Ototoxicity in cystic fibrosis patients receiving intravenous tobramycin for acute pulmonary exacerbation

Harruff, E. Emily; Kil, Jonathan; Ortiz, Maria Gabriela Tupayachi; Dorgan, Daniel; Jain, Raksha; Poth, Elizabeth A.; Fifer, Robert C.; Kim, Yun Jin M.; Shoup, Angela G.; Flume, Patrick A.

doi:10.1016/j.jcf.2020.11.020

Cited by 11 publications

(10 citation statements)

References 18 publications

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“…Tobramycin has been known to cause variable magnitudes of temporary and permanent threshold shift following a single course in animal models ( Gu et al, 2020 ; Ogier et al, 2020 ) and humans ( Garinis et al, 2020 ; Harruff et al, 2020 ). Here we confirmed that a standard course of tobramycin treatment caused consistent, yet small significant mean threshold shifts of roughly 10-15 dB SPL at 16 kHz in a CBA/Ca animal model ( Figure 2 ).…”

Section: Discussionmentioning

confidence: 99%

“…We found that 9 out of 25 mice (36%) experienced gap detection deficits indicative of tinnitus at some point during the 18 weeks of testing after treatment, and similar to hyperacusis and hearing loss ( Figures 2 , 4D ), the incidence decreased over time ( Figure 6G ). AG-induced tinnitus is thought to have an incidence rate between 12 and 37.5% in CF or tuberculosis patients ( Daud et al, 2014 ; Harruff et al, 2020 ; Sabur et al, 2021 ). The other interesting point to note is that tobramycin treatment caused consistent gap detection deficits.…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence indicates that a single course of IV tobramycin can lead to hearing loss in CF patients ( Garinis et al, 2020 ; Harruff et al, 2020 ) and that this loss of hearing sensitivity results in poorer speech discrimination ( Harruff et al, 2020 ). More clinical studies need to document and confirm these results.…”

Section: Discussionmentioning

confidence: 99%

“…Physiological examinations such as the ABR or middle-ear muscle reflex should also investigate if ABR wave III/wave I amplitude ratios are altered in patients taking AGs as they have been in noise/age related hearing loss investigations ( Bharadwaj et al, 2019 ; Guest et al, 2019 ; Refat et al, 2021 ). Preclinical work should investigate the neurotoxic effects of AGs using clinically translatable dosing schedules ( Longenecker et al, 2020 ), to parallel what has been reported in AG treated patients ( Segal et al, 1999 ; Daud et al, 2014 ; Harruff et al, 2020 ; Sabur et al, 2021 ). As discussed above, the CBA/Ca mouse would make a good model for researching this question because of its good hearing sensitivity throughout its lifespan.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, AGs are ototoxic and can often result in permanent hearing loss ( Staecker, 2021 ). Recent prospective clinical studies demonstrated that a single course of tobramycin can lead to hearing threshold shifts, word-in-noise deficits, and tinnitus, or sound perception in the absence of a sound source ( Garinis et al, 2020 ; Harruff et al, 2020 ). For those being treated with AGs for chronic conditions, the cumulative ototoxic effects present an enhanced risk of cochleotoxicity ( American Speech-Language-Hearing Association, 1994 ; Garinis et al, 2017 ; Elson et al, 2020 ; Hong et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Development of Tinnitus and Hyperacusis in a Mouse Model of Tobramycin Cochleotoxicity

Longenecker¹,

Gu²,

Homan³

et al. 2021

Front. Mol. Neurosci.

