Aminoglycoside Treatment Research Articles

Use of polymyxin B in patients with renal impairment: A retrospective examination of 5 cases

In order to provide an idea dose of polymyxin B in Chinese patients with renal impairment, the present study collected the clinical data of all patients with renal impairment who received polymyxin B therapy in the intensive care unit (ICU) of The First Affiliated Hospital of Bengbu Medical College (Bengbu, China). The clinical data of six patients treated in the ICU between February 2018 and May 2019 were retrospectively analyzed. All patients had renal impairment and were treated with polymyxin B combination therapy. The patients in the current study received polymyxin B and carbapenem, or polymyxin, carbapenem, cefoperazon and sulbactam, or polymyxin B, carbapenems and aminoglycoside treatment. One patient discontinued treatment. The other five patients received polymyxin B at a dosage of 50 mg every 12 h (100 mg/day) through an intravenous drip. During treatment, four of the five patients had deteriorating renal function to varying degrees, and continuous renal replacement therapy (CRRT) was initiated. Polymyxin B was discontinued in all patients when the infection was controlled. After treatment, four of five patients showed improvement in renal function, and had normal kidney function at the 1-month follow-up evaluation, whereas one patient had chronic renal disease. During hospitalization, one patient experienced neurotoxicity, showing decreased limb muscle strength and cognitive impairment, which might have been caused by polymyxin B, according to the Naranjo adverse drug reactions probability scale (also known as the Naranjo algorithm) score. The present report demonstrated that the administration of 100 mg daily dosage of polymyxin B to the five patients weighing between 50 and 75 kg, could control pulmonary infection during the course of treatment of Chinese patients with renal impairment, however, further research is needed to verify this result. Risk factors for nephrotoxicity and neurotoxicity need to be fully assessed before initiating polymyxin B therapy in patients with renal impairment.

Tubular injury and cell-cycle arrest biomarkersto predict acute kidney injury in noncritically ill children receiving aminoglycosides.

Aim: NGAL, IL-18, KIM-1as well as urinary TIMP2and IGFBP7and their mathematical product (TIMP2*IGFBP7) were evaluated for detecting pediatric aminoglycoside acute kidney injury (AG-AKI). Methods: In a prospective study, noncritically ill children received aminoglycosides (AG) ≥3days. The area under the curve (AUC) for biomarkers to detect AKI was calculated by a) days before AKI onset; b) treatment days. Results: There were 113 AG episodes (68% febrile neutropenia). The AKI group had a higher proportion with febrile neutropenia. The AKI group had significantly lower NGAL 3days before AKI, as patients with febrile neutropenia had a lower NGAL during AG treatment (p<0.05). NGAL, IL-18 and TIMP2*IGFBP7 had AUC ≥0.73 at 3, 2 and 2days before AKI onset. Conclusion: NGAL, IL-18 and TIMP2*IGFBP7 were modest early biomarkers of AG-AKI. Febrile neutropenia was associated with lower NGAL.

Aminoglycosides are efficient reagents to induce readthrough of premature termination codon in mutant B4GALNT1 genes found in families of hereditary spastic paraplegia.

The readthrough of premature termination codon (PTC) by ribosome sometimes produces full-length proteins. We previously reported a readthrough of PTC of glycosyltransferase gene B4GALNT1 with hereditary spastic paraplegia (HSP). Here we featured the readthrough of B4GALNT1 of two mutants, M4 and M2 with PTC by immunoblotting and flow cytometry after transfection of B4GALNT1 cDNAs into cells. Immunoblotting showed a faint band of full-length mutant protein of M4 but not M2 at a similar position with that of wild-type B4GALNT1. AGC sequences at immediately before and after the PTC in M4 were critical for the readthrough. Treatment of cells transfected with mutant M4 cDNA with aminoglycosides resulted in increased readthrough of PTC. Furthermore, treatment of transfectants of mutant M2 cDNA with G418 also resulted in the induction of readthrough of PTC. Both M4 and M2 cDNA transfectants showed increased/induced bands in immunoblotting and GM2 expression in a dose-dependent manner of aminoglycosides. Results of mass spectrometry supported this effect. Here, we showed for the first time the induction and/or enhancement of the readthrough of PTCs of B4GALNT1 by aminoglycoside treatment, suggesting that aminoglycosides are efficient for patients with HSP caused by PTC of B4GALNT1, in which gradual neurological disorders emerged with aging.

