Gram-negative Bacterial Meningitis Research Articles

Clinical characteristics and antimicrobial therapy of healthcare-associated carbapenem-non-susceptible gram-negative bacterial meningitis: a 16-year retrospective cohort study

ObjectiveHealthcare-associated Gram-negative bacterial meningitis is a substantial clinical issue with poor outcomes, especially for neurosurgical patients. Here, we aimed to study the characteristics and treatment options of patients with healthcare-associated carbapenem-non-susceptible (Carba-NS) Gram-negative bacterial meningitis.MethodsThis observational cohort study was conducted at a teaching hospital from 2004 to 2019. The clinical characteristics of patients with meningitis with Carba-NS and carbapenem-susceptible (Carba-S) bacilli were compared, and the antimicrobial chemotherapy regimens and outcomes for Carba-NS Gram-negative bacterial meningitis were analyzed.ResultsA total of 505 patients were included, of whom 83.8% were post-neurosurgical patients. The most common isolates were Acinetobacter spp. and Klebsiella spp., which had meropenem-resistance rates of 50.6% and 42.5%, respectively, and showed a markedly growing carbapenem-resistance trend. Kaplan–Meier curve analysis revealed that Carba-NS Gram-negative bacilli were associated with a significantly higher in-hospital mortality rate (18.8%, 35/186) compared to the Carba-S group (7.4%, 9/122; P = 0.001). For Carba-NS Enterobacterales meningitis, aminoglycoside-based and trimethoprim-sulfamethoxazole-based regimens yielded significantly higher clinical efficacy rates than non-aminoglycoside-based and non-trimethoprim-sulfamethoxazole-based regimens (69.0% vs. 38.7%, P = 0.019 and 81.8% vs. 46.9%, P = 0.036, respectively). For Carba-NS A. baumannii complex meningitis, tetracycline-based (including doxycycline, minocycline, or tigecycline) therapy achieved a significantly higher clinical efficacy rate (62.9%, 22/35) than the non-tetracycline-based therapy group (40.4%, 19/47; P = 0.044).ConclusionsOur findings revealed that Carba-NS Gram-negative bacilli are associated with higher in-hospital mortality in patients with healthcare-associated meningitis. The combination therapies involving particular old antibiotics may improve patients’ outcome.Trial registrationThis study was registered on the Chinese Clinical Trial Register under ChiCTR2000036572 (08/2020).

CsiR-mediated signal transduction pathway in response to low iron conditions promotes Escherichia coli K1 invasion and penetration of the blood-brain barrier.

Escherichia coli K1 is the leading cause of neonatal Gram-negative bacterial meningitis, but the pathogenesis of E. coli K1 meningitis remains unclear. Blood-brain barrier (BBB) penetration is a crucial step in E. coli meningitis development. Here, we uncovered the crucial role of CsiR, a GntR family regulator, in E. coli K1 virulence. During infection, csiR expression was induced due to the derepression by Fur in the blood and human brain microvascular endothelial cells (HBMECs). CsiR positively regulated ilvB expression, which is associated with branched chain amino acid synthesis. Furthermore, we revealed that IlvB activated the FAK/PI3 K pathway of HBMECs to induce actin cytoskeleton rearrangements, thereby promoting the bacterial invasion and penetration of the BBB. Overall, this study reveals a CsiR-mediated virulence regulation pathway in E. coli K1, which may provide a useful target for the prevention or therapy of E. coli meningitis.

Spontaneous Gram-negative Bacterial Meningitis Following Steroid Therapy for Severe COVID-19

Abstract This case demonstrates an unusual case of spontaneous Gram-negative bacillary meningitis (GNBM) due to Serratia following COVID-19 and steroid exposure. A 52-year-old male presented with clinical features of acute meningitis following a prolonged hospitalization for severe COVID-19 pneumonia, during which he was administered corticosteroids. Neuroimaging was normal. Cerebrospinal fluid (CSF) analysis revealed high protein, hypoglycorrhachia, and neutrophilic pleocytosis. The Gram stain showed plenty of neutrophils but no bacteria. CSF culture demonstrated convex 1–2 mm colonies, slightly umbonate with entire margins, and opaque. On VITEK2, this was identified as Serratia marcescens and was susceptible to all tested antibiotics. Clinical improvement was noted after 48 h with the administration of meropenem (2 g q8 h) and levofloxacin (750 mg once daily). After a week of treatment, repeat CSF analysis showed a decrease in the CSF protein and total white blood cells, lymphocytic pleocytosis, and an increase in the CSF glucose. The patient made a complete recovery following 3 weeks of antibiotic therapy. This case report highlights that steroids should be used cautiously and judiciously in the COVID-19 setting. Serratia is a rare cause of spontaneous GNBM.

Salmonella meningitis, an unusual complication of salmonella species: a case report from Nepal.

A 16-year-old boy presented with high-grade fever and altered sensorium for 2 days associated with vomiting, headache, and photophobia. After invading the abdominal barrier, Salmonella can enter bloodstream and rarely present with meningitis. Cerebrospinal fluid analysis and culture supported with other investigations can diagnose bacterial meningitis and its causative agent. Adequate treatment is essential to completely cure and prevent relapse. Given its invasive nature and potential serious consequences, such as relapse and antibiotic resistance, prompt, and appropriate treatment of Salmonella meningitis is essential.

