scholarly journals Attenuation of Cerebrospinal Fluid Inflammation by the Nonbacteriolytic Antibiotic Daptomycin versus That by Ceftriaxone in Experimental Pneumococcal Meningitis

2010 ◽  
Vol 54 (3) ◽  
pp. 1323-1326 ◽  
Author(s):  
Denis Grandgirard ◽  
Kevin Oberson ◽  
Angela Bühlmann ◽  
Rahel Gäumann ◽  
Stephen L. Leib
Keyword(s):  
Cerebrospinal Fluid ◽  
Brain Damage ◽  
Pneumococcal Meningitis ◽  
Bacterial Killing ◽  
Monocyte Chemoattractant Protein 1 ◽  
Infant Rat ◽  
Inflammatory Protein ◽  
Kinetics Of ◽  
Macrophage Inflammatory Protein ◽  
Experimental Pneumococcal Meningitis

ABSTRACT Antibiotic-induced bacteriolysis exacerbates inflammation and brain damage in bacterial meningitis. Here the quality and temporal kinetics of cerebrospinal fluid (CSF) inflammation were assessed in an infant rat pneumococcal meningitis model for the nonbacteriolytic antibiotic daptomycin versus ceftriaxone. Daptomycin led to lower CSF concentrations of interleukin 1β (IL-1β), IL-10, IL-18, monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1 alpha (MIP-1α) (P < 0.05). In experimental pneumococcal meningitis, daptomycin treatment resulted in more rapid bacterial killing, lower CSF inflammation, and less brain damage than ceftriaxone treatment.

scholarly journals Adjunctive Daptomycin Attenuates Brain Damage and Hearing Loss More Efficiently than Rifampin in Infant Rat Pneumococcal Meningitis

2012 ◽  
Vol 56 (8) ◽  
pp. 4289-4295 ◽  
Author(s):  
Denis Grandgirard ◽  
Melchior Burri ◽  
Philipp Agyeman ◽  
Stephen L. Leib
Keyword(s):  
Hearing Loss ◽  
Bacterial Meningitis ◽  
Brain Damage ◽  
Pneumococcal Meningitis ◽  
Beta Lactam ◽  
Monocyte Chemoattractant Protein 1 ◽  
Gram Positive Bacteria ◽  
Beta Lactam Antibiotics ◽  
Infant Rat ◽  
Initiation Of Therapy

ABSTRACTExacerbation of cerebrospinal fluid (CSF) inflammation in response to bacteriolysis by beta-lactam antibiotics contributes to brain damage and neurological sequelae in bacterial meningitis. Daptomycin, a nonlytic antibiotic acting on Gram-positive bacteria, lessens inflammation and brain injury compared to ceftriaxone. With a view to a clinical application for pediatric bacterial meningitis, we investigated the effect of combining daptomycin or rifampin with ceftriaxone in an infant rat pneumococcal meningitis model.IMPORTANCEEleven-day-old Wistar rats with pneumococcal meningitis were randomized to treatment starting at 18 h after infection with (i) ceftriaxone (100 mg/kg of body weight, subcutaneously [s.c.], twice a day [b.i.d.]), (ii) daptomycin (10 mg/kg, s.c., daily) followed 15 min later by ceftriaxone, or (iii) rifampin (20 mg/kg, intraperitoneally [i.p.], b.i.d.) followed 15 min later by ceftriaxone. CSF was sampled at 6 and 22 h after the initiation of therapy and was assessed for concentrations of defined chemokines and cytokines. Brain damage was quantified by histomorphometry at 40 h after infection and hearing loss was assessed at 3 weeks after infection. Daptomycin plus ceftriaxone versus ceftriaxone significantly (P< 0.04) lowered CSF concentrations of monocyte chemoattractant protein 1 (MCP-1), MIP-1α, and interleukin 6 (IL-6) at 6 h and MIP-1α, IL-6, and IL-10 at 22 h after initiation of therapy, led to significantly (P< 0.01) less apoptosis, and significantly (P< 0.01) improved hearing capacity. While rifampin plus ceftriaxone versus ceftriaxone also led to lower CSF inflammation (P< 0.02 for IL-6 at 6 h), it had no significant effect on apoptosis and hearing capacity. Adjuvant daptomycin could therefore offer added benefits for the treatment of pediatric pneumococcal meningitis.

