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. 2022 May 1;176(5):486-492.
doi: 10.1001/jamapediatrics.2022.0187.

Rapid Point-of-Care Genotyping to Avoid Aminoglycoside-Induced Ototoxicity in Neonatal Intensive Care

John H McDermott  1   2 , Ajit Mahaveer  3 , Rachel A James  1 , Nicola Booth  3 , Mark Turner  4 , Karen E Harvey  4 , Gino Miele  5 , Glenda M Beaman  1   2 , Duncan C Stoddard  6 , Karen Tricker  1 , Rachel J Corry  1 , Julia Garlick  1 , Shaun Ainsworth  5 , Thomas Beevers  5 , Iain A Bruce  7   8 , Richard Body  9   10 , Fiona Ulph  11 , Rhona MacLeod  1   2 , Peter L Roberts  12 , Paul M Wilson  13 , William G Newman  1   2 ; PALOH Study Team
Collaborators, Affiliations

Rapid Point-of-Care Genotyping to Avoid Aminoglycoside-Induced Ototoxicity in Neonatal Intensive Care

John H McDermott et al. JAMA Pediatr. .

Abstract

Importance: Aminoglycosides are commonly prescribed antibiotics used for the treatment of neonatal sepsis. The MT-RNR1 m.1555A>G variant predisposes to profound aminoglycoside-induced ototoxicity (AIO). Current genotyping approaches take several days, which is unfeasible in acute settings.

Objective: To develop a rapid point-of-care test (POCT) for the m.1555A>G variant before implementation of this technology in the acute neonatal setting to guide antibiotic prescribing and avoid AIO.

Design, setting, and participants: This pragmatic prospective implementation trial recruited neonates admitted to 2 large neonatal intensive care units between January 6, 2020, and November 30, 2020, in the UK.

Interventions: Neonates were tested for the m.1555A>G variant via the rapid POCT on admission to the neonatal intensive care unit.

Main outcomes and measures: The primary outcome assessed the proportion of neonates successfully tested for the variant of all infants prescribed antibiotics. Secondary outcomes measured whether implementation was negatively associated with routine clinical practice and the performance of the system. The study was statistically powered to detect a significant difference between time to antibiotic administration before and after implementation of the MT-RNR1 POCT.

Results: A total of 751 neonates were recruited and had a median (range) age of 2.5 (0-198) days. The MT-RNR1 POCT was able to genotype the m.1555A>G variant in 26 minutes. Preclinical validation demonstrated a 100% sensitivity (95% CI, 93.9%-100.0%) and specificity (95% CI, 98.5%-100.0%). Three participants with the m.1555A>G variant were identified, all of whom avoided aminoglycoside antibiotics. Overall, 424 infants (80.6%) receiving antibiotics were successfully tested for the variant, and the mean time to antibiotics was equivalent to previous practice.

Conclusions and relevance: The MT-RNR1 POCT was integrated without disrupting normal clinical practice, and genotype was used to guide antibiotic prescription and avoid AIO. This approach identified the m.1555A>G variant in a practice-changing time frame, and wide adoption could significantly reduce the burden of AIO.

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Conflict of interest statement

Conflict of Interest Disclosures: Drs McDermott, James, and Tricker reported grants from the National Institute for Health Research during the conduct of the study. Drs Miele and Beevers reported instrument patents issued Genedrive Diagnostics Ltd. Dr Body reported personal fees from LumiraDx, Abbott Point of Care, Roche, Beckman Coulter, Siemens, Radiometer, and Aptamer Group; grants from Abbott Point of Care, LumiraDx, Siemens, and StreamBio; nonfinancial support from Horiba, Randox, iXensor, Menarini, BD, and Avacta outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Recruitment and Testing Metrics
Flow diagram demonstrating recruitment to the Pharmacogenetics to Avoid the Loss of Hearing (PALOH) trial, antibiotic therapy, and the outcome of MT-RNR1 testing. VAR indicates variant; WT, wild type. aConfirmation of m.1555 genotype via sanger sequencing.
Figure 2.
Figure 2.. Time to Antibiotic Therapy
Comparison of time to antibiotic during reference and study periods. The upper and lower bounds of the confidence interval (95% CI, −5.96 to 4.23 minutes) lie within the Cohen d margins. The mean difference in time to antibiotic between reference and study periods is −0.87 minutes.
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Comment in

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