Short-course aminoglycosides as adjunctive empirical therapy in patients with Gram-negative bloodstream infection, a cohort study

ObjectiveShort-course aminoglycosides as adjunctive empirical therapy to β-lactams in patients with a clinical suspicion of sepsis are used to broaden antibiotic susceptibility coverage and to enhance bacterial killing. We quantified the impact of this approach on 30-day mortality in a subset of sepsis patients with a Gram-negative bloodstream infection. MethodsFrom a prospective cohort study conducted in seven hospitals in the Netherlands between June 2013 and November 2015, we selected all patients with Gram-negative bloodstream infection (GN-BSI). Short-course aminoglycoside therapy was defined as tobramycin, gentamicin or amikacin initiated within a 48-hour time window around blood-culture obtainment, and prescribed for a maximum of 2 days. The outcome of interest was 30-day all-cause mortality. Confounders were selected a priori for adjustment using a propensity score analysis with inverse probability weighting. ResultsA total of 626 individuals with GN-BSI who received β-lactams were included; 156 (24.9%) also received aminoglycosides for a median of 1 day. Patients receiving aminoglycosides more often had septic shock (31/156, 19.9% versus 34/470, 7.2%) and had an eight-fold lower risk of inappropriate treatment (3/156, 1.9% versus 69/470, 14.7%). Thirty-day mortality was 17.3% (27/156) and 13.6% (64/470) for patients receiving and not receiving aminoglycosides, respectively; yielding crude and adjusted odds ratios for 30-day mortality for patients treated with aminoglycosides of 1.33 (95% CI 0.80–2.15) and 1.57 (0.84–2.93), respectively. ConclusionsShort-course adjunctive aminoglycoside treatment as part of empirical therapy with β-lactam antibiotics in patients with GN-BSI did not result in improved outcomes, despite better antibiotic coverage of pathogens.

Managing multidrug-resistant tuberculosis in South Africa: a budget impact analysis.

SETTING: In South Africa prior to 2016, the standard treatment regimen for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) was 24 months long and required daily injectable aminoglycoside (IA) treatment during the first 6 months. Recent evidence supports the replacement of IA with well-tolerated oral bedaquiline (BDQ) and a shortened 9-12 month regimen.DESIGN: Using a Markov model, we analyzed the 5-year budgetary impact and cost per successful treatment outcome of four regimens: 1) IA long-course, 2) oral long-course, 3) IA short-course, and 4) oral short-course. We used the South African MDR/RR-TB case register (2013-2015) to assess treatment outcomes for the then-standard IA long-course. Data on the improvement in outcomes for BDQ-based regimens were based on the literature. Costs were estimated from the provider perspective using costs incurred to provide decentralized treatment for MDR-TB at a Johannesburg hospital.RESULTS: Based on our analysis, by 2023, the cost/successful outcome for the four regimens was respectively 1) US$7374, 2) US$7860, 3) US$5149, and 4) US$4922. The annual total cost of each regimen was US$37 million, US$43 million, US$26 million, and US$28 million.CONCLUSION: Despite the high cost of BDQ, a BDQ-based shortened regimen for the treatment of MDR/RR-TB will result in improved treatment outcomes and cost savings for South Africa.

Protective Role of Vernonia Amygdalina Leaf Aqueous Extract Against Neomycin-Induced Hair Cell Damage in Transgenic Zebrafish

