A balanced randomised placebo controlled blinded phase IIa multi-centre study to investigate the efficacy and safety of AUT00063 versus placebo in subjective tinnitus: The QUIET-1 trial.

AUT00063 is an experimental new medicine that has been demonstrated to suppress spontaneous hyperactivity by modulating the action of voltage-gated potassium-channels in central auditory cortical neurons of a rodent model. This neurobiological property makes it a good candidate for treating the central component of subjective tinnitus but this has not yet been tested in humans. The main purpose of the QUIET-1 (QUest In Eliminating Tinnitus) trial was to examine the effect of AUT00063 on the severity of tinnitus symptoms in people with subjective tinnitus. The trial was a randomised, placebo-controlled, observer, physician and participant blinded multi-centre superiority trial with two parallel groups and a primary endpoint of functional impact on tinnitus 28 days after the first drug dosing day. The trial design overcame the scale and logistical challenges of delivering a scientifically robust, statistically powered multi-centre study for subjective tinnitus within the National Health Service in England. The trial was terminated early for futility. Overall, 212 participants consented across 18 sites with 91 participants randomised to groups using age, gender, tinnitus symptom severity and hearing status as minimisation factors. While the pharmacokinetic markers confirm the uptake of AUT00063 in the body, within the expected therapeutic range, with respect to clinical benefit findings indicated that AUT00063 was not effective in alleviating tinnitus symptoms (1.56 point change in Tinnitus Functional Index). In terms of clinical harms, results indicated that a daily dose of 800 mg capsules of AUT00063 taken for 28 days was safe and well tolerated. These findings provide significant advances in the drug development field for hearing sciences, but raise questions about the predictive validity of certain rodent models of noise-induced hearing loss and tinnitus, as least for the mechanism evaluated in the present study. Trial Registration: (EudraCT) 2014-002179-27; NCT02315508.

Hold your horses: A comparison of human laryngomalacia with analogous equine airway pathology.

OBJECTIVES: Laryngomalacia is the most common cause of stridor in infants. Dynamic airway collapse is also a well-recognised entity in horses and an important cause of surgical veterinary intervention. We compare the aetiology, clinical features and management of human laryngomalacia with equine dynamic airway collapse. METHODS: A structured review of the PubMed, the Ovid Medline and the Cochrane Collaboration databases (Cochrane Central Register of Controlled Trials, Cochrane Database of Systemic Reviews). RESULTS: There are numerous equine conditions that cause dynamic airway collapse defined specifically by the anatomical structures involved. Axial Deviation of the Aryepiglottic Folds (ADAF) is the condition most clinically analogous to laryngomalacia in humans, and is likewise most prevalent in the immature equine airway. Both conditions are managed either conservatively, or if symptoms require it, with surgical intervention. The operative procedures performed for ADAF and laryngomalacia are technically comparable. CONCLUSION: Dynamic collapse of the equine larynx, especially ADAF, is clinically similar to human laryngomalacia, and both are treated in a similar fashion.

Evaluation of combinations of putative anti-biofilm agents and antibiotics to eradicate biofilms of Staphylococcus aureus and Pseudomonas aeruginosa.

Objectives: To evaluate potential anti-biofilm agents for their ability to enhance the activity of antibiotics for local treatment of localized biofilm infections. Methods: Staphylococcus aureus and Pseudomonas aeruginosa in vitro biofilm models were developed. The putative antibiotic enhancers N-acetylcysteine, acetylsalicylic acid, sodium salicylate, recombinant human deoxyribonuclease I, dispersin B, hydrogen peroxide and Johnson's Baby Shampoo (JBS) were tested for their anti-biofilm activity alone and their ability to enhance the activity of antibiotics for 7 or 14 days, against 5 day old biofilms. The antibiotic enhancers were paired with rifampicin and clindamycin against S. aureus and gentamicin and ciprofloxacin against P. aeruginosa. Isolates from biofilms that were not eradicated were tested for antibiotic resistance. Results: Antibiotic levels 10× MIC and 100× MIC significantly reduced biofilm, but did not consistently eradicate it. Antibiotics at 100× MIC with 10% JBS for 14 days was the only treatment to eradicate both staphylococcal and pseudomonal biofilms. Recombinant human deoxyribonuclease I significantly reduced staphylococcal biofilm. Emergence of resistance of surviving isolates was minimal and was often associated with the small colony variant phenotype. Conclusions: JBS enhanced the activity of antibiotics and several other promising anti-biofilm agents were identified. Antibiotics with 10% JBS eradicated biofilms produced by both organisms. Such combinations might be useful in local treatment of localized biofilm infections.

