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1.  Cerebrospinal fluid outflow resistance in rabbits with experimental meningitis. Alterations with penicillin and methylprednisolone. 
Journal of Clinical Investigation  1980;66(2):243-253.
Acute bacterial meningitis may be associated with increased intracranial pressure, neurological sequelae such as communicating hydrocephalus, and a slow response to antibiotic therapy. Alterations in cerebrospinal hydrodynamics are at least partially responsible for these complications. Constant, low-flow short-duration manometric infusion studies through a hollow-bore pressure monitoring device in direct continuity with the supracortical subarachnoid space were performed in rabbits with experimental meningitis. Maximal resistance to cerebrospinal fluid (CSF) outflow from the subarachnoid to vascular space was markedly increaed in acute pneumococcal meningitis when compared to control, uninfected animals (6.77 +/- 3.52 vs. 0.26 +/- 0.04 mm Hg/microliter per min, P less than 0.001). Similar elevations (8.93 +/- 4.15 mm Hg/microliter per min were found in experimental Escherichia coli meningitis. Despite eradication of viable bacteria from the CSF by penicillin therapy during the acute stage of pneumococcal meningitis, resistance remained elevated (6.07 +/- 4.68 mm Hg/microliter per min) and had not returned to normal up to 15 d later. Administration of methylprednisolone during the early stages of acute pneumococcal meningitis reduced mean peak outflow resistance towards control values (0.59 mm Hg/microliter per min) and no "rebound" effect was apparent 24 h later. These hydrodynamic alterations in experimental meningitis prevent normal CSF absorption and decrease the ability of the bran to compensate for changes in intracranial volume and pressure.
PMCID: PMC371704  PMID: 6995482
2.  Influence of the blood bacterial load on the meningeal inflammatory response in Streptococcus pneumoniae meningitis 
Background
Despite bacteraemia is present in the majority of patients with pneumococcal, little is known about the influence of the systemic infection on the meningeal inflammatory response.
Methods
To explore the role of systemic infection on the meningeal inflammation, experimental meningitis was induced by intracisternal injection of ~1 × 106 CFU Streptococcus pneumoniae, type 3, and the 26 rabbits were either provided with ~1 × 106 CFU S. pneumoniae intravenously at 0 hour ("bacteraemic" rabbits, n = 9), immunized with paraformaldehyde-killed S. pneumoniae for 5 weeks prior to the experiment ("immunized" rabbits", n = 8), or not treated further ("control" rabbits, n = 9). WBC and bacterial concentrations were determined in CSF and blood every second hour during a 16 hours study period together with CSF IL-8 and protein levels. We also studied CSF and blood WBC levels in 153 pneumococcal meningitis patients with and without presence of bacteraemia.
Results
As designed, blood bacterial concentrations were significantly different among three experimental groups during the 16 hours study period (Kruskal Wallis test, P < 0.05), whereas no differences in CSF bacterial levels were observed (P > 0.05). Blood WBC decreased in bacteraemic rabbits between ~10–16 hours after the bacterial inoculation in contrast to an increase for both the immunized rabbits and controls (P < 0.05). The CSF pleocytosis was attenuated in bacteraemic rabbits as compared to the two other groups between 12–16 hours from time of infection (P < 0.017), despite accelerated CSF IL-8 levels in bacteraemic rabbits.
In patients with pneumococcal meningitis, no significant difference in CSF WBC was observed between patients with or without bacteraemia at admission (n = 103, 1740 cells/μL (123–4032) vs. n = 50, 1961 cells/μL (673–5182), respectively, P = 0.18), but there was a significant correlation between CSF and blood WBC (n = 127, Spearman rho = 0.234, P = 0.008).
Conclusion
Our results suggest that a decrease in peripheral WBC induced by enhanced bacteraemia in pneumococcal meningitis results in an attenuated CSF pleocytosis.
doi:10.1186/1471-2334-6-78
PMCID: PMC1475592  PMID: 16643642
3.  Pretreatment with Granulocyte Colony-Stimulating Factor Attenuates the Inflammatory Response but Not the Bacterial Load in Cerebrospinal Fluid during Experimental Pneumococcal Meningitis in Rabbits 
Infection and Immunity  1999;67(7):3430-3436.
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.
PMCID: PMC116528  PMID: 10377123
4.  Rapid differentiation of bacterial meningitides by direct gas-liquid chromatography. 
Journal of Clinical Investigation  1982;69(4):979-984.
Rapid identification of Haemophilus influenzae and other bacillary meningitides was attempted by gas-liquid chromatography (GLC) of the metabolic by-products in broth cultures and in cerebrospinal fluid (CSF) samples obtained from experimental meningitis produced in New Zealand White male rabbits. These results were correlated with the GLC of CSF of meningitis patients. A major peak with retention time of succinic acid was found in the broth cultures of all bacilli tested including H. influenzae, Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Proteus mirabilis, Citrobacter freundii, Pseudomonas aeruginosa, and Listeria monocytogenes. Succinic acid was also found in the CSF of experimental meningitis and in the CSF of all patients with H. influenzae and Esch. coli meningitis. This peak was not detected in the blood samples of experimental animals. It was also absent in the broth cultures of all of the gram-positive and gram-negative cocci tested, such as Streptococcus pneumoniae and Neisseria meningitidis. Succinic acid, which appears to be a by product of fermentation, persisted as a clear cut marker in H. influenzae meningitis for at least 3 d after the initiation of treatment. In one patient, the succinic acid peak disappeared during treatment and reappeared with a clinical relapse. Clearly, the presence of succinic acid that can be rapidly detected by GLC in the CSF excludes pneumococcal or meningococcal meningitis and strongly suggests H. influenzae or other bacillary meningitides.