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Aminoglycosides (AG) antibiotics are a common treatment for recurrent infections in cystic fibrosis (CF) patients. AGs are highly ototoxic, resulting in a range of auditory dysfunctions. It was recently shown that the acoustic startle reflex (ASR) can assess behavioral evidence of hyperacusis and tinnitus in an amikacin cochleotoxicity mouse model. The goal of this study was to establish if tobramycin treatment led to similar changes in ASR behavior and to establish whether ebselen can prevent the development of these maladaptive neuroplastic symptoms. CBA/Ca mice were divided into three groups: Group 1 served as a control and did not receive tobramycin or ebselen, Group 2 received tobramycin (200 mg/kg/s.c.) and the vehicle (DMSO/saline/i.p.) daily for 14 continuous days, and Group 3 received the same dose/schedule of tobramycin as Group 2 and ebselen at (20 mg/kg/i.p.). Auditory brainstem response (ABR) and ASR hearing assessments were collected at baseline and 2, 6, 10, 14, and 18 weeks from the start of treatment. ASR tests included input/output (I/O) functions which assess general hearing and hyperacusis, and Gap-induced prepulse inhibition of the acoustic startle (GPIAS) to assess tinnitus. At 18 weeks, histologic analysis showed predominantly normal appearing hair cells and spiral ganglion neuron (SGN) synapses. Following 14 days of tobramycin injections, 16 kHz thresholds increased from baseline and fluctuated over the 18-week recovery period. I/O functions revealed exaggerated startle response magnitudes in 50% of mice over the same period. Gap detection deficits, representing behavioral evidence of tinnitus, were observed in a smaller subset (36%) of animals. Interestingly, increases in ABR wave III/wave I amplitude ratios were observed. These tobramycin data corroborate previous findings that AGs can result in hearing dysfunctions. We show that a 14-day course of tobramycin treatment can cause similar levels of hearing loss and tinnitus, when compared to a 14-day course of amikacin, but less hyperacusis. Evidence suggests that tinnitus and hyperacusis might be common side effects of AG antibiotics.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Development of Tinnitus and Hyperacusis in a Mouse Model of Tobramycin Cochleotoxicity

Longenecker¹,

Gu²,

Homan³

et al. 2021

Front. Mol. Neurosci.

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Aminoglycoside dosing and monitoring for Pseudomonas aeruginosa during acute pulmonary exacerbations in cystic fibrosis

Ochs

Dillman

Caverly

et al. 2021

Pediatric Pulmonology

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Aminoglycosides are commonly used for the treatment of Pseudomonas aeruginosa (PsA) in the setting of acute pulmonary exacerbations (PEx) in pediatric patients with cystic fibrosis (CF). There are controversies and practice differences between institutions related to aminoglycoside dosing and monitoring strategies. The purpose of this review article is to summarize the currently available literature and identify gaps in the literature related to pharmacokinetic parameter goals, aminoglycoside dosing strategies, and methods for monitoring serum aminoglycoside concentrations for treatment of PsA in CF PEx, and throughout will discuss anticipated changes with the increasing availability of highly effective CF transmembrane conductance regulator modulators. This review focuses on tobramycin, as it is the most commonly used aminoglycoside in CF PEx, and will briefly discuss special circumstances surrounding use of amikacin and gentamicin.

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Treatment response to pulmonary exacerbation in primary ciliary dyskinesia

Gatt

Shaw

Waters

et al. 2023

Pediatric Pulmonology

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IntroductionPulmonary exacerbation (Pex) are common in pediatric primary ciliary dyskinesia (PCD), however changes in forced expiratory volume in 1 s precent predicted (FEV1pp) during Pex are not well described.AimTo assess the evolution of FEV1pp during Pex and to define factors associated with failure to return to baseline lung function.MethodThis was a retrospective study of patients with PCD between 2010 and 2022. Pex were defined as the presence of increased respiratory symptoms treated with intravenous (IV) antibiotics. The main outcomes were the changes in FEV1 during therapy and the proportion of patients (responders) achieving ≥90% of baseline FEV1pp values at the end of admission.ResultsThe study included 52 Pex events in 28 children with PCD. The rate of responders was 32/41 (78%) at the end of admission. Nonresponse was associated with lower median body mass index (BMI) Z‐score (−2.4 vs. −0.4, p < .01) and with a history of IV treated Pex in the previous year (p = .06). For the 22 Pex with available FEV1pp measurements at mid admission, the median relative and absolute improvement from admission to Day 7 was 9.1% and 6.2%, respectively (p‐ .001), and from Days 7 to 14 was 4.4% and 2.8%, respectively (p = .08).ConclusionIn children with PCD treated with IV antibiotics, the majority of lung function recovery happens during the first week of IV therapy. Lower BMI was associated with nonresponse to therapy.

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Ototoxicity in cystic fibrosis patients receiving intravenous tobramycin for acute pulmonary exacerbation

Cited by 11 publications

References 18 publications

Development of Tinnitus and Hyperacusis in a Mouse Model of Tobramycin Cochleotoxicity

Development of Tinnitus and Hyperacusis in a Mouse Model of Tobramycin Cochleotoxicity

Aminoglycoside dosing and monitoring for Pseudomonas aeruginosa during acute pulmonary exacerbations in cystic fibrosis

Treatment response to pulmonary exacerbation in primary ciliary dyskinesia

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