Hearing aids for otitis media with effusion: Do children use them?

INTRODUCTION: ENT surgeons may refer children with otitis media with effusion (OME) to audiology for consideration of hearing aids. They are an option for the treatment of OME, but are only effective if the child actually wears them. Our study investigated what proportion of children referred for hearing aids actually receive them, and whether children use them. METHOD: Retrospective study of children referred to audiology from November 2013 to August 2014, including 70 children referred by ENT for hearing aids for OME, plus a further 5 children with OME given hearing aids through direct access audiology service. RESULTS: During the study period, there were 202 referrals of children to audiology, of which 70 (34.7%) were for consideration of hearing aids for OME. Of these 70 referred children, 37 (52.9%) were not fitted with hearing aids due to normal audiometry (23), asymptomatic mild hearing loss (7), nonattendance (3), clinical decision to just monitor hearing (1), parental decline (2), and unrecorded reason (1). A total of 38 children (including direct access patients) were fitted with hearing aids for OME. Majority (36/38) of children issued aids used them, 16 all day, 7 only at school, 1 only at home, 3 only when needed, and 9 used them for an unspecified duration; 1 child's use of hearing aids was unrecorded, and 1 child refused to use it. 21 were fitted bilaterally and 17 unilaterally. 37 were behind the ear aids and 1 a BAHA softband. CONCLUSIONS: A third of referrals to paediatric audiology by ENT are for consideration of hearing aids for OME. Only about half of children referred to audiology for hearing aids for OME actually receive them, as by the time they see audiology the hearing loss has frequently resolved or is asymptomatic so that aiding is unwarranted. Once fitted, they appear to be well accepted. Hearing aids have fair utilization in children fitted with them for OME.

Which outcome measures are reported by clinical trials investigating OME treatment? A case for standardised reporting.

INTRODUCTION: Many different OME treatment trials have been published using different outcomes measures to evaluate the success of particular interventions. We set out to identify the variation in reporting of outcome measures in OME trials that exists at present. This has been achieved by reviewing published trials to determine which outcome measures have been reported. METHOD: The literature review was carried out using PUBMED database (1980 to 2013). Data were collected on the treatment outcomes reported, with particular focus on the methods of assessment and the number of treatment outcomes used in each study. RESULTS: The 171 studies identified used 12 broad treatment outcome measures. The most common outcome measure was OME resolution (48%) followed by hearing level (36%). Only 95 studies used a single outcome measure, with 76 studies using between 2 and 4 outcome measures. The method of assessment varied between studies that used the same treatment outcome measures. CONCLUSION: OME treatment trials report a wide range of measures and comparison across studies is thus difficult. Establishing a core set of outcome measures to be reported by all trials in the future could be useful, and would allow comprehensive comparison of different studies and minimise potential for reporting bias.

Day-case adenotonsillectomy for sleep apnoea in children?

OBJECTIVES: Many clinicians are concerned about possible airway or respiratory complications following adenotonsillectomy for sleep related breathing disorder (SRBD), and routinely admit such patients for overnight monitoring. However, published guidelines suggest this is unnecessary in some cases. This study firstly aimed to establish current UK practice, and secondly to investigate whether children with mild/moderate SRBD experience respiratory problems during the first post-operative night. METHODS: To establish current UK practice, we carried out a telephone survey asking if the procedure was carried out as a day-case, and admission criteria. For the second aim, a prospective study of children admitted following adenotonsillectomy for mild/moderate SRBD was carried out to investigate occurrence of respiratory complications on first post-operative night. RESULTS: Forty-two UK ENT doctors responded to the telephone survey, 50% routinely admitted patients having adenotonsillectomy for SRBD. Discharge criteria included stable observations and eating and drinking (14 hospitals), no bleeding (1), stable oxygen saturations (1) and age above 5 years (1); four had no specific criteria. Of 51 children admitted following adenotonsillectomy for mild/moderate SRBD, 11 (21.6%) experienced oxygen desaturations overnight. Of these, nine were under 4 years old, and two older children had asthma. Irrespective of comorbidities, 9/27 (33.2%) children under 4 years old experienced desaturations. The only children aged more than 4 years that had desaturations were ones that had additional comorbidities. CONCLUSION: Half of surveyed doctors admit all children following surgery for SRBD. The number of admissions could be reduced, because same-day discharge for otherwise-healthy children over 4 years old having adenotonsillectomy for mild/moderate SRBD appears to be safe.