PMCID: PMC370152  PMID: 7042759
5.  Experimental Study of LY333328 (Oritavancin), Alone and in Combination, in Therapy of Cephalosporin-Resistant Pneumococcal Meningitis 
Using a rabbit model of meningitis, we sought to determine the efficacy of LY333328, a semisynthetic glycopeptide, in the treatment of cephalosporin-resistant pneumococcal meningitis. LY333328 was administered at a dose of 10 mg/kg of body weight/day, alone and in combination with ceftriaxone at 100 mg/kg/day with or without dexamethasone at 0.25 mg/kg/day. The therapeutic groups were treated with LY333328 with or without dexamethasone and LY333328-ceftriaxone with or without dexamethasone. Rabbits were inoculated with a cephalosporin-resistant pneumococcal strain (ceftriaxone MIC, 2 μg/ml; penicillin MIC, 4 μg/ml; LY333328 MIC, 0.008 μg/ml) and were treated over a 26-h period beginning 18 h after inoculation. The bacterial counts in cerebrospinal fluid (CSF), the white blood cell count, the lactic acid concentration, the CSF LY333328 concentration, and bactericidal and bacteriostatic activities were determined at different time points. In vitro, LY333328 was highly bactericidal and its use in combination with ceftriaxone at one-half the MIC was synergistic. In the rabbit model, LY333328 alone was an excellent treatment for cephalosporin-resistant pneumococcal meningitis, with a rapid decrease in colony counts and no therapeutic failures. The use of LY333328 in combination with ceftriaxone improved the activity of LY333328, but no synergistic effect was observed. The combination of LY333328 with dexamethasone was also rapidly bactericidal, but two therapeutic failures were observed. The combination of LY333328 with ceftriaxone and dexamethasone was effective, without therapeutic failures.
doi:10.1128/AAC.47.6.1907-1911.2003
PMCID: PMC155831  PMID: 12760866
6.  Genome-Wide Identification of Streptococcus pneumoniae Genes Essential for Bacterial Replication during Experimental Meningitis▿ †  
Infection and Immunity  2010;79(1):288-297.
Meningitis is the most serious of invasive infections caused by the Gram-positive bacterium Streptococcus pneumoniae. Vaccines protect only against a limited number of serotypes, and evolving bacterial resistance to antimicrobials impedes treatment. Further insight into the molecular pathogenesis of invasive pneumococcal disease is required in order to enable the development of new or adjunctive treatments and/or pneumococcal vaccines that are efficient across serotypes. We applied genomic array footprinting (GAF) in the search for S. pneumoniae genes that are essential during experimental meningitis. A total of 6,000 independent TIGR4 marinerT7 transposon mutants distributed over four libraries were injected intracisternally into rabbits, and cerebrospinal fluid (CSF) was collected after 3, 9, and 15 h. Microarray analysis of mutant-specific probes from CSF samples and inocula identified 82 and 11 genes mutants of which had become attenuated or enriched, respectively, during infection. The results point to essential roles for capsular polysaccharides, nutrient uptake, and amino acid biosynthesis in bacterial replication during experimental meningitis. The GAF phenotype of a subset of identified targets was followed up by detailed studies of directed mutants in competitive and noncompetitive infection models of experimental rat meningitis. It appeared that adenylosuccinate synthetase, flavodoxin, and LivJ, the substrate binding protein of a branched-chain amino acid ABC transporter, are relevant as targets for future therapy and prevention of pneumococcal meningitis, since their mutants were attenuated in both models of infection as well as in competitive growth in human cerebrospinal fluid in vitro.
doi:10.1128/IAI.00631-10
PMCID: PMC3019918  PMID: 21041497
7.  Effect of hydration status on cerebral blood flow and cerebrospinal fluid lactic acidosis in rabbits with experimental meningitis. 
Journal of Clinical Investigation  1992;89(3):947-953.
The effects of hydration status on cerebral blood flow (CBF) and development of cerebrospinal fluid (CSF) lactic acidosis were evaluated in rabbits with experimental pneumococcal meningitis. As loss of cerebrovascular autoregulation has been previously demonstrated in this model, we reasoned that compromise of intravascular volume might severely affect cerebral perfusion. Furthermore, as acute exacerbation of the inflammatory response in the subarachnoid space has been observed after antibiotic therapy, animals were studied not only while meningitis evolved, but also 4-6 h after treatment with antibiotics to determine whether there would also be an effect on CBF. To produce different levels of hydration, animals were given either 50 ml/kg per 24 h of normal saline ("low fluid") or 150 ml/kg 24 h ("high fluid"). After 16 h of infection, rabbits that were given the lower fluid regimen had lower mean arterial blood pressure (MABP), lower CBF, and higher CSF lactate compared with animals that received the higher fluid regimen. In the first 4-6 h after antibiotic administration, low fluid rabbits had a significant decrease in MABP and CBF compared with, and a significantly greater increase in CSF lactate concentration than, high fluid rabbits. This study suggests that intravascular volume status may be a critical variable in determining CBF and therefore the degree of cerebral ischemia in meningitis.
PMCID: PMC442942  PMID: 1541682
8.  High Cerebrospinal Fluid (CSF) Penetration and Potent Bactericidal Activity in CSF of NZ2114, a Novel Plectasin Variant, during Experimental Pneumococcal Meningitis▿  
Plectasin is the first defensin-type antimicrobial peptide isolated from a fungus and has potent activity against gram-positive bacteria. By using an experimental meningitis model, the penetration of plectasin into the cerebrospinal fluid (CSF) of infected and uninfected rabbits and the bactericidal activities in CSF of the plectasin variant NZ2114 and ceftriaxone against a penicillin-resistant Streptococcus pneumoniae strain (NZ2114 and ceftriaxone MICs, 0.25 and 0.5 μg/ml, respectively) were studied. Pharmacokinetic analysis showed that there was a significantly higher level of CSF penetration of NZ2114 through inflamed than through noninflamed meninges (area under the concentration-time curve for CSF/area under the concentration-time curve for serum, 33% and 1.1%, respectively; P = 0.03). The peak concentrations of NZ2114 in purulent CSF were observed ∼3 h after the infusion of an intravenous bolus of either 20 or 40 mg/kg of body weight and exceeded the MIC >10-fold for a 6-h study period. Treatment with NZ2114 (40 and 20 mg/kg at 0 and 5 h, respectively; n = 11) caused a significantly higher reduction in CSF bacterial concentrations than therapy with ceftriaxone (125 mg/kg at 0 h; n = 7) at 3 h (median changes, 3.7 log10 CFU/ml [interquartile range, 2.5 to 4.6 log10 CFU/ml] and 2.1 log10 CFU/ml [interquartile range, 1.7 to 2.6 log10 CFU/ml], respectively; P = 0.001), 5 h (median changes, 5.2 log10 CFU/ml [interquartile range, 3.6 to 6.1 log10 CFU/ml] and 3.1 log10 CFU/ml [interquartile range, 2.6 to 3.7 log10 CFU/ml], respectively; P = 0.01), and 10 h (median changes, 5.6 log10 CFU/ml [interquartile range, 5.2 to 5.9 log10 CFU/ml] and 4.2 log10 CFU/ml [interquartile range, 3.6 to 5.0 log10 CFU/ml], respectively; P = 0.03) after the start of therapy as well compared to the CSF bacterial concentrations in untreated rabbits with meningitis (n = 7, P < 0.05). Also, significantly more rabbits had sterile CSF at 5 and 10 h when they were treated with NZ2114 than when they were treated with ceftriaxone (67% [six of nine rabbits] and 0% [zero of seven rabbits], respectively, at 5 h and 75% [six of eight rabbits] and 14% [one of seven rabbits], respectively, at 10 h; P < 0.05). Due to its excellent CSF penetration and potent bactericidal activity in CSF, the plectasin variant NZ2114 could be a promising new option for the treatment of CNS infections caused by gram-positive bacteria, including penicillin-resistant pneumococcal meningitis.
