Desafios para la prevencion de la Ototoxicidad

Notas del editor

• #2: In this presentation, we will explore the issue of ototoxicity in hearing loss prevention. In theory, ototoxic hearing loss should be one of the easiest types of hearing loss to prevent. Since the injury is generally caused by health professionals, merely eliminating the use of ototoxic medications would eliminate this relatively common cause of hearing loss. Yet, in reality, the pathophysiology and public health issues related to ototoxicity are quite complex.
• #3: In this table we compare some of the substances that are known to be ototoxic according to the degree of ototoxicity and the population at risk. As we compare these substance, however, we see that most of these have either relatively low rate of ototoxicity or a relatively small percentage of people at risk.
• #4: Of these substances, aminoglycoside antibiotics are the most concerning because they are highly toxic to the inner ear, are widely used and, therefore, a large population of people in the world are at risk. I will, therefore, devote most of this presentation to a discussion of aminoglycoside ototoxicity.
• #5: Although exact incidence figures are unknown, it is estimated that cochlear or vestibular toxicity occurs in 1-5% of patients exposed to these medications. Hearing loss is initially in the high frequencies, and may be detected by audiometry before this hearing loss becomes apparent to the patient. Vestibular loss can be completely independent of hearing loss, and the patient may be unaware of an impending balance problem due to visual or central brain compensation mechanisms. Either cochlear or vestibular damage, or both, can occur with any of the different aminoglycoside.
• #6: While all aminoglycosides can cause either cochlear or vestibular damage, there are some variations in the toxicity potential. For example, the order of auditory toxicity of five aminoglycosides, from most to least, is: Neomycin Gentamicin Tobramycin Amikacin And finally, Netilmicin. So, neomycin would be considered to be more cochleotoxic than netilmicin. If an aminoglycoside antibiotic must be used for infection control, it is preferable to consider the least toxic possible.
• #7: We will talk about four factors that influence aminoglycoside ototoxicity in the developing world: Increased exposure to the drug, sicker patients with high comorbid factors, genetic susceptibility in some populations and unregulated and inappropriate use.
• #8: With the advent of safer broad spectrum antibiotics, most of us have seen a dramatic decrease in the use of aminoglycosides in recent years. A program that tracts drug use in the United States documented a 50% reduction in aminoglycoside use from 1999 to 2001. Likewise, ototoxicity appears be a relatively uncommon cause of deafness in several large studies in industrialized nations. This numbers may be biased due to a high percentage of congenital hearing loss, but it is safe to say that in aminoglycoside toxicity is relatively uncommon in these areas, due in large part to lack of exposure.
• #9: Aminoglycosides do continue to be utilized in a some populations. For example, aminoglycosides are still given to 21% of children in the Pediatric and Neonatal Intensive Care Units in the U.S.. Another major concern is the continued use of aminoglycosides in developing countries, due to their low cost and broad spectrum. Aminoglycosides continued to be used both appropriately and inappropriately in these settings. Gentamicin plays an important role in the treatment of neonatal sepsis and streptomycin and gentamicin are used in the treatment of tuberculosis. This higher level of use in some parts of the world has been documented in several studies. They account for 7.4% of all anitibiotic prescriptions in one study in Russia and 11% of those in Trinadad. Finally, a study comparing aminoglycoside use in Hong Kong documented utilization that was 250 times that in Great Brittain.
• #10: Likewise, some areas of the world have recorded much higher rates of aminoglycoside toxicity and/or exposure in deaf populations. The highest incidence of aminoglycoside ototoxicity have been in China, where studies of deaf populations have indicated a rate of aminoglycoside toxicity ranging from 3.7% to as high as 28.4%. Studies in East Africa have also shown higher rates of ototoxicity and our study in Nicaragua documented gentamicin exposure in 31% of deaf children. These higher rates are presumed to be in part due to increased exposure.
