Quinolone Ear Drops and Achilles Tendon Rupture.

BACKGROUND: Delayed eardrum healing has been observed in the ear opposite to the ear treated with otic quinolones (OQ) in rats. Case reports describe tendinopathies after OQ treatment, suggesting adverse systemic effects. METHODS: We studied patients aged 19 to 64 years with diagnosis of otitis externa or media in private insurance between 2005 and 2015. We compared OQ treatment against otic neomycin, oral amoxicillin, or azithromycin. Outcomes included Achilles tendon rupture (ATR), Achilles tendinitis (AT), and all-type tendon rupture (ATTR). We applied an active comparator, new-user design with 1-year look-back and ceased follow-up at initiation of systemic steroids or oral quinolones, external injury, hospitalization, and after 35 days. We used trimmed stabilized inverse probability of treatment weights to balance comparison groups in a survival framework. Negative outcomes (clavicle fractures or sports injuries) were examined to rule out differences from varied physical activity (unmeasured confounding). RESULTS: We examined 1 501 009 treated otitis episodes. Hazard ratios (HR) for OQ exposure associated with ATR were 4.49 (95% confidence interval [CI], 1.83-11.02), AT 1.04 (95% CI, 0.73-1.50), and ATTR 1.71 (95% CI, 1.21-2.41). Weighted risk differences (RD) per 100 000 episodes for OQ exposure were ATR 7.80 (95% CI, 0.72-14.89), AT 1.01 (95% CI, -12.80 to 14.81), and ATTR 18.57 (95% CI, 3.60-33.53). Corresponding HRs for clavicle fractures and sports injuries were HR,1.71 (95% CI, 0.55-5.27) and HR,1.45 (95% CI, 0.64-3.30), suggesting limited residual confounding. CONCLUSIONS: OQ exposure may lead to systemic consequences. Clinicians should consider this potential risk and counsel patients accordingly. Risk factors and mechanisms for this rare, adverse effect deserve further evaluation. Mechanistic and other clinical studies are warranted to corroborate this finding.

Risk for Tympanic Membrane Perforation After Quinolone Ear Drops for Acute Otitis Externa.

BACKGROUND: This study examined whether the use of quinolone ear drops increased the risk of perforation with intact tympanic membranes and acute otitis externa (AOE). METHODS: This was a retrospective cohort study using Medicaid clinical encounter and pharmacy billing records from 1999 through 2010. Children and adults had to have 24 months continuous enrollment in Medicaid prior to the first antibiotic ear drop dispensing (index date), and they had to maintain their enrollment for at least 18 months thereafter. Included ear drops were ofloxacin, ciprofloxacin plus hydrocortisone, ciprofloxacin plus dexamethasone, and neomycin plus hydrocortisone. Tympanic membrane perforation (TMP) was identified as 2 inpatient or outpatient encounters associated with TMP diagnosis at least 30 days apart. A Cox regression model adjusting for patient demographics, calendar year, and the number of ear drop prescriptions was used to compare TMP risk between quinolone and neomycin-exposed patients. RESULTS: A total of 94 333 patients entered the study cohort. Use of quinolone ear drops was associated with increased risk for TMP compared with neomycin plus hydrocortisone, with an adjusted hazard ratio of 2.26 (95% confidence interval [CI], 1.34-3.83). Adjusted hazard ratios were 2.53 (95% CI, 1.27-5.05) for ofloxacin, 2.24 (95% CI, 1.03-4.85) for ciprofloxacin plus hydrocortisone, and 2.30 (95% CI, 1.09-4.87) for ciprofloxacin plus dexamethasone. Sensitivity analyses were consistent with the primary analysis. CONCLUSIONS: Use of quinolone ear drops to treat AOE is associated with a previously unreported increased risk of developing TMPs. Selection of otic preparations to treat self-limited conditions with intact tympanic membranes should consider TMP risk.

Prophylactic antibiotics in head and neck free flap surgery: A novel protocol put to the test.