doi:10.1128/AAC.01202-08
PMCID: PMC2663087  PMID: 19188395
9.  Inhibition of leukocyte rolling with polysaccharide fucoidin prevents pleocytosis in experimental meningitis in the rabbit. 
Journal of Clinical Investigation  1994;93(3):929-936.
Inflammatory recruitment of leukocytes into the cerebrospinal fluid (CSF) during bacterial meningitis has been shown to contribute significantly to the neurological damage commonly associated with this serious disease. In this study we tested whether or not inhibition of leukocyte rolling, a precondition for firm leukocyte adhesion to vascular endothelium in vivo, may reduce CSF leukocyte recruitment and associated inflammatory changes in rabbits with experimental meningitis. As documented by intravital microscopy of small venules in the rabbit mesentery and tenuissimus muscle, leukocyte rolling was rapidly and profoundly reduced by intravenous treatment with the polysaccharide fucoidin, a homopolymer of sulfated L-fucose known to block the function of the leukocytic "rolling receptor" L-selectin. Moreover, fucoidin treatment dramatically reduced the accumulation of both leukocytes and plasma protein in the CSF of rabbits challenged intrathecally with pneumococcal antigen. These main findings thus illustrate that inhibition of leukocyte rolling, an early and obligatory step in the process of leukocyte extravasation, may be an effective therapeutic approach to attenuate leukocyte-dependent central nervous system damage in bacterial meningitis.
Images
PMCID: PMC293995  PMID: 7510720
10.  Experimental pneumococcal meningitis: role of leukocytes in pathogenesis. 
Infection and Immunity  1983;41(1):275-279.
Two groups of rabbits with experimental meningitis induced by direct intracisternal inoculation of Streptococcus pneumoniae cells were studied. One group was rendered profoundly leukopenic by nitrogen mustard, and the other had normal leukocyte counts. The two groups had comparable bacterial growth rates (mean generation time, 60 versus 67 min) and ultimate bacterial populations in the cerebrospinal fluid (CSF) (mean log10 CFU, 9.1 versus 8.7); therefore leukocytes did not effectively slow or limit the growth of pneumococci in the CSF in vivo. Increased CSF protein, decreased CSF glucose, and increased CSF lactate levels were similar in both groups, suggesting that leukocytes are not essential for these changes to occur. Quantitative blood cultures revealed identical levels of pneumococcal bacteremia until 13 to 14 h after the initiation of infection, when the leukopenic rabbits showed a larger number of pneumococci in the blood, ultimately exceeding the number reached in nonleukopenic rabbits by 100-fold. Leukocytes therefore limit the extent of pneumococcal bacteremia after infection of the CSF despite their lack of effect on the course or the CSF manifestations of experimental meningitis.
PMCID: PMC264774  PMID: 6862627
11.  Complement (C5)-derived chemotactic activity accounts for accumulation of polymorphonuclear leukocytes in cerebrospinal fluid of rabbits with pneumococcal meningitis. 
Infection and Immunity  1984;46(1):81-86.
Experiments were performed to identify the chemoattractant for polymorphonuclear leukocytes that appears in the cerebrospinal fluid of rabbits with experimental pneumococcal meningitis. Meningitis was induced in anesthetized New Zealand white rabbits by injecting 10(4) cells of stationary-phase Streptococcus pneumoniae type III intracisternally. Before bacteria were injected, cerebrospinal fluid contained neither polymorphonuclear leukocytes nor chemotactic activity. Significant chemotactic activity for rabbit polymorphonuclear leukocytes was detected 12 h after inoculation with bacteria and was maximal after 18 to 20 h. Chemotactic activity appeared in cerebrospinal fluid while concentrations of pneumococci and total protein were increasing but before there was any accumulation of polymorphonuclear leukocytes. The chemotactic activity in cerebrospinal fluid was heat stable (56 degrees C for 30 min), eluted from Sephadex G-75 with a profile identical to that of the chemotactic activity in zymosan-activated rabbit serum, and was inhibited by treatment with antibodies to native human C5. In addition, preincubation of polymorphonuclear leukocytes with partially purified rabbit C5a selectively inhibited their subsequent chemotactic responses to cerebrospinal fluid. These data indicate that complement (C5)-derived chemotactic activity appears in cerebrospinal fluid during the course of experimental pneumococcal meningitis in rabbits and suggest that this activity accounts for the accumulation of polymorphonuclear leukocytes observed in this infection.
