Department of Medical Biotechnologies, Laboratory of Molecular Microbiology and Biotechnology (LA.M.M.B.), Ospedale Santa Maria alle Scotte, University of Siena, Siena, Italy.
ESCMID Study Group for Infectious Diseases of the Brain (ESGIB), Basel, Switzerland.
BMC Infect Dis. 2020 Jul 13;20(1):505. doi: 10.1186/s12879-020-05226-w.
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.
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.
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.
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.
脑膜炎奈瑟菌（MM）是一种危及生命的疾病，约有 10%的病例死亡率和 10-20%的病例出现神经后遗症。最近，我们发现基质金属蛋白酶（MMP）抑制剂 BB-94 可减少 MM 小鼠模型中的脑损伤。本研究旨在评估多西环素（DOX）是否也具有有益作用，DOX 作为实验性肺炎球菌性脑膜炎（PM）的辅助治疗已显示出神经保护作用，当作为辅助治疗与头孢曲松（CRO）联合使用时，在实验性 MM 中是否也具有有益作用。
BALB/c 小鼠通过脑室内途径感染 C 群脑膜炎奈瑟菌株。感染后 18 小时（hpi），动物随机接受 CRO[100mg/kg 皮下（s.c.）]、CRO 加 DOX（30mg/kg s.c.）或生理盐水（s.c.对照）治疗。抗生素治疗在 24 和 40 hpi 时重复。48 hpi 时评估小鼠存活率和临床症状、小脑细菌计数、脑损伤、MMP-9 和细胞因子/趋化因子水平。
小脑细菌负荷分析表明，CRO 和 CRO+DOX 对控制脑膜炎奈瑟菌复制同样有效。用 CRO（94.4%）或 CRO+DOX（95.5%）治疗的小鼠存活率无差异（p>0.05）。与未治疗对照组相比，CRO+DOX 治疗显著减少了脑内出血的数量（p=0.029）和大脑中 MMP-9 的含量（p=0.046），但与 CRO 治疗组无差异（p>0.05）。接受 CRO 或 CRO+DOX 治疗的小鼠脑内炎症标志物水平无显著差异（p>0.05）。总体而言，单独使用 CRO 或 CRO+DOX 治疗的组之间在评估的参数上没有显著差异。
CRO+DOX 体内的杀菌活性与 CRO 相似，提示 DOX 对 CRO 无拮抗作用。与未治疗动物相比，联合治疗显著提高了小鼠的存活率和疾病严重程度，但与 CRO 单药治疗相比，添加 DOX 并未带来显著益处。与实验性 PM 不同，DOX 在实验性 MM 中没有辅助作用。