OBJECTIVE: Recent evidence supports the use of ampicillin-sulbactam as a favored choice for antibiotic prophylaxis following head and neck free flap reconstructive surgery. However, there is a paucity of evidence guiding the optimal duration of antibiotic prophylaxis. The aim of this study is to compare the infection rates of short courses of ampicillin-sulbactam versus extended courses of various antibiotics in head and neck free flap reconstructive surgery. METHODS: This is a retrospective cohort study conducted from 2012 to 2017 at a tertiary academic center on 266 consecutive patients undergoing head and neck surgery with free flap reconstruction. The primary outcome measure was the rate of any infection within 30 days of surgery. RESULTS: There were 149 patients who received antibiotic prophylaxis for an extended duration of at least seven days. 117 patients received a short course of antibiotics defined as 24 h for non-radiated patients and 72 h for radiated patients. Postoperative infections occurred in 45.9% of patients, of which 92.6% occurred at surgical sites. There was no significant difference in terms of postoperative infection rate between patients receiving an extended duration of antibiotics versus a short duration (p = 0.80). This held true for subgroups of surgical site infections (p = 0.38) and distant infections (p = 0.59 for pneumonia and p = 0.76 for UTI). Risk factors for infections were identified as hypothyroidism (p = 0.047) and clean contaminated wound classification (p = 0.0002). CONCLUSION: Shorter duration of ampicillin-sulbactam prophylaxis in free flap reconstruction of head and neck defects does not negatively affect postoperative infection rates. LEVEL OF EVIDENCE: Level 2b.

Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Noise-induced hearing loss is a leading cause of occupational and recreational injury and disease, and a major determinant of age-related hearing loss. No therapeutic agent has been approved for the prevention or treatment of this disorder. In animal models, glutathione peroxidase 1 (GPx1) activity is reduced after acute noise exposure. Ebselen, a novel GPx1 mimic, has been shown to reduce both temporary and permanent noise-induced hearing loss in preclinical studies. We assessed the safety and efficacy of ebselen for the prevention of noise-induced hearing loss in young adults in a phase 2 clinical trial. METHODS: In this single-centre, randomised, double-blind, placebo-controlled phase 2 trial, healthy adults aged 18-31 years were randomly assigned (1:1:1:1) at the University of Florida (Gainsville, FL, USA) to receive ebselen 200 mg, 400 mg, or 600 mg, or placebo orally twice daily for 4 days, beginning 2 days before a calibrated sound challenge (4 h of pre-recorded music delivered by insert earphones). Randomisation was done with an allocation sequence generated by an independent third party. The primary outcome was mean temporary threshold shift (TTS) at 4 kHz measured 15 min after the calibrated sound challenge by pure tone audiometry; a reduction of 50% in an ebselen dose group compared with the placebo group was judged to be clinically relevant. All participants who received the calibrated sound challenge and at least one dose of study drug were included in the efficacy analysis. All randomly assigned patients were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT01444846. FINDINGS: Between Jan 11, 2013, and March 24, 2014, 83 participants were enrolled and randomly assigned to receive ebselen 200 mg (n=22), 400 mg (n=20), or 600 mg (n=21), or placebo (n=20). Two participants in the 200 mg ebselen group were discontinued from the study before the calibrated sound challenge because they no longer met the inclusion criteria; these participants were excluded from the efficacy analysis. Mean TTS at 4 kHz was 1·32 dB (SE 0·91) in the 400 mg ebselen group compared with 4·07 dB (0·90) in the placebo group, representing a significant reduction of 68% (difference -2·75 dB, 95% CI -4·54 to -0·97; p=0·0025). Compared with placebo, TTS at 4 kHz was non-significantly reduced by 21% in the 200 mg ebselen group (3·23 dB [SE 0·91] vs 4·07 dB [0·90] in the placebo group; difference -0·84 dB, 95% CI -2·63 to 0·94; p=0·3542) and by 7% in the 600 mg ebselen group (3·81 dB [0·90] vs 4·07 dB [0·90] in the placebo group; difference -0·27, 95% CI -2·03 to 1·50; p=0·7659). Ebselen treatment was well tolerated across all doses and no significant differences were seen in any haematological, serum chemistry, or radiological assessments between the ebselen groups and the placebo group. INTERPRETATION: Treatment with ebselen was safe and effective at a dose of 400 mg twice daily in preventing a noise-induced TTS. These data lend support to a role of GPx1 activity in acute noise-induced hearing loss. FUNDING: Sound Pharmaceuticals.

Risk of sudden sensorineural hearing loss in adults using phosphodiesterase type 5 inhibitors: Population-based cohort study.