PMCID: PMC261424  PMID: 6480117
12.  Quinolone antibiotics in therapy of experimental pneumococcal meningitis in rabbits. 
Using a rabbit model of pneumococcal meningitis, we compared the pharmacokinetics and bactericidal activities in cerebrospinal fluid (CSF) of older (ciprofloxacin, ofloxacin) and newer (levofloxacin, temafloxacin, CP-116,517, and Win 57273) quinolones with those of the beta-lactam ceftriaxone. All quinolones penetrated into the inflamed CSF better than ceftriaxone, and the speed of entry into CSF was closely related to their degrees of lipophilicity. At a dose of 10 mg/kg.h, which in the case of the quinolones already in use in clinical practice produced concentrations attainable in the sera and CSF of humans, ciprofloxacin had no antipneumococcal activity (delta log10 CFU/ml.h, +0.20 +/- 0.14). Ofloxacin (delta log10 CFU/ml.h, -0.13 +/- 0.12), temafloxacin (delta log10 CFU/ml.h, -0.19 +/- 0.18), and levofloxacin (delta log10 CFU/ml.h, -0.24 +/- 0.16) showed slow bactericidal activity (not significantly different from each other), while CP-116,517 (delta log10 CFU/ml.h, -0.59 +/- 0.21) and Win 57273 (delta log10 CFU/ml.h, -0.72 +/- 0.20) showed increased bactericidal activities in CSF that was comparable to that of ceftriaxone at 10 mg/kg.h (delta log10 CFU/ml.h, -0.80 +/- 0.17). These improved in vivo activities of the newer quinolones reflected their increased in vitro activities. All quinolones and ceftriaxone showed positive correlations between bactericidal rates in CSF and concentrations in CSF relative to their MBCs. Only when this ratio exceeded 10 did the antibiotics exhibit rapid bactericidal activities in CSF. In conclusion, in experimental pneumococcal meningitis the activities of new quinolones with improved antipneumococcal activities were comparable to that of ceftriaxone.
PMCID: PMC162589  PMID: 7793857
13.  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 
Infection and Immunity  2000;68(6):3153-3157.
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.
PMCID: PMC97550  PMID: 10816457
14.  New Rapid Diagnostic Tests for Neisseria meningitidis Serogroups A, W135, C, and Y 
PLoS Medicine  2006;3(9):e337.
Background
Outbreaks of meningococcal meningitis (meningitis caused by Neisseria meningitidis) are a major public health concern in the African “meningitis belt,” which includes 21 countries from Senegal to Ethiopia. Of the several species that can cause meningitis, N. meningitidis is the most important cause of epidemics in this region. In choosing the appropriate vaccine, accurate N. meningitidis serogroup determination is key. To this end, we developed and evaluated two duplex rapid diagnostic tests (RDTs) for detecting N. meningitidis polysaccharide (PS) antigens of several important serogroups.
Methods and Findings
Mouse monoclonal IgG antibodies against N. meningitidis PS A, W135/Y, Y, and C were used to develop two immunochromatography duplex RDTs, RDT1 (to detect serogroups A and W135/Y) and RDT2 (to detect serogroups C and Y). Standards for Reporting of Diagnostic Accuracy criteria were used to determine diagnostic accuracy of RDTs on reference strains and cerebrospinal fluid (CSF) samples using culture and PCR, respectively, as reference tests. The cutoffs were 105 cfu/ml for reference strains and 1 ng/ml for PS. Sensitivities and specificities were 100% for reference strains, and 93.8%–100% for CSF serogroups A, W135, and Y in CSF. For CSF serogroup A, the positive and negative likelihood ratios (± 95% confidence intervals [CIs]) were 31.867 (16.1–63.1) and 0.065 (0.04–0.104), respectively, and the diagnostic odds ratio (± 95% CI) was 492.9 (207.2–1,172.5). For CSF serogroups W135 and Y, the positive likelihood ratio was 159.6 (51.7–493.3) Both RDTs were equally reliable at 25 °C and 45 °C.
Conclusions
These RDTs are important new bedside diagnostic tools for surveillance of meningococcus serogroups A and W135, the two serogroups that are responsible for major epidemics in Africa.
There are several strains ofNeisseria meningitidis that can cause seasonal outbreaks of meningitis in Africa. Treatment of patients and containment of the epidemic through vaccination depends on which strain is responsible. The new dipstick tests described here are accurate and suitable for storage and use in resource-poor settings.
Editors' Summary
Background
Bacterial meningitis, a potentially deadly infection of tissues that line the brain and spinal cord, affects over 1 million people each year. Patients with bacterial meningitis usually have fever, headache, and stiff neck, and may become unconscious and die if the disease is not treated within hours. Most cases of bacterial meningitis occur in Africa, particularly in the arid savannah region south of the Sahara known as the Sahel, where epidemic outbreaks of meningitis occur periodically. This region, also called the “meningitis belt,” extends from Senegal and adjacent coastal countries in West Africa across the continent to Ethiopia. Although most outbreaks tend to occur in the dry season, they differ in frequency in different areas of the meningitis belt, and may involve any of several kinds of bacteria. One of the major causes of epidemic meningitis is Neisseria meningitidis, a meningococcus bacterium that exists in several different groups. Group A has been a common cause of epidemic meningitis in Africa, and some outbreaks were due to group C. More recently, group W135 has emerged as an epidemic strain. In addition to prompt diagnosis and treatment of individual cases, effective public health strategies for controlling meningococcal meningitis include rapid identification of outbreaks and determination of the type of bacteria involved, followed by mass vaccination of people in the surrounding area without delay. Vaccines are chosen on the basis of the responsible meningococcal serogroup: either the inexpensive bivalent vaccine A/C or the expensive, less readily available trivalent vaccine A/C/W135. Before the advent of W135 as an epidemic clone, bivalent vaccine was applied in the meningitis belt without identification of the serogroup. With the appearance of the W135 strain in 2003, however, the determination of serogroup before vaccination is important to select an effective vaccine and avoid misspending of limited funds.
Why Was This Study Done?
Because there are few laboratories in the affected countries and epidemiological surveillance systems are inadequate, it is difficult for health authorities to mount a rapid and effective vaccination campaign in response to an outbreak. In addition, because the two main bacteria (meningococcus and pneumococcus) that cause meningitis require different antibiotic treatments, it is important for doctors to find out quickly which bacteria is causing an individual case. The authors of this study wanted to develop a rapid and easy test that can tell whether meningococcus is the cause of a particular case of meningitis, and if so, which group of meningococcus is involved. As most outbreaks in the meningitis belt occur in rural areas that are distant from well-equipped medical laboratories, it was necessary to develop a test that can be carried out at the patient's bedside by nurses, does not require refrigeration or laboratory equipment, and is highly accurate in distinguishing among the different groups of meningococcus.
What Did the Researchers Do and Find?
