Combined therapy with ceftriaxone and doxycycline does not improve the outcome of meningococcal meningitis in mice compared to ceftriaxone monotherapy

Susanna Ricci,Tiziana Braccini,Gianni Pozzi,Uwe Koedel,Marco R Oggioni,Ilias Masouris,Denis Grandgirard,Stephen L Leib

doi:10.1186/s12879-020-05226-w

Abstract

BackgroundMeningococcal meningitis (MM) is a life-threatening disease associated with approximately 10% case fatality rates and neurological sequelae in 10–20% of the cases. Recently, we have shown that the matrix metalloproteinase (MMP) inhibitor BB-94 reduced brain injury in a mouse model of MM. The present study aimed to assess whether doxycycline (DOX), a tetracycline that showed a neuroprotective effect as adjuvant therapy in experimental pneumococcal meningitis (PM), would also exert a beneficial effect when given as adjunctive therapy to ceftriaxone (CRO) in experimental MM.MethodsBALB/c mice were infected by the intracisternal route with a group C Neisseria meningitidis strain. Eighteen h post infection (hpi), animals were randomised for treatment with CRO [100 mg/kg subcutaneously (s.c.)], CRO plus DOX (30 mg/kg s.c.) or saline (control s.c.). Antibiotic treatment was repeated 24 and 40 hpi. Mouse survival and clinical signs, bacterial counts in cerebella, brain damage, MMP-9 and cyto/chemokine levels were assessed 48 hpi.ResultsAnalysis of bacterial load in cerebella indicated that CRO and CRO + DOX were equally effective at controlling meningococcal replication. No differences in survival were observed between mice treated with CRO (94.4%) or CRO + DOX (95.5%), (p > 0.05). Treatment with CRO + DOX significantly diminished both the number of cerebral hemorrhages (p = 0.029) and the amount of MMP-9 in the brain (p = 0.046) compared to untreated controls, but not to CRO-treated animals (p > 0.05). Levels of inflammatory markers in the brain of mice that received CRO or CRO + DOX were not significantly different (p > 0.05). Overall, there were no significant differences in the parameters assessed between the groups treated with CRO alone or CRO + DOX.ConclusionsTreatment with CRO + DOX showed similar bactericidal activity to CRO in vivo, suggesting no antagonist effect of DOX on CRO. Combined therapy significantly improved mouse survival and disease severity compared to untreated animals, but addition of DOX to CRO did not offer significant benefits over CRO monotherapy. In contrast to experimental PM, DOX has no adjunctive activity in experimental MM.

Highlights

Meningococcal meningitis (MM) is a life-threatening disease associated with approximately 10% case fatality rates and neurological sequelae in 10–20% of the cases
Combined therapy significantly improved mouse survival and disease severity compared to untreated animals, but addition of DOX to CRO did not offer significant benefits over CRO monotherapy
In contrast to experimental pneumococcal meningitis (PM), DOX has no adjunctive activity in experimental MM

Summary

Introduction

Meningococcal meningitis (MM) is a life-threatening disease associated with approximately 10% case fatality rates and neurological sequelae in 10–20% of the cases. About 10–30% of the human population asymptomatically carries the meningococcus in the nasopharynx, which represents the first step for transmission and onset of invasive meningococcal disease with infants, children and adolescents being the groups at higher risk [2]. The most frequent clinical presentation of invasive disease is meningococcal meningitis (MM) [2], which can affect 30–50% of patients [3, 4]. MM is characterised by 7–18% case fatality rates depending on meningococcal serogroup and patient age [3, 4]. Long-term physical, neurological and psychological sequelae may occur in up to 20% of survivors [5], of which about 7% suffer from neurological sequelae (i.e., hearing loss, cognitive impairment, motor deficits, seizures) [6]

Methods

Results

Discussion

Conclusion