PURPOSE: The objective of the study was to determine the risk of sudden sensorineural hearing loss (SNHL) associated with use of phosphodiesterase type 5 (PDE5) inhibitors. METHODS: We conducted a retrospective cohort study in the MarketScan Commercial Claims and Encounters Database including adult men who initiated a PDE5 inhibitor (n = 377,722) and 1,957,233 nonusers between 1998 and 2007. Periods of drug exposure were assessed on a weekly basis based on pharmacy billing records, assuming use of 1 dose per week (current use). Incident sudden SNHL was defined based on inpatient or outpatient visits with International Classification of Diseases, Ninth Revision, Clinical Modification codes 389.1x, 389.2x, or 388.2 plus ≥2 procedure codes for audiometric hearing testing within ±30 days of sudden SNHL diagnosis. We used age- and propensity score-adjusted Cox proportional hazards model to evaluate the risk of sudden SNHL during periods of current or recent use compared with that of nonuse. We conducted sensitivity analyses by varying the assumed drug utilization frequency and sudden SNHL case definition. RESULTS: We evaluated 1233 sudden SNHL cases, resulting in an incidence of 4.35, 5.58, and 2.38 per 10,000 person-years for current, recent, and nonuse of PDE5 inhibitors, respectively. Compared with nonuse, the adjusted hazard ratio was 1.25 (1.01-1.55) for current use with a risk difference of 1.97 (1.12-2.82) per 10,000 person-years. For recent use, the adjusted hazard ratio was 1.60 (1.33-1.94) and risk difference was 3.19 (2.24-4.14). Estimates were consistent across the sensitivity analyses. CONCLUSIONS: Use of PDE5 inhibitors is associated with a small but significantly increased risk of sudden SNHL.

Quinolone Ear Drops After Tympanostomy Tubes and the Risk of Eardrum Perforation: A Retrospective Cohort Study.

Background: This study investigated whether quinolone ear drops, with or without corticosteroids, increase the risk of perforation requiring tympanoplasty following tympanostomy tube (TT) placement in children. Methods: This was a retrospective cohort study using Medicaid encounter and pharmacy billing data from 29 US states between 1999 and 2006. Children <18 years old without predisposing factors for perforation during a 6-month look-back period entered the cohort after TT placement and first dispensing of antibiotic ear drops. Included ear drops were quinolones (ofloxacin, ciprofloxacin plus hydrocortisone, or ciprofloxacin plus dexamethasone) or neomycin plus hydrocortisone. Children were followed until end of 2006, end of Medicaid enrollment, or occurrence of study outcome. A Cox regression model, adjusted for age, sex, race/ethnicity, initial TT indication, reinsertion of TT, adenoidectomy, and number of ear drop prescriptions was used to compare the rate of perforation between quinolone and neomycin plus hydrocortisone ear drop-exposed children. Perforation was defined by its diagnosis code followed by a tympanoplasty code. Results: A total of 96595 children entered the study cohort. Patients exposed to quinolone ear drops had a higher risk of perforation, with an adjusted hazard ratio of 1.61 (95% confidence interval [CI], 1.15-2.26). The adjusted hazard ratios were 1.49 (95% CI, 1.05-2.09) for ofloxacin, 1.94 (95% CI, 1.32-2.85) for ciprofloxacin plus hydrocortisone, and 2.00 (95% CI, 1.18-3.41) for ciprofloxacin plus dexamethasone. Conclusions: Exposure of children with TT to quinolone ear drops is associated with increased risk of perforations requiring tympanoplasty, which appears to be further exaggerated by corticosteroids. Clinicians should consider the risk of perforation and counsel patients/families accordingly when prescribing quinolone ear drops.

Randomized Clinical Trial of a Sustained-Exposure Ciprofloxacin for Intratympanic Injection During Tympanostomy Tube Surgery.

