Antimicrobial treatment failures in children with acute otitis media and concomitant viral respiratory tract infection prompted us to study the effects of influenza A virus infection on middle ear antimicrobial drug penetration. Using a chinchilla model of Streptococcus pneumoniae we compared middle ear elimination rates in 4 groups of chinchillas: (1) control, (2) influenza A virus inoculation alone intranasally, (3) both influenza A and S. pneumoniae inoculation directly into the middle ear, and (4) S. pneumoniae inoculation alone into the middle ear. After infection was established, a solution containing amoxicillin, sulfamethoxazole, and trimethoprim was instilled into the middle ear and removed 4 hours later. The rate constant of elimination and half-life were calculated from measured drug concentrations initially and at 4 hours. S. pneumoniae infection alone significantly shortened the middle ear elimination half-life compared with the control group: amoxicillin, 2.65 +/- 0.73 vs. 6.63 +/- 2.55 hr; sulfamethoxazole, 1.75 +/- 0.28 vs. 2.74 +/- 0.6 hr; and trimethoprim, 1.06 +/- 0.14 vs. 1.56 +/- 0.34 hr (n = 16 ears, p values all < 0.01). The combined influenza virus and S. pneumoniae infection significantly lengthened the half-life compared with the S. pneumoniae infection alone: amoxicillin, 5.65 +/- 6.44 vs. 2.65 +/- 0.73 hr; sulfamethoxazole, 2.5 +/- 0.85 vs. 1.75 +/- 0.28 hr; and trimethoprim, 1.26 +/- 0.42 vs. 1.06 +/- 0.14 hr (n = 16 ears, p values all < 0.01). Influenza virus produced the longest half-lives for all 3 antimicrobials: amoxicillin 25.52 +/- 14.96 hr; sulfamethoxazole, 5.46 +/- 0.87 hr; and trimethoprim, 2.57 +/- 0.75 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Despite the high incidence and prevalence of otitis media, its pathogenesis is not thoroughly understood. In the last decade, many efforts have been made to provide a better understanding, and abundant information has become available. At the same time the field of immunology has advanced at an extremely rapid pace. We have followed the gradual cellular events in the defense reaction of the middle ear, utilizing eustachian tube obstruction to induce otitis. Seventy-five cats were divided in groups and sacrificed at intervals between one day and six months, and their temporal bones were studied. During an initial phase of inflammation, polymorphonuclears appear at three days in connective tissue; at the same time active fibroblasts synthesize tropocollagen and ground substance while epithelial cells secrete mucus and lysozymes. These cells, together with those involved in the mucociliary transport system and a patent functional eustachian tube, constitute the nonspecific system of defense. The transition cells are the macrophages which appear at one week to interact with T and B cells to produce the specific immune response. Plasma cells appear at two weeks to peak at one month with synthesis of immunoglobulins A, G and M. A secretory immune system is observed. At three and six months, lymphocytes are the predominant cells and occasional accumulations of mononuclears are observed. The reaction involves the entire middle ear, including mucoperiosteum, middle ear muscles and round window membrane. We believe that a better understanding of the middle ear defense system will lead in time to a practical clinical assessment of the immunological status during the evolution of each particular process or disease involving the middle ear, and a more rational approach to the treatment and, hopefully, prevention of chronic ear disease.

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The distribution of collagen types I, III, and IV and of laminin, fibronectin, and keratin was studied in otitis media experimentally induced by Streptococcus pneumoniae in the chinchilla. The expression of interstitial collagen types I and III and of fibronectin was increased in the subepithelial space that was thickened by inflammation in the acute period of infection. The expression of collagen type IV in the subepithelial space could be seen in the early period. The epithelial cells in the middle ear changed from flat cuboidal to pseudostratified columnar in pneumococcus-inoculated ears, and the number of keratin-positive epithelial cells in the middle ear increased remarkably after infection. These results indicate that changes in epithelial cell differentiation effected by the extracellular matrix correlate with changes in expression of keratin. It is proposed that the extracellular matrix may contribute to tissue repair in the middle ear after bacterial infection by interfering with cell proliferation of epithelial cells and fibroblasts.