scholarly journals Pretreatment with Granulocyte Colony-Stimulating Factor Attenuates the Inflammatory Response but Not the Bacterial Load in Cerebrospinal Fluid during Experimental Pneumococcal Meningitis in Rabbits

1999 ◽  
Vol 67 (7) ◽  
pp. 3430-3436 ◽  
Author(s):  
Christian Østergaard ◽  
Thomas Benfield ◽  
Borbola Gesser ◽  
Arsalan Kharazmi ◽  
Niels Frimodt-Møller ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Pneumococcal Meningitis ◽  
Ex Vivo ◽  
Bacterial Load ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Bacterial Killing ◽  
Meningeal Inflammation ◽  
Stimulating Factor ◽  
Experimental Pneumococcal Meningitis

ABSTRACT A possible immunomodulatory role of granulocyte colony-stimulating factor (G-CSF) was investigated in an experimental pneumococcal meningitis model in rabbits. Animals were pretreated with G-CSF (10 μg/kg subcutaneously twice a day) starting 48 h before in vivo and ex vivo experiments, causing a five- to six-fold increase in the peripheral leukocyte level. Meningitis was induced by intracisternal inoculation of ∼4 × 105 CFU of Streptococcus pneumoniae type 3. Neutrophil pleocytosis and interleukin-8 (IL-8) levels were significantly attenuated in G-CSF-pretreated animals compared to untreated animals (P < 0.05). Furthermore, G-CSF pretreatment significantly delayed alterations in cerebrospinal fluid (CSF) tumor necrosis factor alpha and IL-1β levels, as well as protein and glucose levels (P < 0.05). No difference in CSF bacterial concentrations was found, whereas the blood bacterial concentration was significantly decreased in G-CSF-pretreated animals (P < 0.05). Ex vivo chemotaxis of neutrophils isolated from G-CSF-pretreated animals was significantly decreased compared to that of neutrophils from untreated animals (P < 0.05). In conclusion, G-CSF pretreatment attenuates meningeal inflammation and enhances systemic bacterial killing. Further preclinical studies are required to investigate whether this may affect the clinical course of meningitis and thus whether G-CSF treatment may have a beneficial role in pneumococcal meningitis.

Progression of Hearing Loss in Experimental Pneumococcal Meningitis: Correlation with Cerebrospinal Fluid Cytochemistry

1993 ◽  
Vol 167 (3) ◽  
pp. 675-683 ◽  
Author(s):  
S. M. Bhatt ◽  
A. Lauretano ◽  
C. Cabellos ◽  
C. Halpin ◽  
R. A. Levine ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Hearing Loss ◽  
Pneumococcal Meningitis ◽  
Experimental Pneumococcal Meningitis

scholarly journals Inhibition of Leukocyte Entry into the Brain by the Selectin Blocker Fucoidin Decreases Interleukin-1 (IL-1) Levels but Increases IL-8 Levels in Cerebrospinal Fluid during Experimental Pneumococcal Meningitis in Rabbits

2000 ◽  
Vol 68 (6) ◽  
pp. 3153-3157 ◽  
Author(s):  
Christian Østergaard ◽  
Runa Vavia Yieng-Kow ◽  
Thomas Benfield ◽  
Niels Frimodt-Møller ◽  
Frank Espersen ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Pneumococcal Meningitis ◽  
Interleukin 1 ◽  
Treated Group ◽  
Control Group ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Significant Difference ◽  
The Brain ◽  
Experimental Pneumococcal Meningitis