OBJECTIVE: This exploratory clinical trial evaluated the safety and clinical activity of a novel, sustained-exposure formulation of ciprofloxacin microparticulates in poloxamer (OTO-201) administered during tympanostomy tube placement in children. METHODS: Double-blind, randomized, prospective, placebo- and sham-controlled, multicenter Phase 1b trial in children (6 months to 12 years) with bilateral middle ear effusion requiring tympanostomy tube placement. Patients were randomized to intraoperative OTO-201 (4 mg or 12 mg), placebo, or sham (2:1:1 ratio). RESULTS: Eighty-three patients (52 male/31 female; mean age, 2.80 years) were followed for safety (otoscopic exams, cultures, audiometry, and tympanometry) and clinical activity, defined as treatment failure (physician-documented otorrhea and/or otic or systemic antibiotic use ≥3 days post surgery). At baseline, 14.3% to 36.8% of children showed positive cultures of middle ear effusion samples in at least 1 ear. Through day 15, treatment failures accounted for 14.3%, 15.8%, 45.5%, and 42.9% of patients (OTO-201 4 mg, OTO-201 12 mg, placebo, and sham, respectively); treatment failure reductions for OTO-201 doses were significant compared to pooled control (P values = .023 and .043, respectively). Observed OTO-201 safety profile was indistinguishable from placebo or sham. CONCLUSIONS: Results of this first clinical trial suggest that OTO-201 was well tolerated and shows preliminary clinical activity in treating tympanostomy tube otorrhea.

Potential Toxicity of Boric Acid Powder Otic Insufflation.

OBJECTIVE: Boric acid (BA) powder is commonly used to treat otologic conditions, such as mastoid bowl inflammation and chronic otitis externa. Exposure to 50 mg per day is thought to cause systemic toxicity in humans. Inflamed skin and mucosal surfaces readily absorb BA. The aim of this study was to measure the doses of BA commonly used in clinical otology and alert the otolaryngology community to BA's underappreciated potential source of systemic toxicity. STUDY DESIGN: Prospective, controlled. SETTING: Laboratory. METHODS: BA dose administration was measured by weighing the BA generated by common insufflators: accordion bellows, House-Sheehy insufflator, DeVilbiss insufflator, and pneumatic powder blower. Manual insufflation was performed with 3 compressions of the bulb. The pneumatic blower was sprayed for 1 second. Measurements were repeated 10 times. RESULTS: The DeVilbiss insufflator delivered the lowest mean BA dose, 6.1 mg (SD 3.4, range 2.1-13.7), followed by the House-Sheehy 8.9 mg (SD 8.4, range 1.6-27.8), the pneumatic blower 192.8 mg (SD 38.3, range 150.0-261.7), and the accordion, 284.1 mg (SD 215.0, range 37.8-730.8). CONCLUSION: BA dose delivery is highly variable by insufflator type, and doses thought to cause systemic toxicity are commonly generated. Awareness of and further investigation into the potential toxicity of otic administration of BA seems warranted.

Antibiotic treatment to prevent pediatric acute otitis media infectious complications: A meta-analysis.

BACKGROUND: Most US children with acute otitis media [AOM] receive prompt antibiotic treatment, though guidelines encourage watchful waiting. Previous systematic reviews of antibiotics versus watchful waiting have focused on symptom resolution and RCTs, limiting the assessment of serious, rare complications. We sought to evaluate these complications by including observational studies. METHODS: RCTs and observational studies that compared antibiotics to placebo or watchful waiting for pediatric clinician diagnosed AOM were identified [PubMed/MEDLINE, Embase, Cochrane Database of Systematic Reviews, Central Register of Controlled Trials, and Web of Science] and reviewed for meta-analysis. Two reviewers independently extracted study characteristics, patient characteristics, and outcomes. We assessed publication bias, study bias with ROBINS-1 and RoB-2 and used random-effects models to assess treatment effects. RESULTS: 24 studies were included. Antibiotics decreased the risk of acute mastoiditis [incidence 0.02%, RR 0.48, 95% CI 0.40-0.59; NNT 5,368]. This protective effect may be underestimated because of misclassification of non-suppurative conditions as AOM. Intracranial complications remained too rare to assess. Antibiotics markedly increased the risk of adverse effects [incidence 10.5%, RR 1.49, 1.27-1.73; NNH 23]. Studies used non-specific criteria for acute mastoiditis, potentially underestimating treatment effects. CONCLUSIONS: Prompt antibiotic therapy reduces the risk for some AOM complications. The NNT to prevent serious, rare complications is high, while the NNH is relatively low. Large-scale population-based observational studies using real-world datasets with validated measures of severe complications are needed to improve understanding of risk factors for serious AOM complications, facilitate more selective antibiotic therapy, and optimize individual outcomes and public health.

