Debilitating Gentamicin Ototoxicity: Case Report and Recommendations Against Routine Use in Surgical Prophylaxis

Introduction: Aminoglycoside antibiotics such as gentamicin are bactericidal and effective against gram negative organisms and act synergistically against gram positive organisms, including Staphylococcus aureus. However, they have serious adverse effects such as nephrotoxicity and ototoxicity. Gentamicin ototoxicity may occur after a single dose and results in decreased vestibular function, which is frequently debilitating and often permanent. Objective: To emphasize the risk of gentamicin ototoxicity and suggest alternative antibiotics in penicillin-allergic patients undergoing surgery. Case Summary: We present a case of a woman with preexisting Meniere’s Disease who received gentamicin 400 mg perioperatively for a sigmoidectomy due to a penicillin allergy listed in the patient’s medical record. The patient developed severe ototoxicity preventing her from working or driving. Physical examination was remarkable for a broad-based gait requiring assistance to walk and bilateral corrective saccades. Vestibular testing revealed high-grade bilateral vestibular loss associated with all semicircular canals, a considerable decline compared to her function 3 years prior. Discussion: Gentamicin is indicated for surgical prophylaxis when a patient has a true allergy to penicillins and cannot receive cephalosporins, though alternatives exist. True allergies include IgE-mediated illness (anaphylaxis, bronchospasm, or urticaria 30-60 minutes after administration) or exfoliative reactions (Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis). The authors encourage more prudent use of gentamicin, especially in patients susceptible for debilitating otologic insults, and offer recommendations for alternative agents prior to using gentamicin.


Introduction
Gentamicin is a bactericidal aminoglycoside antibiotic, frequently used for prophylaxis in colorectal surgery, which acts by inhibiting bacterial protein synthesis.It is effective against gram negative bacteria and provides synergistic activity against gram positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA).
Unfortunately, gentamicin can contribute to significant systemic toxicity. 1Gentamicin is a well-known cause of nephrotoxicity in the form of reversible acute kidney injury (AKI), especially in patients with preexisting renal dysfunction or limited GFR.Its association with ototoxicity, however, is commonly overlooked, likely due to its rarity. 2totoxicity in this antibiotic class is due to intracellular accumulation of aminoglycosides facilitated by TRPV1 (transient receptor potential vanilloid-1), which is upregulated in response to bacterial infection-induced inflammation. 3Different aminoglycosides injure different hair cells within the inner ear.Gentamicin and streptomycin primarily affect vestibular hair cells, and others (amikacin, neomycin, dihydrostreptomycin, and kanamycin) primarily affect cochlear hair cells. 4Though the predominant effect is on vestibular hair cells, low frequency hearing loss and decreased speech discrimination have been reported with gentamicin use. 1,5,6The risk of ototoxicity is increased in patients with renal failure, but there is no known correlation between dose and severity of toxicity. 1,7As such, there is no safe gentamicin dose for the inner ear.Vestibular toxicity, though rare, is debilitating.It commonly results in an inability to walk or drive and may be permanent despite prolonged vestibular-directed rehabilitation therapy. 1,4se Report We present a 64-year-old female with a history of bilateral Meniere's disease, which was well-controlled on a lowsodium diet, spironolactone, and amitriptyline.Ten days after an elective sigmoidectomy for diverticulitis, she presented with worsening gait instability, imbalance, and a sensation of her eyes "bouncing" (oscillopsia), preventing her from driving.She denied vertigo, describing her imbalance as general "wobbliness."Review of her perioperative record revealed that she received a single dose of prophylactic gentamicin (400 mg, 4.37 mg/kg over 5 minutes) and clindamycin due to a penicillin allergy that was characterized as "rash."Per report, her surgery was completed without incident and there was no documentation during her admission mentioning instability, oscillopsia, or hearing disturbances.She was discharged home on postoperative day 2. Her medical and surgical history was otherwise noncontributory.Her family history was notable for hearing loss throughout both sides of her family.Physical examination at the time of presentation was remarkable for a broad-based gait requiring assistance to walk and bilateral corrective saccades.Dix-Hallpike testing was negative bilaterally.Otoscopy was unremarkable.A subsequent audiogram demonstrated stable severe to profound sensorineural hearing loss bilaterally as tested by pure tone thresholds, which determine how loud a sound must be for the patient to hear it.Her speech discrimination scores, defined as the percentage of words a patient can correctly repeat when presented loudly, decreased from a baseline of 20% (right) and 42% (left) noted 18 months prior to presentation, to 4% and 20%, respectively.Repeat vestibular testing revealed high-grade bilateral vestibular loss associated with all semicircular canals, a considerable decline compared to her function 3 years prior.