Aminoglycoside treatment increases the loss of hair cells in the inner ear. Once the hair cells are lost, they are unable to regenerate spontaneously, and the resulting hearing loss is profound and irreversible in humans. The aqueous extract from the leaves of Vernonia amygdalina has been reported to have antioxidant properties. In this study, we evaluated whether the aqueous extracts of Vernonia amygdalina leaf could protect hair cells from aminoglycoside-induced damage using a transgenic zebrafish line. Our results showed that the EC50 of 1,1-Diphenyl-2 picrylhydrazyl radical scavenging and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonate), a measure of antioxidant capacity, of the aqueous extracts of Vernonia amygdalina leaf was 11.31 mg/mL and 2.73 mg/mL, respectively. Moreover, the total phenolic and flavonoids contents were 11.48 ŷ 3.12 mg gallic acid/g and 6.89 ŷ 0.65 mg catechin/g, respectively. In the toxicology study, the larval survival rate was significantly decreased and was dependent on the dosage of aqueous extracts of Vernonia amygdalina leaf, whereas it had no significant toxicity at doses below 2.5 mg/mL concentration (survival rate = 100%). Furthermore, a hair cell survival study shows that aqueous extracts of Vernonia amygdalina leaf decreased neomycin-induced hair cell death in a dose-dependent manner (survival rate = ∼94.1 ŷ 3.1% at 2 mg/mL concentration). Overall, these results suggest that the aqueous extracts of Vernonia amygdalina leaf possess the antioxidant effect and protects against hair cell loss caused by toxic side effects of neomycin. An optimal aqueous extract of Vernonia amygdalina leaf can be consumed as an herbal medicine without probable toxicity to body tissues and organs.

Patient Benefits of Audiology, Pharmacy Collaboration

Patient Benefits of Audiology, Pharmacy Collaboration

Intravenously delivered aminoglycoside antibiotics, tobramycin and amikacin, are not ototoxic in mice

Many drugs on the World Health Organization’s list of critical medicines are ototoxic, destroying sensory hair cells within the ear. These drugs preserve life, but patients can experience side effects including permanent hearing loss and vestibular dysfunction. Aminoglycoside ototoxicity was first recognised 80 years ago. However, no preventative treatments have been developed. In order to develop such treatments, we must identify the factors driving hair cell death. In vivo, studies of cell death are typically conducted using mouse models. However, a robust model of aminoglycoside ototoxicity does not exist. Previous studies testing aminoglycoside delivery via intraperitoneal or subcutaneous injection have produced variable ototoxic effects in the mouse. As a result, surgical drug delivery to the rodent ear is often used to achieve ototoxicity. However, this technique does not accurately model clinical practice. In the clinic, aminoglycosides are administered to humans intravenously (i.v.). However, repeated i.v. delivery has not been reported in the mouse. This study evaluated whether repeated i.v. administration of amikacin or tobramycin would induce hearing loss. Daily i.v. injections over a two-week period were well tolerated and transient low frequency hearing loss was observed in the aminoglycoside treatment groups. However, the hearing changes observed did not mimic the high frequency patterns of hearing loss observed in humans. Our results indicate that the i.v. delivery of tobramycin or amikacin is not an effective technique for inducing ototoxicity in mice. This result is consistent with previously published reports indicating that the mouse cochlea is resistant to systemically delivered aminoglycoside ototoxicity.

Native-valve Enterococcus hirae endocarditis: a case report and review of the literature

BackgroundEnterococcus hirae is rarely identified in humans and may be a commensal pathogen in psittacine birds. We present the fifth known case of E. hirae endocarditis.Case presentationA 64-year-old Caucasian female presented with fever, hypotension, atrial fibrillation with rapid ventricular response, and a two-week history of lightheadedness. Her previous medical history included COPD, recurrent DVT, atrial fibrillation (on warfarin), hypertension, hypothyroidism, and Hodgkin’s lymphoma. Physical exam was notable for expiratory wheezes and a 2/6 systolic ejection murmur at the right sternal border. 2D echocardiogram revealed severe aortic stenosis. The patient underwent right and left heart catheterization, where she was found to have severe aortic stenosis and mild pulmonary hypertension. She subsequently underwent minimally invasive aortic valve replacement with a bovine pericardial valve, bilateral atrial cryoablation, and clipping of the left atrial appendage. Her aortic valve was found to have a bicuspid, thickened appearance with calcifications, multiple small vegetations, and a root abscess beneath the right coronary cusp. With a new suspicion of infective endocarditis, the patient was placed on broad-spectrum IV antibiotics. Intra-operative blood cultures were negative. A tissue culture from the aortic valve vegetations identified Enterococcus hirae susceptible to ampicillin through MALDI-TOF. Antibiotic treatment was then switched to IV ampicillin and ceftriaxone; she declined aminoglycoside treatment due to toxicity concerns. The patient had an uncomplicated postoperative course and was discharged with 6 weeks of antibiotics. To date, she continues to be followed with no signs of relapsing disease.ConclusionsTo our knowledge, this case constitutes the fifth known case of E. hirae endocarditis, and the second case to have been identified with MALDI-TOF and treated with ampicillin and ceftriaxone. This case reinforces the efficacy of ampicillin and ceftriaxone for the treatment of E. hirae endocarditis.