Microbiome and Otic Quinolone Levels Following Tympanoplasty Assessed by Gelatin Sponge Analysis.

OBJECTIVE: To determine if absorbable gelatin sponge (AGS) can be used to assess the posttympanoplasty microbiome and otic antibiotic exposure. STUDY DESIGN: Prospective. SETTING: Tertiary hospital. METHODS: Patients undergoing tympanoplasty were prospectively enrolled. Intraoperatively, AGS was applied to the medial ear canal/tympanic membrane (TM) for 1 minute after canal incision, then saved for analysis. Ear canals were packed with AGS at the end of surgery. Otic ofloxacin was administered until the first postoperative visit, when AGS was collected. Microbial presence was assessed by culture. Ofloxacin levels were assessed by liquid-chromatography mass-spectrometry. RESULTS: Fifty-three patients were included. AGS was collected in 92.9% of patients seen within 21 days compared to 70.8% of those seen at 22 to 35 days. At surgery, AGS yielded bacteria and fungi in 81% and 11%, respectively, including Staphylococcus species (55%) and Pseudomonas species (25%). Postoperatively, AGS yielded bacteria in 71% and fungi in 21% at the meatus, (staphylococci 57% and pseudomonas 25%). TM samples yielded bacteria in 69%, fungi in 6%, staphylococci in 53%, and pseudomonas in 19%. Ofloxacin concentration at the meatus was 248 µg/mL (95% confidence interval [CI]: 119-377) and at the TM was 126 µg/mL (95% CI: 58-194). Ofloxacin-resistant colonies were found in 75% of patients. CONCLUSION: Analysis of AGS is a viable technique for noninvasively studying healing metrics posttympanoplasty, including the microbiome and otic antibiotic exposure. Despite exposure to a high concentration of quinolones, the tympanoplasty wound is far from sterile, which may impact healing outcomes.

Development of a novel ex vivo porcine skin explant model for the assessment of mature bacterial biofilms.

Bacterial biofilms have been proposed to be a major factor contributing to the failure of chronic wounds to heal because of their increased tolerance to antimicrobial agents and the prolonged inflammation they cause. Phenotypic characteristics of bacterial biofilms vary depending on the substratum to which they attach, the nutritional environment, and the microorganisms within the biofilm community. To develop an ex vivo biofilm model that more closely mimics biofilms in chronic skin wounds, we developed an optimal procedure to grow mature biofilms on a central partial-thickness wound in 12-mm porcine skin explants. Chlorine gas produced optimal sterilization of explants while preserving histological properties of the epidermis and dermis. Pseudomonas aeruginosa and Staphylococcus aureus developed mature biofilms after 3 days that had dramatically increased tolerance to gentamicin and oxacillin (∼100× and 8,000× minimal inhibitory concentration, respectively) and to sodium hypochlorite (0.6% active chlorine). Scanning electron microscopy and confocal microscopy verified extensive exopolymeric biofilm structures on the explants. Despite a significant delay, a ΔlasI quorum-sensing mutant of P. aeruginosa developed biofilm as antibiotic-tolerant as wild-type after 3 days. This ex vivo model simulates growth of biofilms on skin wounds and provides an accurate model to assess effects of antimicrobial agents on mature biofilms.

Cytotoxicity of Tetracyclines in Human Tympanic Membrane Fibroblasts.

HYPOTHESIS: Tetracyclines are less cytotoxic to tympanic membrane (TM) fibroblasts than quinolones. BACKGROUND: Use of quinolone ear drops after tympanostomy tube placement and for acute otitis externa has been linked to an increased risk of TM perforation. This has been verified in animal models. Cell culture studies have shown quinolones to be highly toxic to TM fibroblasts. Tetracyclines are a potential alternative to quinolones as they have been used to treat acute otitis externa and are thought to be nontoxic to the inner ear. We aimed to determine if tetracyclines are cytotoxic to TM fibroblasts. METHODS: Human TM fibroblasts were treated with 1:10 dilutions of ofloxacin 0.3%, ciprofloxacin 0.3%, doxycycline 0.3 and 0.5%, minocycline 0.3 and 0.5%, tetracycline 0.3 and 0.5%, or dilute HCl (control), twice within 24 hours or four times within 48 hours. After 2 hours of treatment, cells were returned to growth media. Cells were observed with phase-contrast microscopy until cytotoxicity was measured. RESULTS: Fibroblasts had lower survival with ciprofloxacin 0.3% and doxycycline 0.5% treatment compared with the control after 24 and 48 hours (all p < 0.0001). Fibroblasts treated with minocycline 0.5% had increased cell survival after 24 hours. Minocycline 0.3 and 0.5% showed increased TM fibroblast survival after 48 hours (all p < 0.0001). Phase-contrast images mirrored the cytotoxicity findings. CONCLUSIONS: Tetracyclines are less toxic to cultured TM fibroblasts than ciprofloxacin. Fibroblast tetracycline toxicity is drug and dose specific. Minocycline shows the most promise for possible otic applications in which fibroblast toxicity is a concern.