Discussion
This patient demonstrates many of the classic signs and symptoms of gentamicin ototoxicity including new oscillopsia, gait instability without vertigo, and bilateral decrease in vestibular function. 1,6Typically, patients do not experience vertigo with gentamicin ototoxicity, as it is a symmetric insult.This patient, however, had preexisting asymmetric vestibular damage from Meniere's disease and likely experienced an asymmetric drop in vestibular function.
It should be noted that unilateral Meniere's disease can be treated with ipsilateral, local (intratympanic) administration of gentamicin to ablate the aberrant vestibular function. 5This quiets the dysfunctional vestibular system, allowing the contralateral, normal vestibular system to compensate over time.This process of intentional vestibular ablation is only effective when administered unilaterally to patient with unilateral disease.It is very different from the bilateral vestibular toxicity resulting from systemic gentamicin administration, which diminishes vestibular function bilaterally.It is not known whether a patient with preexisting vestibular dysfunction is predisposed to gentamicin ototoxicity.However, a patient with bilateral Meniere's disease, such as the patient described above, is expected to have a limited ability to compensate for a bilateral vestibular insult.Other at-risk patients include elderly patients, patients with vision loss, and patients with peripheral neuropathy, as they are unlikely to recover from a bilateral vestibular insult as well as patients with robust proprioceptive, visual, and tactile input. 1 Toxicity after single doses of gentamicin have been reported, and identification of vestibular dysfunction is commonly delayed, 6 as in this scenario.Gentamicin, despite its side effect profile, continues to be used frequently as a first-line agent in patients with penicillin allergies, as recommended in the clinical guidelines for antimicrobial prophylaxis in surgery. 8Per these guidelines, the alternative agents are reserved for patients with Type I (IgE-mediated) allergic reactions and/or a history of an exfoliative dermatitis reaction such as Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis.Type I allergic reactions include anaphylaxis, bronchospasm, and/or urticaria 30 to 60 minutes after antibiotic administration, and may rarely exhibit crossreactivity between penicillin, cephalosporin, and carbapenem antibiotics.A patient with a mild penicillin allergy that is not IgE-mediated, such as a non-urticarial rash, is safe to receive cephalosporin and carbapenem antibiotics. 8When compared to alternative agents for gram negative bacteria and MRSA, gentamicin's adverse effects have more risk of permanent health and quality of life consequences.Its persistent use in penicillin-allergic patients appears to be linked to the limited bacterial resistance to gentamicin compared to alternative agents. 9However, there are numerous alternative agents and combinations of agents besides gentamicin available to cover the anticipated organisms and their resistance patterns, as described in the clinical practice guidelines for perioperative antimicrobial prophylaxis (Table 1). 8he authors encourage readers to ask patients to characterize their allergic reaction and thoughtfully select an appropriate perioperative antibiotic.In many cases, a thorough patient history with comprehensive medication allergy review can uncover information that leads to penicillin allergy delabeling. 10When feasible, skin testing or an antibiotic dose challenge (either as a single dose or as graded dosing) may be performed in advance of surgical procedures and can assist in allergy delabeling or identify the safest alternative antibiotic choice.Once the legitimacy of the allergy and reaction are adjudicated, the use of a prescribing algorithm or cross-reactivity chart can improve appropriate prescribing of beta-lactams. 11,12When gentamicin is indicated such that the benefits outweigh the risks, the authors recommend taking an otologic history to identify any preexisting diagnoses that could compound morbidity in the event of vestibular toxicity.In most patients with a history of Meniere's Disease, Vestibular Neuritis, Acoustic Neuroma (even after treatment), hearing loss, or prior ototoxicity the risk of aminoglycoside administration will outweigh the benefit given available alternative antimicrobial agents.As above, elderly patients and those with vision loss and/or peripheral neuropathy are also less likely to compensate for a vestibular insult.

Conclusion
In summary, aminoglycosides such as gentamicin are wellknown and effective antibiotics, but they have considerable risks, most notable here of ototoxocity.Gentamicin ototoxicity is characterized by a decrease in vestibular function bilaterally with gait instability and oscillopsia.Merely a single dose of gentamicin can result in permanent ototoxicity.Gentamicin may be overused in surgical prophylaxis due to the hesitancy of prescribing cephalosporins in the setting of any penicillin allergy, despite the very limited crossover effects with penicillin allergy outside of IgEmediated such as anaphylaxis, bronchospasm, or true urticaria 30 to 60 minutes after administration. 11The authors suggest that thoughtful organization of alternative agents and when to use them would be prudent for hospitals that utilize preoperative order sets or checklists.The authors' antibiotic alternative recommendations are listed in Table 1 for consideration.Expanding penicillin allergy evaluations and delabeling efforts is an opportunity for improved patient care when resources allow.The recommendation for alternative agents is reserved for patients with a Type I (IgE-mediated) allergic reaction (anaphylaxis, bronchospasm, or urticaria 30-60minutes after administration) and/or an exfoliative dermatitis such as Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis.b These non-aminoglycoside options are preferred in patients at risk for ototoxicty, such as those with underlying vestibular disorders or hearing loss, and in patients with limited ability to compensate for a vestibular insult, such as those with vision loss, peripheral neuropathy, or advanced age.

Table 1 .
Colorectal surgery antimicrobial prophylaxis guidelines, as recommended by the authors.Note.Table adapted from the recommendations table published in the 2013 clinical practice guidelines for antimicrobial prophylaxis in surgery, developed jointly by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Surgical Infection Society, and the Society for Healthcare Epidemiology of America. 8a