• #11: In addition to increased population exposure, other factors may be contributing to these elevated rates. Some of the factors that are known to increase the risk of ototoxicity from aminoglycoside include: Duration of therapy Frequency of dosing, with apparently less toxicity in daily of BID dosing schedules Kidney or liver dysfunction Advanced age Simultaneous use of other ototoxic medications (especially the loop diuretics) Higher serum concentrations of the aminoglycoside More severe infections And, lastly, a genetic predisposition. Due to the lack of regulation and poor health care in general, several of these factors may be more prevalent in poorly developed areas of the world.
• #12: At the hair cell level, a variety of pathophysiological process have been implicated in the ototoxic reaction, including glutamate receptor binding with exicitotoxicity. This is followed by a series of events including free radical formation, intracellular membrane disruption, and a disruption of nucleic acid and protein synthesis. Two of these pathological mechanisms, free radical formation and blocked protein synthesis have important clinical ramifications.
• #13: The first of these is an observation by Sha and Schacht that anti-oxidant treatment with salicylates protected hair cells of guinea pigs exposed to gentamicin as shown on the photomicrographs to the right. The top panel is the normal rows of hair cells, the middle panel shows the hair cells after gentamicin, and the lower panel shows the hair cells when gentamicin is co-administered with salicylate. These same research recently published a clinical study with a group in China that looked at the clinical effectiveness of aspirin administration in the protection of patients from gentamicin ototoxicity in a large blinded, placebo-controlled study. Only 3% of the 89 patients who received 3 grams per day of aspirin along with their gentamicin had audiometric evidence of ototoxicity, which was significantly reduced from the 13% in the placebo group. This is an excellent example of basic science research translating to a clinical tool that will potentially impact the onset of hearing loss in the world.
• #14: A second major breakthrough in our understanding of aminoglycoside ototoxicty came from two independent research teams that identified large families with an increase susceptibility to aminoglycoside ototoxicty that was inherited from the mother.
• #15: Further studies have identified the gene in these families to be located on the mitochondrial DNA in the cell, which is inherited from the mother in both males and females. In particular, the mutations that increase aminoglycoside ototoxicity are located in that part of the DNA that codes for the 12S subunit of the ribosomal RNA. This ribosomal subunit shares a homology with the ribosomal units of bacteria. These mutations change the structure of the human ribosomal unit to more closely resemble the bacterial ribosome. These mutated ribosomal structures are more susceptible to aminoglycoside with a resulting disruption of protein synthesis.
• #16: There are several mutations that have been identified in patients with aminoglycosdie ototoxicity. The most common of these is the A1555G mutation, but other mutations are common in some populations.
• #17: An important concept in understanding the role of mitochondrial mutations and hearing loss is that some patients will eventually develop a progressive non-syndromic hearing loss independent of aminoglycoside exposure. This graph from Estivill et al. shows the probability of hearing loss in two groups of patients with the A1555G mitochondrial mutation. The highest probability of hearing loss is seen in those patients with given aminoglycosides, yet those patients who did not receive aminoglycosides still developed hearing loss, although milder and later than the exposed group.
• #18: To better understand the prevalence and difficulty in studying aminoglycoside ototoxicity in the developing world, let’s briefly look at a recent study by our team on a group of patients in Jinotega Nicaragua with childhood hearing loss.
• #19: In this study of 96 patients, we found that 31 patients (32%) had a history of gentamicin exposure that coincided with their hearing loss. Although some of these patients did have a family history of hearing loss, none of them were found to have mutations in the 12S ribosomal RNA mitochondrial gene. Although the patients with gentamicin exposure seemed to be geographically clustered, we felt that this may represent increased availability of the drug in these regions.
• #20: One of the complicating factors in assessing hearing loss in this population is the high prevalence of multiple risk factors. Although gentamicin exposure is high, this risk factor overlapped with a history of meningitis and perinatal distress.
• #21: We have seen how aminoglycosides are more widely used in some areas, ototoxicity in general and genetic susceptibility are more common in some populations, and patients in developing countries are more likely to have other comorbid factors. Unfortunately, these many of these factors are difficult to control. One area were public health initiatives are likely to have an impact is by limiting the inappropriate and unregulated use of the drug.