2222. Impact of Empiric Aminoglycoside Usage on Outcomes in Bacterial Pneumonia

BackgroundAlthough aminoglycosides are recommended as part of empiric combination therapy in selected patients with healthcare-associated pneumonia, their efficacy and safety remains unclear. The objectives of this study were to evaluate the impact of empiric aminoglycoside treatment on microbiologic cure, recurrent pneumonia and death, and acute kidney injury (AKI) among hospitalized patients treated for pneumonia who were clinically cured.MethodsThis was a nested cohort study including 441 hospitalized subjects with confirmed bacterial pneumonia who achieved clinical cure. All subjects had positive respiratory cultures at the beginning of therapy and also had cultures obtained at the time of antibiotic completion. Subjects with the same pathogen present at both the beginning of and at the end of treatment were categorized as microbiologic failure and all others were categorized as microbiologic cure. Serum creatinine was measured at both the beginning and end of therapy, with an absolute increase in serum creatinine of 0.5 mg/L or greater defined as AKI. Composite outcomes of 30- and 90-day recurrent pneumonia or death following the clinical cure of the index pneumonia were captured. Patients who received empiric aminoglycoside therapy were compared with patients who did not receive aminoglycoside therapy.ResultsOf 441 included subjects, 14.5% (N = 64) received aminoglycoside therapy and 85.5% (N = 377) did not. The mean age was 54.7 years, with 70.5% male and 78.2% white. Characteristics of the two groups (including Charlson Comorbidity Indices and APACHE II scores) were similar. Rates of microbiologic cure, death/recurrent pneumonia at 30- and 90-days and AKI and were similar in both groups (table). In subgroup analyses restricted to different pathogen groups these associations remained unchanged.ConclusionAmong hospitalized patients with pneumonia who were clinically cured, empiric aminoglycoside therapy was not associated with an increased likelihood of microbiologic cure, death or recurrent pneumonia or AKI. Disclosures All authors: No reported disclosures.

Drug-induced Stress Granule Formation Protects Sensory Hair Cells in Mouse Cochlear Explants During Ototoxicity

Stress granules regulate RNA translation during cellular stress, a mechanism that is generally presumed to be protective, since stress granule dysregulation caused by mutation or ageing is associated with neurodegenerative disease. Here, we investigate whether pharmacological manipulation of the stress granule pathway in the auditory organ, the cochlea, affects the survival of sensory hair cells during aminoglycoside ototoxicity, a common cause of acquired hearing loss. We show that hydroxamate (-)-9, a silvestrol analogue that inhibits eIF4A, induces stress granule formation in both an auditory cell line and ex-vivo cochlear cultures and that it prevents ototoxin-induced hair-cell death. In contrast, preventing stress granule formation using the small molecule inhibitor ISRIB increases hair-cell death. Furthermore, we provide the first evidence of stress granule formation in mammalian hair cells in-vivo triggered by aminoglycoside treatment. Our results demonstrate that pharmacological induction of stress granules enhances cell survival in native-tissue, in a clinically-relevant context. This establishes stress granules as a viable therapeutic target not only for hearing loss but also other neurodegenerative diseases.

Functional and morphological analysis of different aminoglycoside treatment regimens inducing hearing loss in mice.

Aminoglycoside ototoxicity is common in clinical practice but reliable protective agents currently do not exist. Aminoglycoside regimens causing ototoxicity in different laboratory animals are under investigation. The assessment method used most commonly to determine auditory effects is the auditory brainstem response (ABR). Distortion product otoacoustic emissions (DPOAE) have been used less frequently. A precise recommendation on the specific method to assess peripheral auditory function before and after aminoglycoside toxicity in mice does not exist. In order to evaluate various mouse models for ototoxic injury caused by various aminoglycoside regimens, there is a need for performing preliminary tests in small cohorts before large experiments. The aim of our study was to investigate different aminoglycoside regimens that cause substantial ototoxic damage in vivo. Aminoglycosides are safe and produce a detectable hearing threshold shift in a small cohort of mice that can be used as a model for preliminary tests. Different ototoxic regimens were assessed by ABR and DPOAE measurements pre- and post-treatment. Further, the sensory cell loss was quantified by counting hair cells in the cochlea. It was revealed that an ototoxic regimen with kanamycin twice daily for 15 consecutive days is safe, well tolerated and produces an early significant hearing threshold shift detected by DPOAE in a small cohort of mice. The study compared ABR and DPOAE in mentioned regimens for the first time and illustrated that DPOAE is well suited for detecting hearing threshold shifts in high frequencies before ABR threshold shifts occur in accordance with predominating outer hair cell damage mainly in the basal turn of the cochlea.

