A novel mouse model of chronic suppurative otitis media and its use in preclinical antibiotic evaluation

Khomtchouk, Kelly; Kouhi, Ali; Xia, Anping; Bekale, L.; Massa, Solange; Sweere, Jolien; Pletzer, Daniel; Hancock, Robert E. W.; Bollyky, Paul L.; Maria, Peter L. Santa

doi:10.1126/sciadv.abc1828

Cited by 19 publications

(25 citation statements)

References 40 publications

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“…Topical fluoroquinolones effectively convert active disease to inactive but, by mechanism, do not address persister cells, which are the key drivers of CSOM recurrence. 42-44 However, these findings are limited by possible selection bias, as patients at a tertiary center likely represent the more severe spectrum of disease. We aimed to account for this by not setting a minimum follow-up time for medical outcomes and analyzing if prior surgery influenced outcomes.…”

Section: Discussionmentioning

confidence: 99%

Long‐Term Health Utilization and Outcomes in Chronic Suppurative Otitis Media

Thai¹,

Aaron²,

Kaufman³

et al. 2021

Otolaryngol.--head neck surg.

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Objective To report health utilization patterns and outcomes of medical and surgical management in patients with chronic suppurative otitis media (CSOM). Study Design Retrospective cohort. Setting Academic otology clinic. Methods This study included 175 patients with CSOM with a first clinic visit at our institution between March 2011 and November 2016. All patients displayed a diagnosis of CSOM by International Classification of Diseases code, had at least 1 episode of active CSOM (defined as perforation with otorrhea), and had a documented history of chronic ear infections. The mean age was 49.5 ± 1.5 years, 53% were female, and mean follow-up time was 3.5 ± 0.3 years. Results Patients had an average of 9.5 ± 0.5 otology visits, 4.7 ± 0.4 prescriptions, and 1.7 ± 0.1 surgeries, with estimated per patient cost ranging from $3927 to $20,776. Under medical management, 69% of patients displayed recurrence of disease, with a median time to recurrence of 4 months. For tympanoplasty and tympanomastoidectomy, median time to recurrence was similar at 5 and 7 years, respectively ( P = .73). At the most recent visit, the prevalence of all patients with CSOM displaying moderate or worse sensorineural hearing loss (SNHL) was 41%. Conclusions CSOM represents a major public health issue with high health care utilization and associated costs. Surgery is superior to medical therapy for achieving short- to medium-term inactive disease. Patients with CSOM display a high SNHL burden.

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Section: Discussionmentioning

confidence: 99%

Long‐Term Health Utilization and Outcomes in Chronic Suppurative Otitis Media

Thai¹,

Aaron²,

Kaufman³

et al. 2021

Otolaryngol.--head neck surg.

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“…We used a validated model of CSOM 33 , 47 . In brief, a sub-total tympanic membrane perforation and trans-tympanic Eustachian tube occlusion were performed 1 day prior to bacterial inoculation under anesthesia intraperitoneal injection of ketamine (65 mg/kg) and xylazine (5 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

“…Building off the foundation of many previously published animal models of acute and chronic otitis media that established microbial and host determinants of chronic infection 28 – 32 , we validated an animal model for CSOM 33 . In that model, we uncovered that chronic infection was dependent on dose, phenotype, and the proportion of P. aeruginosa persister cells, and demonstrated the ability of P. aeruginosa to form biofilm in vivo within 24 h 33 .…”

Section: Introductionmentioning

confidence: 99%

Treatment with a neutrophil elastase inhibitor and ofloxacin reduces P. aeruginosa burden in a mouse model of chronic suppurative otitis media

Khomtchouk

Joseph

Khomtchouk

et al. 2021

npj Biofilms Microbiomes

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Chronic suppurative otitis media (CSOM) is a widespread, debilitating problem with poorly understood immunology. Here, we assess the host response to middle ear infection over the course of a month post-infection in a mouse model of CSOM and in human subjects with the disease. Using multiparameter flow cytometry and a binomial generalized linear machine learning model, we identified Ly6G, a surface marker of mature neutrophils, as the most informative factor of host response driving disease in the CSOM mouse model. Consistent with this, neutrophils were the most abundant cell type in infected mice and Ly6G expression tracked with the course of infection. Moreover, neutrophil-specific immunomodulatory treatment using the neutrophil elastase inhibitor GW 311616A significantly reduces bacterial burden relative to ofloxacin-only treated animals in this model. The levels of dsDNA in middle ear effusion samples are elevated in both humans and mice with CSOM and decreased during treatment, suggesting that dsDNA may serve as a molecular biomarker of treatment response. Together these data strongly implicate neutrophils in the ineffective immune response to P. aeruginosa infection in CSOM and suggest that immunomodulatory strategies may benefit drug-tolerant infections for chronic biofilm-mediated disease.

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“…To overcome this gap, we recently developed and validated a CSOM animal model that represents the human disease [ 13 ]. Using this model, we began a stepwise investigation to understand how SNHL develops in CSOM.…”

Section: Introductionmentioning

confidence: 99%

Chronic suppurative otitis media causes macrophage-associated sensorineural hearing loss

Xia

Thai

Cao

et al. 2022

J Neuroinflammation

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Background Chronic suppurative otitis media (CSOM) is the most common cause of permanent hearing loss in children in the developing world. A large component of the permanent hearing loss is sensory in nature and our understanding of the mechanism of this has so far been limited to post-mortem human specimens or acute infection models that are not representative of human CSOM. In this report, we assess cochlear injury in a validated Pseudomonas aeruginosa (PA) CSOM mouse model. Methods We generated persisters (PCs) and inoculated them into the mouse middle ear cavity. We tracked infection with IVIS and detected PA using RT-PCR. We assessed cochlear damage and innate immunity by Immunohistochemistry. Finally, we evaluated cytokines with multiplex assay and quantitative real-time PCR. Results We observed outer hair cell (OHC) loss predominantly in the basal turn of the cochlear at 14 days after bacterial inoculation. Macrophages, not neutrophils are the major immune cells in the cochlea in CSOM displaying increased numbers and a distribution correlated with the observed cochlear injury. The progression of the morphological changes suggests a transition from monocytes into tissue macrophages following infection. We also show that PA do not enter the cochlea and live bacteria are required for cochlear injury. We characterized cytokine activity in the CSOM cochlea. Conclusions Taken together, this data shows a critical role for macrophages in CSOM-mediated sensorineural hearing loss (SNHL).

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A novel mouse model of chronic suppurative otitis media and its use in preclinical antibiotic evaluation

Cited by 19 publications

References 40 publications

Long‐Term Health Utilization and Outcomes in Chronic Suppurative Otitis Media

Long‐Term Health Utilization and Outcomes in Chronic Suppurative Otitis Media

Treatment with a neutrophil elastase inhibitor and ofloxacin reduces P. aeruginosa burden in a mouse model of chronic suppurative otitis media

Chronic suppurative otitis media causes macrophage-associated sensorineural hearing loss

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