Tympanoplasty Healing Outcomes With Use of Postoperative Otic Quinolones.

OBJECTIVE: Tympanoplasty usually results in tympanic membrane perforation (TMP) closure, but healing may be suboptimal (e.g., excess scarring). Factors that have been linked to impaired TM healing have become widely adopted (especially, postoperative use of quinolone ear drops). The aim of this study is to assess the frequency of suboptimal tympanoplasty healing with the use of otic quinolones postoperatively. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care facility. PATIENTS: One hundred patients undergoing tympanoplasty for TMP. INTERVENTIONS: Tympanoplasty +/- canalplasty. MAIN OUTCOME MEASURES: Healing complications (e.g., granulation tissue, TMP, myringitis, bone exposure, lateralization, anterior blunting, medial canal fibrosis, and canal stenosis) and hearing loss. METHODS: Charts were reviewed for postoperative healing issues and hearing outcomes at 1 to 2 years postoperatively. RESULTS: TMP closure was found in 93.2%, but 34.2% had healing issues at 1 to 2 years postoperatively, with 20.6% having adverse healing outcomes (perforation (6.9%), granulation tissue (6.9%), medial fibrosis (4.1%), and myringitis, bone exposure, and webbing (all 1.4%). Another 13.7% had notable postoperative issues, such as protracted otorrhea (11.0%), otitis externa (9.6%), otitis media (1.4%), and atelectasis (2.7%). No medical, surgical, or patient factors impacted outcomes. Average air-bone gap at 1 to 2 years did not differ between patients with and without healing issues and patients with other postoperative issues ( p = 0.5). CONCLUSIONS: Suboptimal healing is common after tympanoplasty. There may be significant opportunity to improve post-tympanoplasty healing beyond improving the TMP closure rate.

Digital music exposure reliably induces temporary threshold shift in normal-hearing human subjects.

OBJECTIVES: One of the challenges for evaluating new otoprotective agents for potential benefit in human populations is the availability of an established clinical paradigm with real-world relevance. These studies were explicitly designed to develop a real-world digital music exposure that reliably induces temporary threshold shift (TTS) in normal-hearing human subjects. DESIGN: Thirty-three subjects participated in studies that measured effects of digital music player use on hearing. Subjects selected either rock or pop music, which was then presented at 93 to 95 (n = 10), 98 to 100 (n = 11), or 100 to 102 (n = 12) dBA in-ear exposure level for a period of 4 hr. Audiograms and distortion product otoacoustic emissions (DPOAEs) were measured before and after music exposure. Postmusic tests were initiated 15 min, 1 hr 15 min, 2 hr 15 min, and 3 hr 15 min after the exposure ended. Additional tests were conducted the following day and 1 week later. RESULTS: Changes in thresholds after the lowest-level exposure were difficult to distinguish from test-retest variability; however, TTS was reliably detected after higher levels of sound exposure. Changes in audiometric thresholds had a "notch" configuration, with the largest changes observed at 4 kHz (mean = 6.3 ± 3.9 dB; range = 0-14 dB). Recovery was largely complete within the first 4 hr postexposure, and all subjects showed complete recovery of both thresholds and DPOAE measures when tested 1 week postexposure. CONCLUSIONS: These data provide insight into the variability of TTS induced by music-player use in a healthy, normal-hearing, young adult population, with music playlist, level, and duration carefully controlled. These data confirm the likelihood of temporary changes in auditory function after digital music-player use. Such data are essential for the development of a human clinical trial protocol that provides a highly powered design for evaluating novel therapeutics in human clinical trials. Care must be taken to fully inform potential subjects in future TTS studies, including protective agent evaluations, that some noise exposures have resulted in neural degeneration in animal models, even when both audiometric thresholds and DPOAE levels returned to pre-exposure values.

