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

Abstract

BACKGROUND:

Meningococcal 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.

METHODS:

BALB/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.

RESULTS:

Analysis 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.

CONCLUSIONS:

Treatment 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.

• Authors: Susanna Ricci, Denis Grandgirard, Ilias Masouris, Tiziana Braccini, Gianni Pozzi, Marco R Oggioni, Uwe Koedel, Stephen L Leib
• Journal: BMC infectious diseases (BMC Infect Dis) Vol. 20 Issue 1 Pg. 505 (Jul 13 2020) ISSN: 1471-2334 [Electronic] England
• PMID: 32660552 (Publication Type: Journal Article)

Chemical References

• Anti-Bacterial Agents
• Chemokines
• Ceftriaxone
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse
• Doxycycline

Topics

• Animals
• Anti-Bacterial Agents (administration & dosage, therapeutic use)
• Bacterial Load (drug effects)
• Ceftriaxone (administration & dosage, therapeutic use)
• Cerebral Hemorrhage (drug therapy)
• Chemokines (analysis, metabolism)
• Disease Models, Animal
• Doxycycline (administration & dosage, therapeutic use)
• Drug Therapy, Combination
• Female
• Humans
• Kaplan-Meier Estimate
• Matrix Metalloproteinase 9 (analysis, metabolism)
• Meningitis, Meningococcal (drug therapy, mortality)
• Mice
• Mice, Inbred BALB C
• Neisseria meningitidis, Serogroup C
• Random Allocation
• Treatment Outcome