Renal function after treatment for childhood cancer: A report from the St. Jude Lifetime Cohort Study.

10048 Background: We assessed renal function in a large, clinically assessed cohort of childhood cancer survivors. Methods: Creatinine and qualitative urine protein was measured in 2753 survivors (&gt;10 years (years) post-diagnosis, age ≥18 years). Renal function was graded per the Kidney Disease International Global Outcomes 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD). Multivariable logistic regression was used to estimate associations between demographics, treatment exposures, and CKD (grades 1-5 and 3-5). Radiation treatment was expressed as percentage of total kidney volume treated with 5 (V5), 10 (V10), 15 (V15) and 20 (V20) Gray. Results: Among 2753 survivors, 48.7% were female and 82.5% non-Hispanic white. Median age at diagnosis - 7.3 years (interquartile range [IQR]=3.3-13.2), median age at evaluation - 31.4 years (IQR=25.8-37.8), and median time from diagnosis to evaluation - 23.2 years (IQR=17.6-29.7). Prevalence of grades 1-5 and 3-5 CKD was 7.4% and 2.1%, respectively (grade 1=113, grade 2=30, grade 3=44, grade 4=5, and grade 5=8). Individual and cumulative aminoglycoside doses and treatment with high-dose methotrexate were not associated with CKD (data not shown). Cumulative number of doses of ambisome/abelcet and of amphotericin B were significant risk factors for grades 1-5 and grades 3-5 CKD in models for V15 and V20 (data not shown). The multivariable results for V10 are shown in the Table. Conclusions: In addition to nephrotoxic antineoplastic and supportive care therapy, race, ethnicity, and body composition contribute to risk of CKD in long-term survivors. These novel results inform late effects reduction strategies for future treatment protocols and identify survivors at highest risk for CKD. [Table: see text]

Standards of aminoglycoside therapeutic drug monitoring in a South African private hospital: perspectives and implications.

Therapeutic drug monitoring (TDM) is essential to ensure that aminoglycoside peak concentrations are high enough for effective antimicrobial treatment and trough levels are low enough to minimise toxicity. Inappropriate utilisation of TDM may lead to suboptimal therapy, toxicity and waste of resources. This study aimed to investigate the standard of aminoglycoside TDM performed in adult hospitalised patients. An observational, descriptive, cross-sectional study. A 221-bed private hospital. All patients, older than 18 years, on intravenous aminoglycosides for more than 48 hours were included. None, was observational. A computerised database and patient files were used to obtain the information required for this study. Descriptive statistical analysis was used. Aminoglycoside blood levels and estimated glomerular filtration rate (eGFR) in the patients. One hundred and three (103) patients were included: 65 on gentamicin and 38 on amikacin. Blood levels were performed in only 19 gentamicin (29.23%) and 22 amikacin (57.89%) patients. Trough levels were taken more than 2 hours before the next dose in 12 gentamicin (63.16%) and 12 amikacin (54.54%) patients. The majority of patients (96.92% on gentamicin and 84.21% on amikacin) received once daily doses. TDM was performed in all patients with an estimated glomerular filtration rate (eGFR) lower than 60 mL/min/1.73m2 and in 23.31% of gentamicin patients and 56.76% of amikacin patients with an eGFR higher than 60 mg/min/1.73m2. Incorrect sampling times and unnecessary levels taken in patients with normal renal function indicate a need for aminoglycoside treatment guidelines in the private hospital. None.