Watchful Waiting for Acute Otitis Media.

BACKGROUND AND OBJECTIVES: Updated guidelines continue to support watchful waiting as an option for uncomplicated acute otitis media (AOM) and provide explicit diagnostic criteria. To determine treatment prevalence and associated determinants of watchful waiting for AOM in commercially insured pediatric patients. METHODS: This was a retrospective cohort study using IBM Marketscan Commercial Claims Databases (2005 to 2019) of patients 1 to 12 years old with AOM, without otitis-related complications within 6 months prior, with no tympanostomy tubes, and no other infections around index diagnosis of AOM. We examined monthly antibiotic treatment prevalence (defined as pharmacy dispensing within 3 days of AOM diagnosis) and used multivariable logistic regression models to examine determinants of watchful waiting. RESULTS: Among 2 176 617 AOM episodes, 77.8% were treated within 3 days. Whereas some clinical characteristics were moderate determinants for watchful waiting, clinician antibiotic prescribing volume and specialty were strong determinants. Low-volume antibiotic prescribers (≥80% of AOM episodes managed with watchful waiting) had 11.61 (95% confidence interval 10.66-12.64) higher odds of using watchful waiting for the index AOM episode than high-volume antibiotic prescribers (≥80% treated). Otolaryngologists were more likely to adopt watchful waiting (odds ratio 5.45, 95% CI 5.21-5.70) than pediatricians, whereas other specialties deferred more commonly to antibiotics. CONCLUSIONS: Adoption of watchful waiting for management of uncomplicated, nonrecurrent AOM was limited and stagnant across the study period and driven by clinician rather than patient factors. Future work should assess motivators for prescribing and evaluate patient outcomes among clinicians who generally prefer versus reject watchful waiting approaches to guide clinical decision-making.

Triangulation of pharmacoepidemiology and laboratory science to tackle otic quinolone safety.

BACKGROUND: The scientific method requires studies with high internal and external validity. Though both are necessary, they do not go hand-in-hand: The more controlled a study is to enhance internal validity, the less applicable to real-world clinical care, and vice versa. In the many instances where evidence from clinical trials is not available, scientific inference must rely on more extreme approaches on this spectrum, such as mechanistic (limited generalizability/strong bias control) and real-world evidence (RWE) studies (higher generalizability/lesser bias control). OBJECTIVES: Illustrate how triangulating mechanistic and RWE studies can enhance scientific inference by delivering the supporting evidence for both. METHODS: We describe our research on an unexpected and highly unlikely drug safety issue: the risk of tympanic membrane (TM) perforations resulting from otic quinolone therapy. Tightly controlled laboratory studies using cell culture and rodent models were complemented with pharmacoepidemiological studies of real-world data to translate mechanistic findings and corroborate RWE. RESULTS: We present a cascade of mechanistic and RWE studies investigating fibroblast cytotoxicity, delayed healing of perforated TMs, and spontaneous TM perforations after otic quinolone exposure, all suggesting local tissue toxicity. CONCLUSION: Triangulation of mechanistic and RWE studies allowed incremental progress toward robust evidence on otic quinolone toxicity.

Prospective clinical trial comparing outcome measures between Furlow and von Langenbeck Palatoplasties for UCLP.

The goal of this prospective randomized clinical trial was to compare 2 cohorts of standardized cleft patients with regard to functional speech outcome and the presence or absence of palatal fistulae. The 2 cohorts are randomized to undergo either a conventional von Langenbeck repair with intravelar velarplasty or the double-opposing Z-plasty Furlow procedure. A prospective 2 × 2 × 2 factorial clinical trial was used in which each subject was randomly assigned to 1 of 8 different groups: 1 of 2 different lip repairs (Spina vs. Millard), 1 of 2 different palatal repair (von Langenbeck vs. Furlow), and 1 of 2 different ages at time of palatal surgery (9-12 months vs. 15-18 months). All surgeries were performed by the same 4 surgeons. A cul-de-sac test of hypernasality and a mirror test of nasal air emission were selected as primary outcome measures for velopharyngeal function. Both a surgeon and speech pathologist examined patients for the presence of palatal fistulae. In this study, the Furlow double-opposing Z-palatoplasty resulted in significantly better velopharyngeal function for speech than the von Langenbeck procedure as determined by the perceptual cul-de-sac test of hypernasality. Fistula occurrence was significantly higher for the Furlow procedure than for the von Langenbeck. Fistulas were more likely to occur in patients with wider clefts and when relaxing incisions were not used.

