Otitis Media Model

Otitis media is inflammation of the middle ear, and it is one of the most common infections of childhood – second in frequency only to upper respiratory infection among illnesses diagnosed in children, and the condition for which antimicrobial agents are most often prescribed in childhood. It typically follows a viral upper respiratory infection: the eustachian tube stops ventilating the middle ear properly, fluid collects behind the tympanic membrane, and bacteria ascending from the nasopharynx establish infection in that fluid. Children under seven are most susceptible, because the eustachian tube functions poorly at that age and the immune system is still developing.

The clinical consequences of otitis media extend past the acute episode. Recurrent and persistent disease can cause hearing loss during the years when speech and language are developing. Tympanostomy tube placement is the most common ambulatory surgery performed on children in the United States. Pneumococcal conjugate vaccines have reduced overall incidence, but non-vaccine serotypes, other bacterial causes, and resistance continue to sustain the burden.

The otitis media model at TransPharm Preclinical Solutions establishes bacterial infection in the middle ear of rats and measures how far a test article lowers the bacterial burden there.

Research Applications

This model is appropriate when the question is whether a candidate reduces bacterial burden in the infected middle ear. Infection is established at the anatomical site rather than delivered systemically, so the readout reflects how much active drug actually reaches the middle ear compartment – a compartment that is poorly perfused, fluid-filled, and separated from the ear canal by the tympanic membrane.

That makes the dosing routes the distinguishing feature. Test article can be given as ear drops or by any of four systemic routes, which supports several development questions:

• Otic formulations and topical antimicrobials, where the exposure that matters is at the middle ear rather than in plasma, and where in vitro potency does not by itself establish that drug crosses or bypasses the tympanic membrane in useful concentrations
• Systemic agents for acute otitis media, dosed by the oral or parenteral route the program will ultimately use
• Comparison of otic against systemic delivery for the same candidate, which many efficacy models are not configured to support
• Activity against a characterized resistant pneumococcal isolate, where such a strain is sourced and validated for the study and the comparator is expected to underperform

Where the target site is the lower airway rather than the middle ear, the related pulmonary infection model applies, and invasive pneumococcal disease can be assessed in the bacteremia model.

Scientific Scope

TransPharm Preclinical Solutions has validated the otitis media model with Streptococcus pneumoniae, which together with non-typeable Haemophilus influenzae accounts for the majority of bacterial otitis media:

• Streptococcus pneumoniae – SPEC6B, serotype 6B

Additional validations are available on request. Non-typeable H. influenzae and Moraxella catarrhalis – the other principal bacterial causes of otitis media – can be sourced and validated on request, as can defined resistant pneumococcal isolates and client-supplied strains.

The otitis media model carries the same add-on measurements available across all in vivo work at TransPharm Preclinical Solutions: pharmacokinetic profiling and PK/PD analysis, blood chemistry, additional tissue harvests, and histopathology, each available on request. All studies run in an AAALAC-accredited facility.

Study Design

Procedure

Studies are run in rats. Histamine is administered through the tympanic membrane into the middle ear cavity ahead of challenge, impairing mucociliary clearance through the eustachian tube. This reproduces the drainage failure that precedes clinical otitis media and creates the middle ear environment in which infection establishes. Animals then receive a single challenge with the infectious agent by intranasal instillation, so that the organism reaches the middle ear by the same ascending route it takes in patients rather than by direct inoculation.

Routes of Administration

Test article may be administered as ear drops, by oral gavage (PO), or by subcutaneous (SC), intravenous (IV), intramuscular (IM), or intraperitoneal (IP) injection, so dosing can match the route the program intends to use clinically.

Endpoint

The primary readout is CFU burden in the infected middle ear. Additional tissue harvests and blood sampling are available where systemic spread is part of the question. Pharmacokinetic profiling, blood chemistry, and histology can be added to any study on request.

Because the model is designed around exposure at a site that systemic dosing reaches poorly, pairing the burden readout with pharmacokinetic sampling is worth considering here specifically: it separates a candidate that is inactive against the organism from one that is active but not reaching the compartment in sufficient concentration.

Customization

Every study parameter is configurable to the scientific question: challenge strain, host strain, comparator agents, dosing route, and dosing schedule. Programs comparing otic against systemic delivery can run both arms against the same challenge in the same study rather than across separate studies.