Combining Ceftriaxone with Doxycycline and Daptomycin Reduces Mortality, Neuroinflammation, Brain Damage and Hearing Loss in Infant Rat Pneumococcal Meningitis.

Despite available antibiotic therapy, pneumococcal meningitis (PM) is associated with a case fatality rate of up to 30% in high-income countries. Survivors often suffer from severe lifelong disabilities. An excessive inflammatory reaction drives the pathophysiology leading to brain damage and neurologic sequelae. We aimed to improve the outcome of experimental PM by simultaneously targeting different pathophysiological mechanisms with combined adjunctive therapies previously shown to be neuroprotective. In vitro , the anti-inflammatory effect of doxycycline and daptomycin were evaluated on primary rat astroglial cells stimulated with S. pneumoniae Eleven day old infant Wistar rats were infected intracisternally with S. pneumoniae and randomized for treatment with ceftriaxone or combination adjuvant therapy consisting of ceftriaxone, daptomycin and doxycycline. During acute PM, combined adjuvant therapy with ceftriaxone, daptomycin and doxycycline increased survival rate from 64.1% to 85.8% (p<0.01) and alleviated weight loss compared to ceftriaxone monotherapy (p<0.01). Levels of inflammatory cytokines were significantly reduced by combined adjuvant therapy in vitro (p<0.0001) and in cerebrospinal fluid in vivo (p<0.05). In infected animals treated with combined adjunctive therapy, cortical damage was significantly reduced (p<0.05) and they showed a trend towards better hearing capacity three weeks after the infection (p=0.089), an effect which was significant in mildly infected animals (48dB vs 67.22dB, p<0.05). These mildly infected animals showed significantly reduced cochlear fibrous occlusion (p<0.01). By combining non-bacteriolytic daptomycin and anti-inflammatory doxycycline with ceftriaxone, their previously reported beneficial effects were cumulated and identified the triple antibiotic therapy as a promising therapeutic option for paediatric PM.