The researchers have developed a rapid test to determine whether a patient's meningitis is caused by one of the four most common groups of meningococcus circulating in Africa. The test is done on the patient's spinal fluid, which is obtained by a lumbar puncture (spinal tap) as part of the usual evaluation of a patient thought to have meningitis. The test uses two paper strips, also called dipsticks (one for groups A and W135/Y, and the other for groups C and Y), that can be placed in two separate tubes of the patient's spinal fluid. After several minutes, the appearance of red lines on the dipsticks shows whether one of the four groups of meningococcus is present. The dipsticks can be produced in large quantities and relatively cheaply. The researchers showed that the test dipsticks are stable for weeks in hot weather, and are therefore practical for bedside use in resource-poor settings. They examined the test on stored spinal fluid from patients in Niger and found that the dipstick test was able to identify the correct group of meningococcus more than 95% of the time for the three groups represented in these specimens (the results were compared to a standard DNA test or culture that are highly accurate for identifying the type of bacteria present but much more complicated and expensive).
What Do These Findings Mean?
The new dipstick test for meningococcal meningitis represents a major advance for health-care workers in remote locations affected by meningitis epidemics. This test can be stored without refrigeration and used at bedside in the hot temperatures typical of the African savannah during the meningitis season. The dipsticks are easier to use than currently available test kits, give more rapid results, and are more accurate in telling the difference between group Y and the increasingly important group W135. Further research is needed to determine whether the test can be used with other clinical specimens (such as blood or urine), and whether the test is dependable for detecting group C meningococcus, which is common in Europe but rare in Africa. Nonetheless, the dipstick test promises to be an important tool for guiding individual treatment decisions as well as public health actions, including vaccine selection, against the perennial threat of epidemic meningitis.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030337.
World Health Organization fact sheet on meningococcal meningitis
PATH Meningitis Vaccine Project
US Centers for Disease Control and Prevention page on meningococcal disease
doi:10.1371/journal.pmed.0030337
PMCID: PMC1563501  PMID: 16953658
15.  Rosaramicin Versus Penicillin G in Experimental Pneumococcal Meningitis 
Rosaramicin, a new macrolide antibiotic, was compared with penicillin G in the treatment of pneumococcal meningitis in rabbits. Animals were infected intracisternally with 104 colony-forming units of Streptococcus pneumoniae type III (rosaramicin minimal inhibitory/bactericidal concentrations, 0.25/0.5 μg/ml; penicillin G minimal inhibitory/bactericidal concentrations, 0.03/0.06 μg/ml). Treatment was instituted 96 h later. Infusion of rosaramicin at 25 mg/kg per h intravenously for 8 h produced a peak cerebrospinal fluid (CSF) drug concentration of 1.54 μg/ml (range, 0.87-3.6 μg/ml). During this infusion the numbers of pneumococci in CSF decreased from 6.2 ± 0.5 to 3.36 ± 1.12 log10 colony-forming units per ml. Penicillin G, infused at 30 mg/kg per h for 8 h, reached a similar concentration in CSF but caused a greater reduction (P < 0.01) in CSF bacteria, from 6.4 ± 0.36 to 1.3 ± 0.67 log10 colony-forming units per ml. Penicillin G, at 100 mg/kg per day intramuscularly for 5 days, cured 7 of 10 rabbits with pneumococcal meningitis. A higher dose, 300 mg/kg per day for 5 days, was no more efficacious: 11 of 14 rabbits were cured. Rosaramicin at 100 mg/kg per day intramuscularly for 5 days cured only 5 of 15 rabbits with meningitis, but a higher dosage regimen of that drug (250 mg/kg per day intramuscularly) produced acute, fulminant enterocecitis and death within 48 h in seven of eight rabbits. No cytotoxin was detected in the feces of one rabbit with acute enterocecitis. Thus the efficacy of rosaramicin in experimental pneumococcal meningitis, measured by bacterial clearance from CSF and by treatment outcome, was less than that of penicillin G. In addition, high-dose parenteral rosaramicin caused acute, fulminant enterocecitis in a high proportion of treated rabbits.
PMCID: PMC352952  PMID: 43705
16.  Macrophage migration inhibitory factor in cerebrospinal fluid from patients with central nervous system infection 
Critical Care  2009;13(3):R101.
Introduction
Macrophage migration inhibitory factor (MIF) plays an essential pathophysiological role in septic shock, but its role in central nervous system infection (CNS) remains to be defined.
Methods
We investigated cerebrospinal fluid (CSF) levels of MIF in 171 patients who were clinically suspected of having meningitis on admission. Of these, 31 were found to have purulent meningitis of known aetiology, 20 purulent meningitis of unknown aetiology, 59 lymphocytic meningitis and 11 encephalitis, whereas 50 were suspected of having but had no evidence of CNS infection.
Results
CSF MIF levels were significantly higher in patients with purulent meningitis of known aetiology (median [interquartile range]: 8,639 [3,344 to 20,600] ng/l) than in patients with purulent meningitis of unknown aetiology (2,209 [1,516 to 6,550] ng/l; Mann-Whitney test, P = 0.003), patients with lymphocytic meningitis (1,912 [1,302 to 4,105] ng/l; P < 0.001) and patients suspected of having but without evidence of CNS infection (1,472 [672 to 3,447] ng/l; P < 0.001). Also, patients with encephalitis (6,937 [3,961 to 8,353] ng/l) had higher CSF MIF than did patients without CNS infection (P < 0.01). Among patients with purulent meningitis, CSF MIF levels were significantly higher in patients infected with pneumococci than in those with meningococcal infection (11,569 [8,615 to 21,935] ng/l versus 5,006 [1,717 to 10,905] ng/l; P = 0.02), in patients who required versus those not requiring assisted ventilation (10,493 [5,961 to 22,725] ng/l versus 3,240 [1,563 to 9,302] ng/l; P = 0.003), and in patients with versus those without impaired consciousness (8,614 [3,344 to 20,935] ng/l versus 2,625 [1,561 to 7,530] ng/l; P = 0.02). CSF MIF levels correlated significantly with meningeal inflammation (P < 0.05) but not with systemic inflammatory response (P > 0.05) in patients with purulent meningitis of known aetiology, those with lymphocytic meningitis and those with encephalitis.