ABSTRACT The polysaccharide fucoidin is a selectin blocker that inhibits leukocyte recruitment into the cerebrospinal fluid (CSF) during experimental pneumococcal meningitis. In the present study, the effect of fucoidin treatment on the release of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and IL-8 into the CSF was investigated. Rabbits (n = 7) were treated intravenously with 10 mg of fucoidin/kg of body weight every second hour starting 4 h after intracisternal inoculation of ∼106 CFU of Streptococcus pneumoniae type 3 (untreated control group, n = 7). CSF samples were obtained every second hour during a 16-h study period. Treatment with fucoidin caused a consistent and significant decrease in CSF IL-1 levels (in picograms per milliliter) between 12 and 16 h (0 versus 170, 0 versus 526, and 60 versus 1,467, respectively;P < 0.02). A less consistent decrease in CSF TNF-α levels was observed in the fucoidin-treated group, but with no significant difference between the two groups (P > 0.05). In contrast, there was no attenuation in CSF IL-8 levels. Indeed, there was a significant increase in CSF IL-8 levels (in picograms per milliliter) in the fucoidin-treated group at 10 and 12 h (921 versus 574 and 1,397 versus 569, respectively;P < 0.09). In conclusion, our results suggest that blood-derived leukocytes mainly are responsible for the release of IL-1 and to some degree TNF-α into the CSF during pneumococcal meningitis, whereas IL-8 may be produced by local cells within the brain.

Acceleration of Palatal Wound Healing in Smad3-deficient Mice

2009 ◽  
Vol 88 (8) ◽  
pp. 757-761 ◽  
Author(s):  
K. Jinno ◽  
T. Takahashi ◽  
K. Tsuchida ◽  
E. Tanaka ◽  
K. Moriyama
Keyword(s):  
Wound Healing ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Monocyte Chemoattractant Protein 1 ◽  
Inflammatory Protein ◽  
Complex Process ◽  
Dermal Cells ◽  
Macrophage Inflammatory Protein ◽  
Tgf Β1

Wound healing is a well-orchestrated complex process leading to the repair of injured tissues. It is suggested that transforming growth factor (TGF)-β/Smad3 signaling is involved in wound healing. The purpose of this study was to investigate the role of TGF-β/Smad3 signaling in palatal wound healing in Smad3-deficient (Smad3−/−) mice. Histological examination showed that wound closure was accelerated by the proliferation of epithelium and dermal cells in Smad3−/− mice compared with wild-type (WT) mice. Macrophage/monocyte infiltration at wounded regions in Smad3−/− mice was decreased in parallel with the diminished production of TGF-β1, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1α compared with WT mice. Fibrocytes, expressing hematopoietic surface marker and fibroblast products, were recruited and produced α-smooth-muscle actin in WT mice, but were not observed in Smad3−/− mice. These results suggest that TGF-β/Smad3 signaling may play an important role in the regulation of palatal wound healing.

scholarly journals BMS-284756 in Experimental Cephalosporin-Resistant Pneumococcal Meningitis

2001 ◽  
Vol 45 (11) ◽  
pp. 3098-3103 ◽  
Author(s):  
Violeta Rodriguez-Cerrato ◽  
Faryal Ghaffar ◽  
Jesus Saavedra ◽  
Ian C. Michelow ◽  
Robert D. Hardy ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Cerebrospinal Fluid ◽  
Single Dose ◽  
Standard Deviation ◽  
Pneumococcal Meningitis ◽  
Combined Therapy ◽  
Bactericidal Effect ◽  
Bacterial Killing ◽  
Elimination Half ◽  
Pharmacodynamic Profile