Do orally administered antibiotics reach concentrations in the middle ear sufficient to eradicate planktonic and biofilm bacteria? A review.

INTRODUCTION: Infectious conditions of the middle ear are a common and significant cause of morbidity and mortality worldwide. Systemic antibiotics are frequently used, but their effectiveness will depend on whether an adequate antibiotic concentration is achieved in the middle ear; this is especially important in biofilm infections such as otitis media with effusion (OME), where high antibiotic concentrations are typically required for effective treatment. OBJECTIVE: This review examines what antibiotic levels can be reached in the middle ear with oral administration, as a means of guiding rational antibiotic choice in the clinic and future research, and to determine whether levels high enough for biofilm eradication are reached. METHODS: A literature search of studies measuring levels of antibiotics in the plasma and in the middle ear after oral administration was conducted. These levels were compared to the minimum inhibitory concentrations (MIC) provided by the European Committee for Antimicrobial Susceptibility Testing (EUCAST) to determine if antibiotic doses were reaching sufficient levels to inhibit planktonic bacteria. The middle ear concentrations were then calculated as a multiple of the MIC to determine if the concentrations were reaching biofilm eradication concentrations (typically up to 1000×MIC). RESULTS: The highest antibiotic levels against Staphylococcus aureus reach 8.3×MIC, against Moraxella catarrhalis 33.2×MIC, against Haemophilus influenzae 31.2×MIC, and against Streptococcus pneumoniae 46.2×MIC. The macrolide antibiotics reach higher levels in the middle ear than in plasma. CONCLUSIONS: Orally administered antibiotics reach levels above the MIC in the middle ear. However, they do not reach levels that would be likely to eradicate biofilms.

Laryngotracheal stenosis and airway surgery--an outcomes based approach.

OBJECTIVES: To review the outcomes of endoscopic, open or a combination of both surgical modalities for laryngotracheal stenosis and establish which factors influence results. METHODS: Records of all children undergoing laryngotracheal procedures (excluding laryngomalacia and aspirated foreign bodies) by the Department of Otolaryngology at The Children's Hospital at Westmead between January 2003 and November 2011 were reviewed. Specific data on population, intervention, covariates and outcomes were recorded and analysed. RESULTS: A total of 104 patients undergoing 277 procedures were included. 211 (76%) of the procedures were endoscopic, remaining 66 (24%) open. Patients undergoing open surgery were more likely to have significant co-morbidity, prior intubation, require ICU admission or tracheostomy and have a longer hospital stay. 57 (54.8%) patients were successfully treated with a single procedure (48 endoscopic and 9 open). Of the endoscopic patients requiring further surgery, 16 were managed with multiple endoscopic procedures, whilst 12 underwent subsequent open procedures. Open surgery was performed on 66 patients, 63.6% (42/66) of all open procedures required further endoscopic intervention and 45.2% (19/42) of these avoided further open surgery. CONCLUSIONS: Both open and endoscopic surgery have a role in laryngotracheal stenosis, and many patients benefit from a combination of both. Ultimately the decision depends on experience of the treating team, social considerations, and institutional capabilities. A multi-centre prospective data collection would be a useful tool to further investigate optimal management approach.

Acute airway obstruction by Ascaris lumbricoides in a 14-month-old boy.

We describe the case of a 14-month-old child with airway obstruction caused by a mature Ascaris lumbricoides worm. The child had been admitted to the paediatric intensive care unit due to overwhelming sepsis, and during the course of his illness developed acute airway obstruction that resolved once the worm was removed from the airway. The Ascaris life-cycle is detailed, and a literature review of patients with airway obstruction due to Ascaris worms is presented.

Update on otitis media - prevention and treatment.

Acute otitis media and otitis media with effusion are common childhood disorders, a source of significant morbidity, and a leading cause of antibiotic prescription in primary health care. Although effective treatments are available, some shortcomings remain, and thus better treatments would be welcome. Recent discoveries within the field of otitis media research relating to its etiology and pathogenesis have led to further investigation aimed at developing novel treatments. This article provides a review of the latest evidence relating to the understanding of acute otitis media and otitis media with effusion, current treatment strategies, their limitations, new areas of research, and novel strategies for treatment.