Conclusions
MIF was significantly increased in the CSF of patients with purulent meningitis and encephalitis, and was to some degree associated with severity of the infection. Our findings indicate that MIF may play an important role in CNS infection.
doi:10.1186/cc7933
PMCID: PMC2717473  PMID: 19558639
17.  Genetic Variation in the β2-Adrenocepter Gene Is Associated with Susceptibility to Bacterial Meningitis in Adults 
PLoS ONE  2012;7(5):e37618.
Recently, the biased β2-adrenoceptor/β-arrestin pathway was shown to play a pivotal role in crossing of the blood brain barrier by Neisseria meningitidis. We hypothesized that genetic variation in the β2-adrenoceptor gene (ADRB2) may influence susceptibility to bacterial meningitis. In a prospective genetic association study we genotyped 542 patients with CSF culture proven community acquired bacterial meningitis and 376 matched controls for 2 functional single nucleotide polymorphisms in the β2-adrenoceptor gene (ADRB2). Furthermore, we analyzed if the use of non-selective beta-blockers, which bind to the β2-adrenoceptor, influenced the risk of bacterial meningitis. We identified a functional polymorphism in ADRB2 (rs1042714) to be associated with an increased risk for bacterial meningitis (Odds ratio [OR] 1.35, 95% confidence interval [CI] 1.04–1.76; p = 0.026). The association remained significant after correction for age and was more prominent in patients with pneumococcal meningitis (OR 1.52, 95% CI 1.12–2.07; p = 0.007). For meningococcal meningitis the difference in genotype frequencies between patients and controls was similar to that in pneumococcal meningitis, but this was not statistically significant (OR 1.43, 95% CI 0.60–3.38; p = 0.72). Patients with bacterial meningitis had a lower frequency of non-selective beta-blockers use compared to the age matched population (0.9% vs. 1.8%), although this did not reach statistical significance (OR 1.96 [95% CI 0.88–4.39]; p = 0.09). In conclusion, we identified an association between a genetic variant in the β2-adrenoceptor and increased susceptibility to bacterial meningitis. The potential benefit of pharmacological treatment targeting the β2-adrenoceptor to prevent bacterial meningitis in the general population or patients with bacteraemia should be further studied in both experimental studies and observational cohorts.
doi:10.1371/journal.pone.0037618
PMCID: PMC3356289  PMID: 22624056
18.  Evaluation of Moxifloxacin, a New 8-Methoxyquinolone, for Treatment of Meningitis Caused by a PenicillinResistant Pneumococcus in Rabbits 
Moxifloxacin is a new 8-methoxyquinolone with high activity against gram-positive bacteria, including penicillin-resistant pneumococci. In an experimental meningitis model, we studied the pharmacokinetics of moxifloxacin in infected and uninfected rabbits and evaluated the antibiotic efficacies of moxifloxacin, ceftriaxone, and vancomycin against a penicillin-resistant Streptococcus pneumoniae strain (penicillin, ceftriaxone, vancomycin, and moxifloxacin MICs were 1, 0.5, 0.5, and 0.125 μg/ml, respectively). Moxifloxacin entered cerebrospinal fluid (CSF) readily, with peak values within 15 to 30 min after bolus intravenous infusion and with a mean percent penetration into normal and purulent CSF of approximately 50 and 80%, respectively. The bactericidal effect of moxifloxacin was concentration dependent, and regrowth was seen only when the concentration of moxifloxacin in CSF was below the minimal bactericidal concentration. All antibiotic-treated groups (moxifloxacin given in two doses of 40 mg/kg of body weight, moxifloxacin in two 20-mg/kg doses, ceftriaxone in one 125-mg/kg dose, and vancomycin in two 20-mg/kg doses) had significantly higher reductions in CSF bacterial concentration than the untreated group (P < 0.05). Moxifloxacin was as effective as vancomycin and ceftriaxone in reducing bacterial counts at all time points tested (3, 5, 10, and 24 h). Moreover, moxifloxacin given in two 40-mg/kg doses resulted in a significantly higher reduction in CSF bacterial concentration (in log10 CFU per milliliter) than vancomycin within 3 h after the start of antibiotic treatment (3.49 [2.94 to 4.78] versus 2.50 [0.30 to 3.05]; P < 0.05). These results indicate that moxifloxacin could be useful in the treatment of meningitis, including penicillin-resistant pneumococcal meningitis.
PMCID: PMC105670  PMID: 9661008
19.  CSF Proteins as Discreminatory Markers of Tubercular and Pyogenic Meningitis 
Introduction: Meningitis is still a major cause of illness in many parts of the world. Though substantial improvement has been occurred in the diagnosis of meningitis, conclusive differentiation between tubercular and pyogenic meningitis remains to be an unsolved problem. Patients with meningitis often have severe neurological deficit or die inspite of antibiotic therapy. Thus, improvement in diagnostic test and therapy is required. The objective of the present study was to find a simple biochemical marker for diagnosis of meningitis and differentiation of tubercular and pyogenic meningitis.
Materials and Methods: CSF samples were collected from 90 paediatric patients from Nilofer Hospital, Hyderabad, India, from age group of 4 months to 12 years. CSF samples were collected by performing Lumbar Puncture under aseptic conditions and with required precaution. CSF samples were divided into 3 groups where Group 1 included Control that was without CSF inflammation, Group 2 with Tuberculous Meningitis & Group 3 consisting of Pyogenic Meningitis with 30 samples in each group. Electrophoretic analysis of CSF proteins was performed which separated as bands of pre-albumin, albumin, alpha, beta and gamma globulins.
Result: Protein content in CSF was 259 ± 409 mg/dl in tuberculous meningitis, whereas in pyogenic meningitis it was 111 ± 83.94 mg/dl and in control group was 19 ± 13.3 mg/dl. Electrophoretic analysis revealed pre-albumin band to be 2.8 ± 1.2 % in tuberculous meningitis, which was significantly decreased when compared with control and pyogenic meningitis. Albumin band in tuberculous meningitis was 34.8 ± 9.9 %, which was also significantly decreased when compared to control and pyogenic meningitis. Alpha band was 19.7 ± 6.9 % in pyogenic meningitis, but in control and tubeculous meningitis it was 10.4 ± 2.9% and 10.3 ± 5.2% respectively. Beta band was found similar in all the three groups. Gamma band was 33.2 ± 8.08% in tuberculous meningitis, 13.8 ± 4.55% in control and 16.7 ± 13.18% in pyogenic meningitis.
