Attenuation of the Bacterial Load in Blood by Pretreatment with Granulocyte-Colony-Stimulating Factor Protects Rats from Fatal Outcome and Brain Damage duringStreptococcus pneumoniaeMeningitis

Abstract

A model of pneumococcal meningitis in young adult rats receiving antibiotics once the infection was established was developed. The intent was to mimic clinical and histopathological features of pneumococcal meningitis in humans. The primary aim of the present study was to evaluate whether medical boosting of the peripheral neutrophil count affected the outcome of the meningitis. The risk of terminal illness over the first 7 days after infection was significantly reduced for rats who had elevated peripheral white blood cell counts after receiving granulocyte-colony-stimulating factor (G-CSF) prior to the infection compared to that for untreated rats (P ‫؍‬ 0.039 by the log rank test). The improved outcome was associated with reduced signs of cerebral cortical damage (P ‫؍‬ 0.008). Furthermore, the beneficial effects of G-CSF were associated with reduced bacterial loads in the cerebrospinal fluid (median, 1.1 ؋ 10 5 versus 2.9 ؋ 10 5 CFU/ml; P ‫؍‬ 0.023) and in blood (median, 2.9 ؋ 10 2 versus 6.3 ؋ 10 2 CFU/ml; P ‫؍‬ 0.024), as well as attenuated pleocytosis (median, 800 ؋ 10 6 versus 1,231 ؋ 10 6 cells/liter; P ‫؍‬ 0.025), 24 h after the infection. Conversely, initiation of G-CSF therapy 28 h postinfection did not alter the clinical or histological outcome relative to that for non-G-CSFtreated rats. The magnitude of bacteremia and pretreatment with G-CSF were found to be prognostic factors for both outcome and brain damage. In summary, elevated neutrophil levels prior to the development of meningitis result in reduced risks of death and brain damage. This beneficial effect is most likely achieved through improved control of the systemic disease.

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

“…CSF leukocytosis and protein content and levels of IL-8, TNF-␣, and IL-1␤ were decreased in G-CSF-pretreated animals, indicating a decreased subarachnoid inflammatory response (362). Similar results were found in a study with rats (58). However, late administration of G-CSF (28 h after infection) did not have any influence on disease parameters (58).…”

“…Similar results were found in a study with rats (58). However, late administration of G-CSF (28 h after infection) did not have any influence on disease parameters (58). In 22 patients with pneumococcal meningitis, adjunctive treatment with recombinant G-CSF was performed together with standard treatment with ceftriaxone and dexamethasone.…”

Clinical, biochemical and microbiological factors associated with the prognosis of pneumococcal meningitis in children

“…In such cases, when antibiotherapy is administered, the consequent bacterial lysis results in more pronounced inflammatory changes within the meninges and vascular complications are encouraged. 26,27 Biological markers, such as CRP and PCT, are useful for discrimination between viral and bacterial etiology, 28,29 but there are few studies that demonstrate their prognostic utility or changes in them with effective treatment. 30 In our study, patients who had higher initial CRP and PCT values had statistically significant poorer evolution.…”

Bacterial Meningitis: Insights Into Pathogenesis and Evaluation of New Treatment Options: A Perspective from Experimental Studies

“…G-CSF increases the number of systemically circulating neutrophils and may thus be beneficial to better control the infection [100]. In a rat model of pneumococcal meningitis, G-CSF reduced bacterial loads in CSF and blood; however, only pretreatment, but not adjuvant treatment lowered mortality rates and brain damage [101]. Adjuvant treatment with G-CSF resulted in improved spatial learning in a mouse model, which may also be attributed to its neurotrophic effects and may thus be compared with an experimental study evaluating lithium in BM [100,123].…”