1. In a prospective implementation trial, more than 400 infants were tested for the MT-RNR1 m.1555A>G variant using a point-of-care buccal swab test in neonatal intensive care units (NICUs).

2. In a real-world setting, 80.6% of infants treated with aminoglycosides were successfully tested for the m.1555A>G variant with a sensitivity of 100% and specificity of 99.2%.

Evidence Rating Level: 2 (Good)

Study Rundown: Specific genetic variants, including MT-RNR1 m.1555A>G, are associated with increased risk of aminoglycoside-induced ototoxicity (AIO). This study aimed to determine the diagnostic accuracy and feasibility of a rapid point-of-care genotyping assay for the m.1555A>G variant in the neonatal intensive care unit (NICU) setting, where gentamicin is often used to treat neonatal sepsis. A case-control study was conducted for preclinical assay validation. Based on testing of about 160 neonates in comparison with Sanger sequencing, the assay had a sensitivity and specificity of 100% without cross-reactivity. A prospective trial was then conducted examining real-world implementation of this buccal swab test in NICUs. 424 neonates were tested for the m.1555A>G variant, representing 80.6% of infants who were prescribed aminoglycosides. 17.1% of point-of-care tests failed. After implementation of the rapid test, time to antibiotic therapy was essentially unchanged at 55 minutes. Testing returned 3 true positive and 5 false positive results; all of these infants received a cephalosporin antibiotic rather than gentamicin. This study demonstrates encouraging validation data on a genotyping test that is far more clinically useful in high-stakes clinical settings such as suspected neonatal sepsis than existing, slower assays. The balance between cost and benefit of universal genotypic screening must certainly be considered here, particularly in light of this test’s rates of failure and false positives. Though the m.1555A>G variant is present in only about 0.2% of the population and the penetrance of the ototoxicity risk phenotype is unclear, preventing avoidable neonatal hearing loss must also be considered a high-priority goal.

Click to read the study in JAMA Pediatrics

Click to read an accompanying editorial in JAMA Pediatrics

Relevant Reading: Benefit of preemptive pharmacogenetic information on clinical outcome

In-Depth [prospective cohort]: All patients treated at 2 NICUs in the United Kingdom in 2020 were eligible for inclusion. At both centers, benzylpenicillin and gentamicin are used as empiric therapy for suspected bacterial infection before 28 days, while gentamicin in combination with other antibiotics is used for infants older than 28 days. Patients who were determined to require immediate antibiotic therapy on admission were excluded. Subjects had a median age of 2.5 days, and 70% of included neonates received antibiotic therapy. The real-world sensitivity of the assay was 100% with a 95% confidence interval (CI) of 29.2-100%, while the real-world specificity was 99.2% (98-99.7%). A design update to the point-of-care testing system and a change in the assay preparation process were made during the trial and resulted in reduced rates of test failure.

Image: PD

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