Oral vs intratympanic corticosteroid therapy for idiopathic sudden sensorineural hearing loss: a randomized trial.

CONTEXT: Idiopathic sudden sensorineural hearing loss has been treated with oral corticosteroids for more than 30 years. Recently, many patients' symptoms have been managed with intratympanic steroid therapy. No satisfactory comparative effectiveness study to support this practice exists. OBJECTIVE: To compare the effectiveness of oral vs intratympanic steroid to treat sudden sensorineural hearing loss. DESIGN, SETTING, AND PATIENTS: Prospective, randomized, noninferiority trial involving 250 patients with unilateral sensorineural hearing loss presenting within 14 days of onset of 50 dB or higher of pure tone average (PTA) hearing threshold. The study was conducted from December 2004 through October 2009 at 16 academic community-based otology practices. Participants were followed up for 6 months. INTERVENTION: One hundred twenty-one patients received either 60 mg/d of oral prednisone for 14 days with a 5-day taper and 129 patients received 4 doses over 14 days of 40 mg/mL of methylprednisolone injected into the middle ear. MAIN OUTCOME MEASURES: Primary end point was change in hearing at 2 months after treatment. Noninferiority was defined as less than a 10-dB difference in hearing outcome between treatments. RESULTS: In the oral prednisone group, PTA improved by 30.7 dB compared with a 28.7-dB improvement in the intratympanic treatment group. Mean pure tone average at 2 months was 56.0 for the oral steroid treatment group and 57.6 dB for the intratympanic treatment group. Recovery of hearing on oral treatment at 2 months by intention-to-treat analysis was 2.0 dB greater than intratympanic treatment (95.21% upper confidence interval, 6.6 dB). Per-protocol analysis confirmed the intention-to-treat result. Thus, the hypothesis of inferiority of intratympanic methylprednisolone to oral prednisone for primary treatment of sudden sensorineural hearing loss was rejected. CONCLUSION: Among patients with idiopathic sudden sensorineural hearing loss, hearing level 2 months after treatment showed that intratympanic treatment was not inferior to oral prednisone treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00097448.

Otologic and audiologic outcomes with the Furlow and von Langenbeck with intravelar veloplasty palatoplasties in unilateral cleft lip and palate.

OBJECTIVE: Cleft palate increases the risk of chronic middle ear disease and hearing loss. The goal of this report was to determine which of two palate surgeries and which timing of palate surgery were associated with better otologic and audiologic outcomes in children with unilateral cleft lip and palate at 5 to 6 years of age. DESIGN: Subjects were randomly assigned to the von Langenbeck with intravelar veloplasty or Furlow palate repair, to palate surgery at 9 to 12 months or 15 to 18 months of age, and to the Spina or Millard lip repair. SETTING: Centralized, tertiary care craniofacial treatment center. PATIENTS: A total of 673 infants with unilateral cleft lip and palate. INTERVENTIONS: Palate and lip were repaired using established techniques. Serial otoscopic and audiometric evaluations were performed. MAIN OUTCOME MEASURES: Hearing and otoscopic findings at 5 to 6 years old. RESULTS: There were 370 children available for analysis. Hearing and need for tympanostomy tube placement did not differ by palatoplasty, age at palatoplasty, cheiloplasty, or surgeon. Risk of developing cholesteatoma or perforation was higher with Millard cheiloplasty (odds ratio  =  5.1, 95% confidence interval  =  1.44 to 18.11, p  =  .012). Type and age at palatoplasty were not significantly associated with either the rate of developing these sequelae or the rate of achieving bilaterally normal hearing and ear examinations. CONCLUSIONS: Type of palatoplasty did not influence otologic and audiologic outcomes in 5- to 6-year-olds with unilateral cleft lip and palate. The potential influence of lip repair on otologic outcomes warrants further investigation.