Association Between Duration of Aminoglycoside Treatment and Outcome of Cavitary Mycobacterium avium Complex Lung Disease

Although aminoglycosides are recommended for cavitary Mycobacterium avium complex lung disease (MAC-LD), the optimal duration of treatment is unclear. We investigated the association between duration of aminoglycoside treatment and outcomes in cavitary MAC-LD. Among patients diagnosed with macrolide-susceptible cavitary MAC-LD between 2000 and 2013, 101 who received treatment up to August 2017 with a regimen containing aminoglycosides were enrolled at a tertiary referral center in South Korea. Their medical records were retrospectively reviewed. The duration of aminoglycoside treatment was at the discretion of the attending physician. A total of 75 patients (74.3%) were administered aminoglycosides for ≥3 months (median 164 days), whereas the remaining 26 patients (25.7%) received treatment for <3 months (median 59 days). The overall treatment success rate was 63.4% (64/101). Patients treated with aminoglycosides for ≥3 months had a significantly higher success rate than those treated for <3 months (69.3% vs 46.2%; P = .035). Multivariate analysis revealed that aminoglycoside treatment for ≥3 months was a significant factor for treatment success (adjusted odds ratio, 3.602; 95% confidence interval, 1.249-10.390; P = .018). Recurrence occurred in 8 (22.9%) of 35 patients who were followed up for at least 3 years after the end of treatment; all 8 patients received aminoglycosides for ≥3 months. Patients with cavitary MAC-LD treated with aminoglycosides for ≥3 months showed higher treatment success rate than those treated for <3 months. However, treatment for ≥3 months was not associated with the development of recurrence.

Aminoglycoside exposure and renal function before lung transplantation in adult cystic fibrosis patients.

Patients with cystic fibrosis (CF) are at risk of kidney injury even before undergoing lung transplantation, because of prolonged exposure to aminoglycosides (AGs), chronic dehydration and complications of diabetes mellitus. The usual equations estimating the glomerular filtration rate (GFR), such as Cockcroft-Gault and Modification of Diet in Renal Disease, are not adapted to the CF population due to patients' low body weight and reduced muscle mass. The aim of this study was to precisely measure GFR in adult CF patients and to see whether repeated AG treatment would impair renal function before lung transplantation. Inulin or iohexol clearances were performed in 25 adult CF patients when they entered the lung transplant waiting list. No patient was treated with AGs at the time of GFR measurement. Body mass index (BMI), history of diabetes mellitus and blood pressure were recorded. Exposure to intravenous (IV) AGs within 5 years prior to the GFR measurement was obtained from the patient's medical files. Urine samples were collected to check for albuminuria and proteinuria. The population was predominantly female (67%). The mean age was 32 years, the mean BMI was 19 kg/m2 and 28% had CF-related diabetes. Median exposure to IV AG within 5 years before GFR measurement was 155 days with a mean dosage of 7.7mg/kg/day. The mean measured GFR was 106 mL/min/1.73 m2 and the mean estimated GFR according to the Chronic Kidney Disease Epidemiology Collaboration formula was 124 mL/min/1.73 m2. Despite prolonged exposure to high-dose IV AG, no decline in GFR was observed in these patients.

Topical application of aminoglycoside antibiotics enhances host resistance to viral infections in a microbiota-independent manner

Antibiotics are widely used to treat infections in humans. However, the impact of antibiotic use on host cells is understudied. Here we identify an antiviral effect of commonly used aminoglycoside antibiotics. We show that topical mucosal application of aminoglycosides prophylactically increased host resistance to a broad range of viral infections including herpes simplex viruses, influenza A virus and Zika virus. Aminoglycoside treatment also reduced viral replication in primary human cells. This antiviral activity was independent of the microbiota as aminoglycoside treatment protected germ-free mice. Microarray analysis uncovered a marked upregulation of transcripts for interferon-stimulated genes (ISGs) following aminoglycoside application. ISG induction was mediated by TLR3, and required TIR-domain-containing adapter-inducing interferon-β (TRIF), signaling adaptor, and interferon regulatory factors 3 (IRF3) and IRF7, transcription factors that promote ISG expression. XCR1+ dendritic cells, which uniquely express TLR3, were recruited to the vaginal mucosa upon aminoglycoside treatment and were required for ISG induction. These results highlight an unexpected ability of aminoglycoside antibiotics to confer broad antiviral resistance in vivo.

Genetic disruption of fractalkine signaling leads to enhanced loss of cochlear afferents following ototoxic or acoustic injury.