ABSTRACT BMS-284756 is a novel des-fluoro(6) quinolone with a broad antimicrobial activity, including Streptococcus pneumoniae. The purpose of this study was to evaluate the pharmacodynamic profile and effectiveness of BMS-284756 for therapy of experimental meningitis caused by penicillin- and cephalosporin-resistant S. pneumoniae (CRSP). Meningitis was induced in rabbits by intracisternal inoculation of CRSP. BMS-284756 was given intravenously 16 h after intracisternal inoculation in single doses of 2.5 (n = 5 animals), 5 (n = 6), 10 (n = 6), 20 (n = 8), and 30 mg/kg (n = 6), in two doses of 10 mg/kg each separated by 5 h (n = 4), and as a 20-mg/kg dose followed 5 h later by 10 mg/kg (n = 5). The MICs and MBCs of BMS-284756, ceftriaxone, and vancomycin were 0.06 and 0.06, 4 and 4, and 0.25 and 0.25 μg/ml, respectively. After single doses of 10, 20, and 30 mg/kg, the maximum concentrations in cerebrospinal fluid (CSF) (mean ± standard deviation) were 0.32 ± 0.12, 0.81 ± 0.38, and 1.08 ± 0.43 μg/ml, respectively; the elimination half-life in CSF was 4.5 to 6.3 h. The CSF bacterial killing rates (BKR) at 5 h of the single-dose regimens of 10, 20 and 30 mg/kg were −0.84 ± 0.48, −1.09 ± 0.32, and −1.35 ± 0.05 Δlog10 CFU/ml/h. The BKR0–5 of the divided regimens (10 mg/kg twice and 20 mg/kg followed by 10 mg/kg) was −0.82 ± 0.52 and −1.24 ± 0.34 Δlog10CFU/ml/h, respectively. The BKR0–5 of the combined therapy with vancomycin and ceftriaxone was −1.09 ± 0.39 Δlog10 CFU/ml/h. The penetration of BMS-284756 into purulent CSF relative to plasma was 14 to 25%. The bactericidal effect of BMS-284756 in CSF was concentration dependent. BMS-284756 at 30 mg/kg as a single or divided dose was as effective as standard therapy with vancomycin and ceftriaxone.

scholarly journals MCP-1, not MIP-1α, Is the Endogenous Chemokine That Cooperates With TGF-β to Inhibit the Cycling of Primitive Normal but not Leukemic (CML) Progenitors in Long-Term Human Marrow Cultures

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2338-2344 ◽  
Author(s):  
J.D. Cashman ◽  
C.J. Eaves ◽  
A.H. Sarris ◽  
A.C. Eaves
Keyword(s):  
Inhibitory Activity ◽  
Neutralizing Antibodies ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Monocyte Chemoattractant Protein 1 ◽  
Inflammatory Protein ◽  
Progenitor Cell Proliferation ◽  
Normal Human ◽  
Macrophage Inflammatory Protein

Abstract The long-term culture (LTC) system has been useful for analyzing mechanisms by which stromal cells regulate the proliferative activity of primitive normal, but not chronic myeloid leukemia (CML), hematopoietic progenitor cells. In previous studies, we identified two endogenous inhibitors in this system. One is transforming growth factor-β (TGF-β), which is equally active on primitive normal and CML progenitors. The other we now show to be monocyte chemoattractant protein-1 (MCP-1). Thus, MCP-1, when added to LTC, blocked the activation of primitive normal progenitors but did not arrest the cycling of primitive CML progenitors. Moreover, the endogenous inhibitory activity of LTC stromal layers could be overcome by the addition of neutralizing antibodies to MCP-1, but not to macrophage inflammatory protein-1α (MIP-1α). However, neither of these antibodies antagonized the inhibitory activity of NAc-Ser-Asp-Lys-Pro (AcSDKP) on primitive normal but not CML progenitor cycling in this system. Moreover, none of six other -C-C- or -C-X-C- chemokines, previously shown to inhibit primitive normal human CFC proliferation in semisolid assays, were found to act as negative regulators when added to normal LTC. These results provide further support for the concept that primitive CML progenitor cell proliferation is deregulated when these cells are exposed to limiting concentrations of multiple inhibitors, only some of which have differential actions on normal and Ph+/BCR-ABL+ cells.

Sign in / Sign up

Export Citation Format

Share Document