Conclusion: Pre-albumin band was found to be decreased and gamma band was shown to be increased in tuberculous meningitis. Alpha band was increased in pyogenic meningitis. Thus, CSF protein fraction separated and quantitated by native Polyacrylamide slab gel electrophoresis, could be used as markers in differentiation of tubercular and pyogenic meningitis.
doi:10.7860/JCDR/2013/6361.3226
PMCID: PMC3782903  PMID: 24086846
Cerebrospinal fluid (CSF); Tubercular meningitis; Pyogenic meningitis; Polyacrylamide slab gel electrophoresis
20.  Effect of Probenecid on Cerebrospinal Fluid Concentrations of Penicillin and Cephalosporin Derivatives 
Probenecid may elevate the cerebrospinal fluid (CSF) concentration of penicillin G by inhibiting the excretion of organic acids from CSF. We have studied this phenomenon with various penicillin and cephalosporin derivatives. Penicillin concentrations were determined in rabbits under steady-state conditions before and after intravenous probenecid administration. With both low-dose and high-dose probenecid, CSF penicillin levels increased two to three times as did CSF concentration as a percentage of serum level. The same probenecid effect was consistently demonstrated in animals with experimental pneumococcal meningitis. Probenecid likewise increased the CSF concentration of ampicillin, carbenicillin, nafcillin, cephacatrile, and cefazolin. Probenecid may prove useful in certain bacterial infections where high CSF antibiotic levels are necessary.
PMCID: PMC444667  PMID: 4157341
21.  Adjuvant TACE inhibitor treatment improves the outcome of TLR2-/- mice with experimental pneumococcal meningitis 
Background
Streptococcus (S.) pneumoniae meningitis has a high lethality despite antibiotic treatment. Inflammation is a major pathogenetic factor, which is unresponsive to antibiotics. Therefore adjunctive therapies with antiinflammatory compounds have been developed. TNF484 is a TNF-alpha converting enzyme (TACE) inhibitor and has been found efficacious in experimental meningitis. Toll-like receptor 2 (TLR2) contributes to host response in pneumococcal meningitis by enhancing bacterial clearing and downmodulating inflammation. In this study, TNF484 was applied in mice, which lacked TLR2 and exhibited a strong meningeal inflammation.
Methods
103 CFU S. pneumoniae serotype 3 was inoculated subarachnoidally into C57BL/6 wild type (wt) mice or TLR2-/-, CD14-/- and CD14-/-/TLR2-/- mice. Severity of disease and survival was followed over 9 days. Response to antibiotics (80 mg/kg ceftriaxone i.p. for 5 days) and/or TACE inhibitor treatment (1 mg/kg s.c. twice daily for 4 days) was evaluated. Animals were sacrificed after 12, 24, and 48 h for analysis of bacterial load in cerebrospinal fluid (CSF) and brain and for TNF and leukocyte measurements in CSF.
Results
TLR2-/- mice were significantly sicker than the other mouse strains 24 h after infection. All knockout mice showed higher disease severity after 48 h and died earlier than wt mice. TNF release into CSF was significantly more elevated in TLR2-/- than in the other strains after 24 h. Brain bacterial numbers were significantly higher in all knockout than wt mice after 24 h. Modulation of outcome by antibiotic and TACE inhibitor treatment was evaluated. With antibiotic therapy all wt, CD14-/- and TLR2-/-/CD14-/- mice, but only 79% of TLR2-/- mice, were rescued. TACE inhibitor treatment alone did not rescue, but prolonged survival in wt mice, and in TLR2-/- and CD14-/- mice to the values observed in untreated wt mice. By combined antibiotic and TACE inhibitor treatment 95% of TLR2-/- mice were rescued.
Conclusion
During pneumococcal meningitis strong inflammation in TLR2-deficiency was associated with incomplete responsiveness to antibiotics and complete response to combined antibiotic and TACE inhibitor treatment. TACE inhibitor treatment offers a promising adjuvant therapeutic strategy in pneumococcal meningitis.
doi:10.1186/1471-2334-7-25
PMCID: PMC1855056  PMID: 17428319
22.  Bactericidal versus Bacteriostatic Antibiotic Therapy of Experimental Pneumococcal Meningitis in Rabbits 
Journal of Clinical Investigation  1983;71(3):411-419.
A rabbit model of pneumococcal meningitis was used to examine the importance of bactericidal vs. bacteriostatic antimicrobial agents in the therapy of meningitis 112 animals were infected with one of two strains of type III Streptococcus pneumoniae. Both strains were exquisitely sensitive to ampicillin, minimum inhibitory concentration (MIC)/minimum bactericidal concentration (MBC)<0.125 μg/ml. The activity of chloramphenicol against the two strains varied: strain1—MIC 2 μg/ml, MBC 16 μg/ml; strain2—MIC 1 μg/ml, MBC 2 μg/ml. Animals were treated with either ampicillin or chloramphenicol in dosages that achieved a peak bactericidal effect in cerebrospinal fluid (CSF) for ampicillin against both strains. Two different dosages were used for chloramphenicol. The first dosage achieved a peak CSF concentration of 4.4±1.1 μg/ml that produced a bacteriostatic effect against strain1 and bactericidal effect against strain2. The second dosage achieved a bactericidal effect against both strains (mean peak CSF concentration 30.0 μg/ml). All animals were treated intramuscularly three times a day for 5 d. CSF was sampled daily and 3 d after discontinuation of therapy for quantitative bacterial cultures. Results demonstrate that only antimicrobial therapy that achieved a bactericidal effect in CSF was associated with cure. Over 90% of animals treated with one of the bactericidal regimens (i.e., animals in which the bacterial counts in CSF dropped >5 log10 colony-forming units [cfu]/ ml after 48 h) had sterile CSF after 5 d of treatment. On the other hand, the regimen that achieved bacteriostatic concentrations (CSF drug concentrations between the MIC and MBC) produced a drop of 2.4 log10 cfu/ml by 48 h; however, none of the animals that survived had sterile CSF after 5 d. These studies clearly demonstrate in a strictly controlled manner that maximally effective antimicrobial therapy of experimental pneumococcal meningitis depends on achieving a bactericidal effect in CSF.