Cochlear hair cells are vulnerable to a variety of insults like acoustic trauma and ototoxic drugs. Such injury can also lead to degeneration of spiral ganglion neurons (SGNs), but this occurs over a period of months to years. Neuronal survival is necessary for the proper function of cochlear prosthetics, therefore, it is of great interest to understand the mechanisms that regulate neuronal survival in deaf ears. We have recently demonstrated that selective hair cell ablation is sufficient to attract leukocytes into the spiral ganglion, and that fractalkine signaling plays a role in macrophage recruitment and in the survival of auditory neurons. Fractalkine (CX3 CL1), a chemokine that regulates adhesion and migration of leukocytes is expressed by SGNs and signals to leukocytes via its receptor CX3 CR1. The present study has extended the previous findings to more clinically relevant conditions of sensorineural hearing loss by examining the role of fractalkine signaling after aminoglycoside ototoxicity or acoustic trauma. Both aminoglycoside treatment and acoustic overstimulation led to the loss of hair cells as well as prolonged increase in the numbers of cochlear leukocytes. Lack of CX3 CR1 did not affect macrophage recruitment after injury, but resulted in increased loss of SGNs and enhanced expression of the inflammatory cytokine interleukin-1β, when compared to mice with intact CX3 CR1. These data indicate that the dysregulation of macrophage response caused by the absence of CX3 CR1 may contribute to inflammation-mediated neuronal loss in the deafened ear, suggesting a key role for inflammation in the long-term survival of target-deprived afferent neurons.

Dynamic Editome of Zebrafish under Aminoglycosides Treatment and Its Potential Involvement in Ototoxicity.

RNA editing is an important co- and post-transcriptional event that generates RNA and protein diversity. Aminoglycosides are a group of bactericidal antibiotics and a mainstay of antimicrobial therapy for several life-threatening infections. However, aminoglycosides can induce ototoxicity, resulting in damage to the organs responsible for hearing and balance. At low concentrations, aminoglycosides can bind to many RNA sequences and critically influence RNA editing. We used a bioinformatics approach to investigate the effect of aminoglycosides on global mRNA editing events to gain insight into the interactions between mRNA editing and aminoglycoside ototoxicity. We identified 6,850 mRNA editing sites in protein coding genes in embryonic zebrafish, and in about 10% of these, the degree of RNA editing changed more than 15% under aminoglycosides treatment. Twelve ear-development or ototoxicity related genes, including plekhm1, fgfr1a, sox9a, and calrl2, exhibited remarkable changes in mRNA editing levels in zebrafish treated with aminoglycosides. Our results indicate that aminoglycosides may have a widespread and complicated influence on the progress of mRNA editing and expression. Furthermore, these results highlight the potential importance of mRNA editing in the pathogenesis and etiology of aminoglycoside-induced ototoxicity.

Mitochondrial hearing loss mutations among Finnish preterm and term-born infants.

Mitochondrial ribosomal 12S subunit gene (MTRNR1) is a hot spot for hearing loss mutations. Mutations such as m.1555A&gt;G, m.1494C&gt;T and m.1095C&gt;T, cause sensitivity to aminoglycosides. Aminoglycoside treatment induces permanent hearing loss or deafness in the carriers and should therefore be avoided. The prevalence of these sensitivity mutations varies in different countries and populations. Over 90% of preterm children need aminoglycoside treatment during their first weeks of life. Infants who carry a mitochondrial sensitivity mutation can develop a life-long sensorineural hearing impairment as a side-effect of aminoglycoside treatment. Total of 813 Finnish preterm (born G, m.1494T&gt;C and m.1095C&gt;T mutations. The population prevalence of m.1555A&gt;G was determined to be 0.12% in Finland. M.1494C&gt;T and m.1095C&gt;T mutations were absent. Out of the 813 infants, a term-born infant was found to harbor m.1555A&gt;G at 81% heteroplasmy, while his mother’s heteroplasmy was 68%. Both had normal hearing and had not received aminoglycosides. Mothers with a family history of hearing loss who are at risk of preterm labor would benefit from antenatal genotyping of m.1555A&gt;G mutation. The prevalence of m.1555A&gt;G in Finns was close to other European countries. M.1494C&gt;T and m.1095C&gt;T mutations either do not occur in the Finnish population or they are very rare. This study highlights the importance of population-specific genotyping of MTRNR1 aminoglycoside sensitivity mutations, especially in countries with liberal aminoglycoside use.