National Institute for Clinical Excellence guidelines on the surgical management of otitis media with effusion: are they being followed and have they changed practice?

OBJECTIVE: UK National Institute of Clinical Excellence (NICE) guidelines on surgical management of otitis media with effusion (OME) in children call for an initial 3 month period of observation, with ventilation tube (VT) insertion considered for children with persistent bilateral OME with a hearing level in better ear of 25-30 dB HL or worse ("core criteria"), or for children not meeting those audiologic criteria but when OME has significant impact on developmental, social or educational status (exceptional circumstances). We aimed to establish whether guidelines are followed and whether they have changed clinical practice. METHODS: Retrospective case-notes review in five different centres, analysing practice in accordance with guidelines in all children having first VT insertion before (July-December 06) and after (July-December 08) guidelines introduction. RESULTS: Records of 319 children were studied, 173 before and 146 after guidelines introduction. There were no significant differences in practice according to guidelines before and after their introduction with respect to having 2 audiograms 3 months apart (57.8 vs. 54.8%), OME persisting at least 3 months (94.8 vs. 92.5%), or fulfilment of the 25 dB audiometric criteria (68.2 vs. 61.0%). Practice in accordance with the core criteria fell significantly from 43.9 to 32.2% (Chi squared p=0.032). However, if the exceptional cases were included there was no significant difference (85.5 vs. 87.0%), as the proportion of exceptional cases rose from 48.3 to 62.2% (Chi squared p=0.021). CONCLUSION: This study shows that 87.0% of children have VTs inserted in accordance with NICE guidelines providing exceptional cases are included, but only 32.2% comply with the core criteria. A significant number have surgery due to the invoking of exceptional criteria, suggesting that clinicians are personalising the treatment to each individual child.

Biofilm eradication with biodegradable modified-release antibiotic pellets: a potential treatment for glue ear.

OBJECTIVE: To develop a biodegradable, modified-release antibiotic pellet capable of eradicating biofilms as a potential novel treatment for biofilm infections. DESIGN: Pellets containing poly(DL-lactic-co-glycolic acid) microparticles, rifampin and clindamycin hydrochloride (3.5%, 7%, or 28% antibiotic by weight), and carrier gel (carboxymethylcellulose or poloxamer 407) were tested in vitro. Drug release was assessed using serial plate transfer testing and high-performance liquid chromatography, and pellets were tested against biofilms in an in vitro model of Staphylococcus aureus biofilm grown on silicone. RESULTS: Serial plate transfer testing demonstrated continuing bacterial inhibition for up to 21 days for all pellets studied. High-performance liquid chromatography showed high levels of drug release for 2 to 4 days, with greatly reduced levels subsequently; continued measurable clindamycin (but not rifampin) release for up to 21 days was achieved. Pellets made with poloxamer released higher drug levels for a longer period. Irrespective of the carrier gel used, pellets containing 7% and 28% (but not 3.5%) antibiotic eradicated biofilms successfully. CONCLUSIONS: Antibiotic pellets can release antibiotics for up to 21 days and are able to eradicate biofilms in an in vitro model. Use of modified-release antibiotic formulations in the middle ear as a treatment for biofilms appears to be a potentially promising new therapy for otitis media with effusion.

Vocal cord reconstruction to treat aspiration caused by a post-intubation posterior glottic furrow.

OBJECTIVE: To present the case of a premature child with a furrow in the posterior vocal cord as a result of prolonged intubation, with symptoms of aspiration and poor voice, treated with a novel method of vocal cord reconstruction. METHODS: The vocal cord was reconstructed endoscopically by freeing up the edge of cord remnant and suturing this to a flap of inter-arytenoid mucosa to create a new cord. RESULTS: The resulting neo-cord was able to achieve full glottic closure with resolution of aspiration, and this was also accompanied by improvement in voice quality. CONCLUSION: The described vocal cord reconstruction method proved to be a useful treatment for aspiration and poor voice caused by a post-intubation vocal cord furrow.

Neonatal stridor.

Neonatal stridor is an important condition, in many cases implying an impending disaster with a very compromised airway. It is a sign that has to be considered with the rest of the history and examination findings, and appropriate investigations should then be undertaken to confirm the source of the noise. Neonates with stridor should be managed in a multidisciplinary setting, by clinicians familiar with the intricate physiology of these children, and with access to the multitude of medical and surgical investigative and therapeutic options required to provide first-rate care.