PMCID: PMC436888  PMID: 6826714
23.  Effects of Polysaccharide Fucoidin on Cerebrospinal Fluid Interleukin-1 and Tumor Necrosis Factor Alpha in Pneumococcal Meningitis in the Rabbit 
Infection and Immunity  1999;67(5):2071-2074.
The inflammatory response in bacterial meningitis is mediated by cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1), which are produced in the subarachnoid space by different cells, e.g., leukocytes, astrocytes, and microglia. The recruitment of leukocytes into the cerebrospinal fluid (CSF) has been shown to contribute to the neurological damage in this disease, a process which could be enhanced by treatment with antibiotics. In this study, we have used a rabbit meningitis model for two sets of experiments with intracisternal (i.c.) injections of Streptococcus pneumoniae. First, pneumococcal cell wall (PCW) components were injected i.c., inducing an inflammatory response with pleocytosis and increased levels of CSF TNF-α) and IL-1 at 6 and 12 h after PCW injection. Treatment with fucoidin, known to inhibit leukocyte rolling, abolished pleocytosis and inhibited the release of TNF-α and IL-1. In the second experiment, live pneumococcal bacteria were injected i.c. and treatment with one dose of ampicillin (40 mg/kg of body weight intravenously) was given 16 h after induction of meningitis, causing a sevenfold increase in CSF leukocytes over a 4-h period. CSF IL-1 levels at 16 h were high but did not increase further at 20 h. Also, CSF TNF-α levels were high at 16 h and tended to increase at 20 h. Fucoidin treatment prevented the antibiotic-induced increase of CSF leukocytes but had no effect on the TNF-α and IL-1 levels. Taken together, fucoidin reduced CSF TNF-α and IL-1 levels in acute bacterial meningitis induced by PCW fragments but had no effect later in the course of the disease, when live bacteria were used and an inflammatory increase was caused by a dose of antibiotics.
PMCID: PMC115939  PMID: 10225856
24.  Increase in hippocampal water diffusion and volume during experimental pneumococcal meningitis is aggravated by bacteremia 
BMC Infectious Diseases  2014;14:240.
Background
The hippocampus undergoes apoptosis in experimental pneumococcal meningitis leading to neurofunctional deficits in learning and memory function. The aim of the present study was 1) to investigate hippocampal apparent diffusion coefficient (ADC) and volume with MRI during the course of experimental pneumococcal meningitis, 2) to explore the influence of accompanying bacteremia on hippocampal water distribution and volume, 3) and to correlate these findings to the extent of apoptosis in the hippocampus.
Methods
Experimental meningitis in rats was induced by intracisternal injection of live pneumococci. The study comprised of four experimental groups. I. Uninfected controls (n = 8); II. Meningitis (n = 11); III. Meningitis with early onset bacteremia by additional i.v. injection of live pneumococci (n = 10); IV. Meningitis with attenuated bacteremia by treatment with serotype-specific anti-pneumococcal antibodies (n = 14). T2 and diffusion weighted MR images were used to analyze changes in hippocampus volume and water diffusion (ADC). The results were correlated to ADC of the cortex, to ventricular volume, and to the extent of hippocampal apoptosis.
Results
Both ADC and the volume of hippocampus were significantly increased in meningitis rats compared to uninfected controls (Kruskal-Wallis test, p = 0.0001, Dunns Post Test, p < 0.05), and were significantly increased in meningitis rats with an early onset bacteremia as compared to meningitis rats with attenuated bacteremia (p < 0.05). Hippocampal ADC and the volume and size of brain ventricles were positively correlated (Spearman Rank, p < 0.05), whereas no association was found between ADC or volume and the extent of apoptosis (p > 0.05).
Conclusions
In experimental meningitis increase in volume and water diffusion of the hippocampus are significantly associated with accompanying bacteremia.
doi:10.1186/1471-2334-14-240
PMCID: PMC4016615  PMID: 24886045
Magnetic resonance imaging; ADC; Volume; Oedema; Meningitis; Apoptosis; Hippocampus
25.  Garenoxacin (BMS-284756) and Moxifloxacin in Experimental Meningitis Caused by Vancomycin-Tolerant Pneumococci 
The emergence of multidrug-resistant strains of Streptococcus pneumoniae drives the development and evaluation of new antipneumococcal agents, especially for the treatment of bacterial meningitis. The aims of the present study were to assess the antibacterial effectiveness of two new quinolones, garenoxacin (BMS; BMS-284756) and moxifloxacin (MOX) in experimental meningitis caused by a vancomycin (VAN)-tolerant S. pneumoniae strain and to compare the results with those obtained by therapy with VAN and ceftriaxone (CRO) in combination. Meningitis was induced in young male New Zealand White rabbits by intracisternal inoculation of a VAN-tolerant pneumococcal strain (strain Tupelo) from a child with meningitis. Sixteen hours after inoculation, therapy was given by intravenous administration of BMS at 20 mg/kg of body weight, followed 5 h later by administration at a dosage of 10 mg/kg (n = 9 animals) or MOX as two doses of 20 mg/kg every 5 h (n = 8 animals). For comparison, we studied the following groups: (i) animals treated with VAN (20 mg/kg every 5 h, three doses) and CRO (125 mg/kg, one dose) (n = 9), (ii) animals infected with a VAN-tolerant strain but not treated (n = 8), (iii) animals infected with a VAN-tolerant pneumococcus isolated from the nasopharynx of a carrier and treated with BMS (n = 8), and (iv) animals infected with a cephalosporin-resistant type 6B S. pneumoniae strain and treated with BMS (n = 6). The MICs of penicillin, CRO, VAN, BMS, and MOX for the Tupelo strain were 2, 1, 0.5, 0.06, and 0.03 μg/ml, respectively. The rates of killing of strain Tupelo (the change in the log10 number of CFU per milliliter per hour) in cerebrospinal fluid at 5 h were −0.70 ± 0.35, −0.61 ± 0.44, and −0.49 ± 0.36 for BMS, MOX, and VAN-CRO, respectively. Therapy with BMS and MOX was as effective as therapy with VAN-CRO against VAN-tolerant pneumococcal meningitis in rabbits.
doi:10.1128/AAC.47.1.211-215.2003
PMCID: PMC148949  PMID: 12499193

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