration of therapy.  Therapeutic dose monitoring should also be done for the patient to achieve the best results with aminoglycoside treatment. In many institutions, the clinician initiates aminoglycoside therapy, and the clinical pharmacist handles all the dosing and subsequent adjustments, using kinetic dosing criteria. When in the hospital, nurses must assess for any potential toxicities developing in a patient. Because toxicity outcome typically depends on early detection, healthcare professionals need to monitor patients for any adverse signs and communicate with the team for the next step in therapy. Nurses will administer the drug and should be alert to signs of toxicity, interactions, and therapeutic effectiveness. Laboratory technologists and audiometric technicians are essential for checking serum creatinine in all patients and performing audiometry. Lastly, the role of a social worker is significant in preparing a patient for discharge while still on aminoglycoside therapy. All healthcare disciplines working as part of the interprofessional teams have their roles to play, making communication and collaboration key in providing patients with the best outcome care leading to optimal outcomes. [Level V]