By Philip R. Fischer, MD, DTM&H
Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; Department of Pediatrics, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
SYNOPSIS: Mitochondrially inherited, aminoglycoside-induced ototoxicity can cause irreversible hearing loss. Approximately 0.2% of the population is at risk, and new point-of-care genetic testing potentially can prompt avoidance of aminoglycoside use without undue delay in antibiotic administration.
SOURCE: McDermott JH, Mahaveer A, James RA, et al. Rapid point-of-care genotyping to avoid aminoglycoside-induced ototoxicity in neonatal intensive care. JAMA Pediatr 2022; March 21. doi 10.1001/jamapediatrics.2022.0187. [Online ahead of print].
In addition to the more common dose-related risks of ototoxicity and nephrotoxicity with gentamicin use, a familial condition of irreversible and profound hearing loss following even single doses of gentamicin has been identified. A variant in the mitochondrial RNR1 gene m.1555A>G is responsible for this severe susceptibility to gentamicin toxicity. This mutation is associated with a structural change in the human 12S ribosomal ribonucleic acid (RNA) subunit, making it more similar in structure to a bacterial 12S ribosomal RNA subunit, especially in the hair cells of the inner ear. Aminoglycosides then “recognize” the altered RNA and bind to it, causing cellular damage and hearing loss.
More than 7 million neonates receive amino-glycosides each year as presumptive treatment of neonatal sepsis. This antimicrobial treatment saves many lives. However, if the estimated 0.2% prevalence of the mutation is correct, that would mean that 14,000 newborns per year risk severe hearing loss from aminoglycosides. Testing for the mitochondrial mutation, if results were rapidly available, would potentially allow for substitution of a second-line antibiotic that carries less risk.
British investigators developed a point-of-care assay for the relevant mitochondrial mutation and validated it on samples from 159 individuals. The point-of-care test was 100% sensitive and specific. Test results were available in just 26 minutes.
Testing then was implemented in two neonatal intensive care units to test if the results could helpfully alter treatment and to see how “real world” testing compared with later, more definitive, laboratory testing. From January through November 2020, a total of 526 babies were enrolled on arrival in a neonatal care unit (median age 2.5 days, mean gestational age 37 weeks) prior to antibiotic administration if the treating clinician did not require antibiotic administration within less than 30 minutes. Of the enrolled infants, testing via buccal swab was successful in 81%, with 17% test failures (less after sample processing was altered) and 2% inadvertently not tested. There were five false-positive results (about 1% of those tested) and no false-negative test results. Three test results were true positives, representing less than 1% of the tested infants. Testing did not alter the time to initial antibiotic administration (56 minutes in a pre-study period and 55 minutes during the study).
A vast majority of study subjects came from just one of the study hospitals, presumably because of difficulty implementing the study at the other related to the evolving COVID pandemic. In the hospital responsible for most of the study subjects, the study went smoothly. Potential profound hearing loss was avoided in three babies for whom test results prompted the substitution of the aminoglycoside with a different antibiotic. The “real world” sensitivity (100%) and specificity (99%) were good.
COMMENTARY
Aminoglycoside-induced deafness is discussed in the Online Mendelian Inheritance in Man (OMIM) website as condition 580000.1 The ototoxicity is not dose-related and was reported with the use of streptomycin for tuberculosis in Africa during the second half of the 20th century.1 Maternal transmission of risk was identified, and affected kindreds were characterized in China and the Middle East.1 A thorough literature review revealed that the A1555G mutation is most common and that a related mutation C1494T results in similarly affected patients; 14 patients with other mutations also have been identified.2 The two most common mutations usually are seen in individuals of Chinese ancestry.2
Ding and colleagues reported successful testing for the mitochondrial mutations conferring risk of ototoxicity with aminoglycoside use, but the rapidity of result availability was not explicitly described.3 The various steps of their assay require approximately 15 minutes, but they did not describe the duration of intervening cooling phases,3 and it is not known if their assay would yield results rapidly enough to alter treatment in individuals who need life-saving antimicrobial therapy.
This current study shows that rapid testing is possible and can favorably affect clinical care in those who should not receive an aminoglycoside, without delaying antibiotic administration in the others. However, the test is not yet widely available. There were some “failures” in their test, although the failures were reduced with ongoing experience during the trial. In addition, implementation of the testing was difficult in one hospital, even with research-savvy staff, related to the COVID-19 pandemic. For widespread implementation, the test will have to be readily available and feasibly used, without significant numbers of failed tests.
A Chinese study of one family over three generations suggested that children carrying the mitochondrial mutation who received an aminoglycoside at younger ages were more susceptible to more profound hearing loss than were children treated with an aminoglycoside later in childhood.4 Thus, initial implementation of testing could, indeed, be targeted in neonatal and pediatric settings.
Chloramphenicol was removed from markets because of causing idiosyncratic (not dose-related) aplastic anemia in one of each 20,000 treated patients. Knowing that one of each 500 individuals treated with an aminoglycoside is at risk of profound hearing loss (separate from the renal and ocular toxicity that can be largely prevented by checking levels and adjusting doses to keep trough levels below a range of potential toxicity), one wonders if testing for the relevant mitochondrial mutations will be required one day before allowing aminoglycoside treatment.
REFERENCES
- Kniffin CL. Deafness, aminoglycoside-induced. Online Mendelian Inheritance in Man. Updated March 4, 2022. https://www.omim.org/entry/580000
- Nguyen T, Jeyakumar A. Genetic susceptibility to aminoglycoside ototoxicity. Int J Pediatr Otorhinolaryngol 2019;120:15-19.
- Ding Y, Lang J, Zhang J, et al. Screening for deafness-associated mitochondrial 12S rRNA mutations by using a multiplex allele-specific PCR method. Biosci Rep 2020;40:BSR20200778.
- Yuan H, Qian Y, Xu Y, et al. Cosegregation of the G7444A mutation in the mitochondrial COI/tRNA(Ser(UCN)) genes with the 12S rRNA A1555G mutation in a Chinese family with aminoglycoside-induced and nonsyndromic hearing loss. Am J Med Genet A 2005;138A:133-140.
Mitochondrially inherited, aminoglycoside-induced ototoxicity can cause irreversible hearing loss. Approximately 0.2% of the population is at risk, and new point-of-care genetic testing could prompt avoidance of aminoglycoside use without undue delay in antibiotic administration.
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