• #22: It is important for us to recognize that aminoglycosides have an important role in the treatment of severe infections that may be life threatening. Neonatal sepsis, for example, accounts for 36% of neonatal deaths worldwide. Researchers in India and Bangladesh have recently shown that neonatal sepsis can be safely and effectively treated with a straightforward dosing regiment of gentamicin. Aminoglycosides are also important tools in the treatment of tuberculosis.
• #23: The rising incidence of tuberculosis, multiple drug resistant tuberculosis and the subsequent use of potentially ototoxic drugs in the treatment is a good example of how we are unable to separate ourselves from the world around us. Tuberculosis is still much more prevalent outside of the U.S. as shown in this map from the WHO, but tuberculosis and drug resistance are problems that we face at home as well.
• #24: Aside from these appropriate uses of the drug, gentamicin is often given in settings that are poorly controlled and may not even involve a physician. Often regulations exist, but are not enforced. In developing countries antibiotics, including parenteral antibiotics, are often provide to patients directly from pharmacies without a prescription. Studies in Bangladesh and Venezuela have shown that over 90% of antibiotics are dispensed this way. Outpatient use of gentamicin has also been demonstrated to be common in India and Hong Kong. Finally, one study found that even when physicians are involved with prescribing aminoglycosides, the dose and or indications are often inappropriate,
• #25: The prevention of aminoglycoside ototoxicity depends upon the ability to regulate it’s use and educate providers about ototoxicity. If possible, less toxic alternatives should be provided. Finally, the co-administration of aspirin has shown great promise in preventing hearing loss when an aminoglycoside must be used.
• #26: In contrast to aminoglycosides, vancomycin is less commonly used worldwide and certainly less toxic.
• #27: Despite the similarity of names, vancomycin is not an aminoglycoside. The toxic effect of vancomycin alone on the inner ear is somewhat controversial. Vancomycin may facilitate the toxicity of aminoglycosides and does appear to have an ototoxic effect when given at high dose for prolonged periods of time.
• #28: Next we have the loop diuretics, which relatively low toxicity and moderate to low percent of the population at risk.
• #29: The final systemic ototoxic medication that will be discussed is loop diuretics, with the most common being furosemide and ethacrynic acid. The mechanism of ototoxicity does not appear to be hair cell damage, but rather reversible reductions in endocochlear potential, electrolyte changes in cochlear fluids, and histologic changes in the stria vascularis. These are changes that could be predicted from the action of diuretics on fluid balance in the kidney and other parts of the body. The greatest risk of ototoxicity is in premature infants, patients with renal impairment, and in the concomitant use of another ototoxic medication, most notably aminoglycosides.
• #30: With loop diuretics, the hearing loss can be either permanent or reversible, and after either oral or intravenous administration. The biggest demonstrated risk of furosemide is with a rapid intravenous administration, greater than 5 milligrams per minute, or with a bolus dose. The clinician should be aware of bumetanide, which has comparable effects to furosemide, but is less toxic. It is an alternative in patients with a higher risk of ototoxicity, but is more expensive.
• #31: Although we have already seen how aspirin can play an important role in the prevention of aminoglycoside ototoxicity, paradoxically salicylates may be ototoxic themselves.
• #32: Salicylates are commonly used for their anti-inflammatory, antipyretic, analgesic, and anti-platelet effects. The toxic effect to the auditory system is usually a mild to moderate, bilaterally symmetrical sensorineural hearing loss, which is usually reversible within 24 to 72 hours after cessation of the drug. It can be accompanied by high-pitched tinnitus, which may be the initial symptom of ototoxicity, and is also usually reversible. The audiogram may show a flat or high frequency hearing loss.
• #33: Salicylates rapidly enter all areas of the cochlea. The toxic effect of salicylates seems to be more a biochemical effect without significant changes in the hair cells of the cochlea. For monitoring purposes, the ototoxicity seems to be correlated more with unbound serum levels than total serum levels.
