Doxycycline reduces mortality and injury to the brain and cochlea in experimental pneumococcal meningitis.

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 microM 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.

Oral immunization of rabbits against Pasteurella multocida with an alginate microsphere delivery system.

Oral delivery of microencapsulated antigens is a potential means to vaccinate rabbits against Pasteurella multocida, a common bacterial pathogen. Groups of five rabbits were dosed orally on days 0, 7, and 14 with alginate microspheres prepared to contain no added protein, 5 mg of a potassium thiocyanate extract of P. multocida (PTE), or 5 mg of PTE with 200 micrograms of cholera toxin (CT). In addition, groups were dosed orally with 5 mg of soluble PTE with or without 200 micrograms CT, intranasally (IN) with 1 mg of soluble PTE, or with saline. Serum and nasal lavage samples collected prior to initial immunization and 10, 16, and 21 days later were assayed by ELISA for anti-PTE IgG and IgA. Strong nasal lavage IgA and serum IgG activities were found in samples from rabbits immunized with PTE IN or orally when incorporated into microspheres. Addition of CT did not significantly enhance either response. To examine the development of protective immunity, groups were similarly immunized and challenge-exposed IN on day 16 with 10(6) CFU of P. multocida. One week later, rabbits were euthanized, and specimens from the lungs, nasopharynx, liver, and inner ear were cultured for P. multocida. Less severe infections of the lung and nasopharynx developed in rabbits immunized with PTE IN or orally in microspheres, with or without added CT. In addition, culture of liver and tympanic bullae samples from these rabbits yielded growth of P. multocida less frequently compared to other P. multocida-challenged rabbits. Coadministration of CT and PTE did not significantly improve protective immunity to challenge.