Hearing loss and pneumococcal meningitis: An animal model

Bhatt, Samir M.; Halpin, Chris; Hsu, Wen; Thedinger, Britt A.; Levine, Robert A.; Tuomanen, Elaine; Nadol, Joseph B.

doi:10.1002/lary.5541011206

Cited by 60 publications

(61 citation statements)

References 27 publications

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“…Hearing loss results from involvement of the inner ear due to inflammation as pneumococci and leukocytes extend from the CSF to the perilymph via the cochlear aqueduct (4,5,11). In a model of pneumococcal meningitis the severity of permanent hearing impairment as assessed by the increase in the ABR thresholds 2 weeks after (20).…”

Section: Discussionmentioning

confidence: 99%

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

et al. 2006

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Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 M in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats. Pneumococcal meningitis has a high level of mortality (up to 30%), and brain and/or cochlear damage occurs in up to 50% of the survivors (2). Inflammatory mediators, such as tumor necrosis factor alpha (TNF-␣) and matrix metalloproteinases (MMPs), are produced during the host response to bacteria and contribute to the pathophysiology that can ultimately lead to death, brain damage, and hearing impairment (23,26,29,36). The role of cytokines and MMPs in the pathophysiology of the cochlear damage associated with pneumococcal meningitis is still unknown. However, it has been demonstrated that MMPs are constitutively expressed at high levels in the cochlea (8) and that in meningitis pneumococci and polymorphonuclear leukocytes (PMNs) extend from the cerebrospinal fluid (CSF) to the perilymph via the cochlear aqueduct (5).Tetracyclines are bacteriostatic agents with broad-spectrum antimicrobial activity (3). Doxycycline is a semisynthetic, longacting, second-generation tetracycline which is absorbed rapidly and penetrates well into the brain and CSF (48). Doxycycline has been shown to have anti-inflammatory effects that are separate and distinct from its antimicrobial action (13,16,35,43). These effects include the reduction of cytokine release and the inhibition of MMPs (7, 38). Experimental and clinical studies have indicated that treatment with doxycycline may be beneficial in inflammatory diseases associated with excessive MMP activity (7,13,35).In pneumococcal meningitis massive subarachnoid and ventricular space inflammation is triggered by the presence of bacteria in the CSF space (7,1...

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Section: Discussionmentioning

confidence: 99%

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

et al. 2006

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“…Outbred strains, including Wistar, Sprague-Dawley, and CD (derived from Sprague-Dawley) rats, have been extensively utilized as experimental models (2,49,71,79,101,103,145,147,166,193,214,221,242,253). The New Zealand White rabbit is the most commonly used strain to induce pneumococcal pneumonia, sepsis, and meningitis (26,57,69,98,106,119,196,246). Finally, the chinchilla (only outbred strains are available), gerbil, and guinea pig are commonly used animal models of experimental otitis media (81,89,90,260).…”

Section: Considerations Of Animal and Pneumococcal Strainsmentioning

confidence: 99%

“…The availability of clinical isolates is also important in attempting the reproduction of human disease in laboratory animals. Several groups have preferred serotype 3 and 6 strains isolated from patients with pneumococcal meningitis and have successfully induced this disease in the mouse, the rat, and the rabbit (26,35,69,76,85,95,145,192,268,269). Clinical isolates of serotypes 3, 6, 9, and 19 have also been employed in laboratory animal models to elucidate features of pneumococcal pneumonia and sepsis (12,14,40,49,196,223,234,251).…”

Section: Considerations Of Animal and Pneumococcal Strainsmentioning

confidence: 99%

Animal Models ofStreptococcus pneumoniaeDisease

2008

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SUMMARY Streptococcus pneumoniae is a colonizer of human nasopharynx, but it is also an important pathogen responsible for high morbidity, high mortality, numerous disabilities, and high health costs throughout the world. Major diseases caused by S. pneumoniae are otitis media, pneumonia, sepsis, and meningitis. Despite the availability of antibiotics and vaccines, pneumococcal infections still have high mortality rates, especially in risk groups. For this reason, there is an exceptionally extensive research effort worldwide to better understand the diseases caused by the pneumococcus, with the aim of developing improved therapeutics and vaccines. Animal experimentation is an essential tool to study the pathogenesis of infectious diseases and test novel drugs and vaccines. This article reviews both historical and innovative laboratory pneumococcal animal models that have vastly added to knowledge of (i) mechanisms of infection, pathogenesis, and immunity; (ii) efficacies of antimicrobials; and (iii) screening of vaccine candidates. A comprehensive description of the techniques applied to induce disease is provided, the advantages and limitations of mouse, rat, and rabbit models used to mimic pneumonia, sepsis, and meningitis are discussed, and a section on otitis media models is also included. The choice of appropriate animal models for in vivo studies is a key element for improved understanding of pneumococcal disease.

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“…From human and animal studies, it can be shown that labyrinthitis can develop during bacterial meningitis, probably by bacteria reaching the perilymphatic channels via the cochlear aqueduct. [10][11][12] The resulting invasion may lead to destruction of the organ of Corti and calcification of the perilymphatic channels. Nitric oxide may contribute to mediating this injury as well.…”

Section: Pathophysiologymentioning

confidence: 99%

Adjunctive Therapy in Children with Bacterial Meningitis

Kaplan

1997

Ann Saudi Med

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Hearing loss and pneumococcal meningitis: An animal model

Cited by 60 publications

References 27 publications

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

Animal Models ofStreptococcus pneumoniaeDisease

Adjunctive Therapy in Children with Bacterial Meningitis

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