• #34: Nonsteroidal anti-inflammatory drugs, or “NSAIDs”, are analgesic and anti-inflammatory medications that inhibit the cyclooxygenase pathway, and have a similar hearing loss, and reversibility, as aspirin.
• #35: Although chemotherapeutic agent like Cisplatin are highly ototoxic, the exposed population to these drugs is thankfully low.
• #36: The next class of ototoxic medication that we will discuss is chemotherapy agents, and the prototype ototoxic medication is cisplatin. The side effects of cisplatin, in general, include nausea and vomiting, nephropathy, and neurotoxicity. Neurotoxicity can include peripheral sensory neuropathy, autonomic neuropathy, and, of interest to us, high frequency sensorineural hearing loss.
• #37: The hearing loss associated with cisplatin is initially a bilateral, high frequency, symmetrical sensorineural loss, but with a higher cumulative dose, the hearing loss progresses to the lower frequencies as well. The loss is permanent, and tinnitus is common. The incidence of hearing loss is high, estimated at 50% of patients, and is dose dependent, usually with a cumulative dose greater than 200 milligrams.
• #38: Since cisplatin presents first with a high frequency loss, high frequency audiometry may detect early ototoxicity, and allow modification of treatment protocols. Histologic damage is seen in the stria vascularis, spiral ganglion cells, and outer hair cells of the cochlea. As damage progresses, cochlear inner hair cells are involved. Carboplatin, a second-generation analog, is more toxic initially to the inner hair cells, than cisplatin. Fortunately, cisplatin toxicity is mainly cochlear, and not vestibular.
• #39: Because of the high incidence of malaria in some areas of the world, chloroquine ototoxicity is mostly a concern for developing countries. It is estimated that 300 – 500 million people are infected with malaria each year and it is unknown exactly how many of these are treated and with what medications. It some areas of sub-saharan Africa malaria or the treatment of malaria accounts for nearly one third of all cases of deafness.
• #41: Like aspirin and NSAIDs, quinine has a similar reversible hearing loss and tinnitus, but has common vestibular symptoms. The mechanism of ototoxicity is unknown, but the outer hair cells seem to be the site of action. Quinine still is used as an alternative medication for malaria, and commonly used for leg cramps, although efficacy is unproven.
• #42: Like Chloroquine, heavy metal and industrial chemical toxicity seem to be much more common in the developing world were these substances are not well controlled or regulated. In addition to the ototoxic effect alone, these substances may facilitate the noise induced hearing loss that often accompanies their exposure in industrial settings. Like chloroquine very little research is done on the effect of these substances on hearing specifically.
• #43: Our next category of ototoxic substances is heavy metals, such as mercury and lead. These chemicals can lead to hearing loss from either exposure during development, or as an adult. Since the auditory brainstem response, or ABR, shows a prolonged I-V interval, the ototoxicity of these substances may be in the auditory nerve or brainstem. As such, monitoring changes in the ABR may detect early toxicity.
• #44: Some toxins that are known or suspected to aggravate Noise Induced Hearing Loss include the organic solvents toluene, (used in printing and wood finishing); methylbenzene and styrene, used in plastics industry). In addition, asphyxiants, such as carbon monoxide (due to poor ventilation) and hydrogen cyanide (found in metal and fabric processing as well as cigarette smoke) increase the susceptibility to noise. Some metals such as lead (found in paint) and mercury (found in industry and fish) may also potentate noise induced hearing loss. Finally, the pesticides paraquat and organophosphates may increase the susceptibility to noise exposure.
• #45: We will now shift our discussion to prevention of ototoxicity. There are several methods to consider before treatment with an ototoxic medication or chemical. It is important to search for a history of prior ototoxicity, renal or liver dysfunction, and a family history of aminoglycoside induced hearing loss. If available, a baseline hearing and balance test should be obtained. In the future, genetic screening may be available for the most common mutations responsible for drug induced hearing loss, especially with a positive family history.
• #46: During treatment, monitoring of serum drug levels, kidney and liver function, and auditory or vestibular function should be performed. Ototoxic medications should be avoided if there is a satisfactory alternative. The fluoroquinolones, such as ciprofloxacin or ofloxacin, or broad-spectrum cephalosporins, for example, have largely replaced the need for aminoglycosides as a first line antibiotic. And, it is important to avoid use of different ototoxic medications at the same time, such as loop diuretics and aminoglycosides. As well, rescue or preventative substances are being developed, and should be used when they become available.
• #47: The purpose of auditory monitoring is to attempt early detection of a hearing loss that might change during treatment. A baseline test series should be obtained before treatment, if available and if testing does not significantly delay treatment. These tests could include pure tone audiometry and word recognition, high frequency audiometry above the standard 8000 kilohertz high tone limit, and otoacoustic emissions, if available.
• #48: Since many of the medications initially cause outer hair cell damage and a high frequency hearing loss, otoacoustic emissions and/or high frequency audiometry may detect hearing loss before it becomes apparent on standard audiometry. Possible protocols for audiologic monitoring are as follows: For platinum-based chemotherapy: testing should be accomplished prior to each cycle and for 1-2 years after treatment. For aminoglycosides, testing should be every 1-2 weeks, and for 6 months after treatment.
• #49: Development of unsteadiness or a bobbing visual field, known as oscillopsia, is important and should alert the health care worker that vestibular damage may be present. Although there is no specific protocol for vestibular monitoring, the health care worker does have tests that can evaluate the status, and, possibly, change in vestibular function. Clinical tests include the dynamic visual acuity, post-head shake nystagmus, and high-frequency head thrust. Standard laboratory tests include electronystagmography or videonystagmography, slow or high frequency rotation tests, and computed dynamic posturography. A description of these tests is beyond the scope of this presentation, but the clinician can find descriptions in standard vestibular textbooks.
• #50: Intriguing for the future is the possibility of protective therapy when ototoxic medications are used. The goal of such therapy would be to prevent ototoxicity, while not reducing the effectiveness of medications. These protective substances might be given systemically, or even intratympanically. The intratympanic route might allow round window absorption of the protective substance into the inner ear, while not interfering with the desired medication effect systemically.
• #51: Here is a partial list of substances that can lessen the ototoxic effect. For aminoglycosides, there are: Anti-oxidants, like iron chelating agents, salicylates, and superoxide dismutase Growth factors such as transforming growth factor alpha Inhibitors of cell death pathways such as c-Jun N-Terminal kinase inhibitory peptide and caspase inhibitors And, finally, spintrapping agents. For cisplatin or carboplatin, there are thiol compounds, anti-oxidants, and inhibitors of cell death pathways.
• #52: As a final subject, the audience should be aware of the World Health Organization initiatives to help prevent ototoxicity. It is part of the “Program for Prevention of Blindness and Deafness”. It is organized into primary, secondary, and tertiary prevention. The primary prevention initiatives are recognition of the problem, technical meetings to discuss the issue, and production of guidelines on the most common causes of hearing impairment, which are exposure to ototoxic drugs, chronic otitis media, and noise-induced hearing loss.
• #53: The secondary and tertiary prevention are pointed toward eliminating or reducing the effects of established deafness and hearing impairment. A part of this initiative is rehabilitation with the “Initiative for Affordable Hearing Aids and Services in Developing Countries”. Future strategies and goals are: prevention of childhood deafness, hearing impairment screening programs, prevention of inherited causes of deafness, and treatment of presbycusis.
• #54: Here is a summary of some of the most important points of our presentation: Ototoxic medications, especially aminoglycosides and platinum chemotherapy agents are a major cause of worldwide hearing impairment. Prevention of ototoxicity should include education of health care providers, use of alternative or less ototoxic medications, and research and development of preventive or rescue medications.
• #56: A few references, among many, are included for review. We thank you for your attention to this most important, potentially preventable, cause of sensorineural hearing loss.