A high-throughput sequencing approach identifies immunotherapeutic targets for bacterial meningitis in neonates.

Worldwide, Escherichia coli is the leading cause of neonatal Gram-negative bacterial meningitis, but full understanding of the pathogenesis of this disease is not yet achieved. Moreover, to date, no vaccine is available against bacterial neonatal meningitis. Here, we used Transposon Sequencing of saturated banks of mutants (TnSeq) to evaluate E.coli K1 genetic fitness in murine neonatal meningitis. We identified E.coli K1 genes encoding for factors important for systemic dissemination and brain infection, and focused on products with a likely outer-membrane or extra-cellular localization, as these are potential vaccine candidates. We used invitro and invivo models to study the efficacy of active and passive immunization. We selected for further study the conserved surface polysaccharide Poly-β-(1-6)-N-Acetyl Glucosamine (PNAG), as a strong candidate for vaccine development. We found that PNAG was a virulence factor in our animal model. We showed that both passive and active immunization successfully prevented and/or treated meningitis caused by E.coli K1 in neonatal mice. We found an excellent opsonophagocytic killing activity of the antibodies to PNAG and invitro these antibodies were also able to decrease binding, invasion and crossing of E.coli K1 through two blood brain barrier cell lines. Finally, to reinforce the potential of PNAG as a vaccine candidate in bacterial neonatal meningitis, we demonstrated that Group B Streptococcus, the main cause of neonatal meningitis in developed countries, also produced PNAG and that antibodies to PNAG could protect invitro and invivo against this major neonatal pathogen. Altogether, these results indicate the utility of a high-throughput DNA sequencing method to identify potential immunotherapy targets for a pathogen, including in this study a potential broad-spectrum target for prevention of neonatal bacterial infections. ANR Seq-N-Vaq, Charles Hood Foundation, Hearst Foundation, and Groupe Pasteur Mutualité.

The Epidemiology of Meningitis in Infants under 90 Days of Age in a Large Pediatric Hospital.

Background: Meningitis is associated with substantial morbidity and mortality, particularly in the first three months of life. Methods: We conducted a retrospective review of patients <90 days of age with meningitis at Texas Children’s Hospital from 2010–2017. Cases were confirmed using the National Healthcare Safety Network (NHSN) definition of meningitis. Results: Among 694 infants with meningitis, the most common etiology was viral (n = 351; 51%), primarily caused by enterovirus (n = 332; 95%). A quarter of cases were caused by bacterial infections (n = 190; 27%). The most common cause of bacterial meningitis was group B Streptococcus (GBS, n = 60; 32%), followed by Gram-negative rods other than E. coli (n = 40; 21%), and E. coli (n = 37; 19%). The majority of Gram-negative organisms (63%) were resistant to ampicillin, and nearly one-fourth of Gram-negative rods (23%) other than E. coli and 2 (6%) E. coli isolates were resistant to third-generation cephalosporins. Significant risk factors for bacterial meningitis were early preterm birth and the Black race. Conclusions: Enteroviruses most commonly caused viral meningitis in infants; GBS was the most common bacterial cause despite universal screening and intrapartum prophylaxis. The emergence of MRSA and resistance to third-generation cephalosporins in Gram-negative bacterial meningitis challenges the options for empirical antimicrobial therapy.

The clinical characteristics of spontaneous Gram-negative bacterial meningitis in adults: A hospital-based study

The epidemiologic trend of acute bacterial meningitis can change more dramatically than any other bacterial disease, and a decrease in spontaneous adult bacterial meningitis (ABM) has been noted in serial studies of the epidemiologic trend of ABM in Taiwan. The purpose of this study was to analyze the clinical characteristics, laboratory data and therapeutic outcomes of 149 patients with spontaneous Gram-negative (G(−)) ABM collected during a study period of 31 years (1986–2016). The 149 patients included 107 men and 42 women, aged 18–86 years. The common underlying conditions were diabetes mellitus, liver cirrhosis and alcoholism, and the leading clinical presentations were fever, altered consciousness and septic shock. Compared the clinical characteristics of the patients identified in the study period of 2001–2106 to the patients identified in the study period of 1986–2000, the former group of patients had a significantly higher incidence of systemic malignance. In the recent 16 years (2001–2016), Klebsiella pneumoniae, Pseudomonas spp. and Escherichia coli were the leading three implicated bacterial pathogens of spontaneous G(−) ABM, accounting for 61.3% (38/62), 11.3% (7/62) and 11.3% (7/62%) of all cases, respectively. The overall mortality rate from spontaneous G(−) ABM was high (47.0%, 70/149) and the presence of septic shock and lower cerebrospinal fluid glucose level were significant prognostic factors. Because of the decreasing incidence of spontaneous ABM in Taiwan, close examination of this specific infectious syndrome is important in order to monitor the epidemiologic trend and improve the therapeutic strategy.

Caspr1 is a host receptor for meningitis-causing Escherichia coli

Escherichia coli is the leading cause of neonatal Gram-negative bacterial meningitis, but the pathogenesis of E. coli meningitis remains elusive. E. coli penetration of the blood–brain barrier (BBB) is the critical step for development of meningitis. Here, we identify Caspr1, a single-pass transmembrane protein, as a host receptor for E. coli virulence factor IbeA to facilitate BBB penetration. Genetic ablation of endothelial Caspr1 and blocking IbeA–Caspr1 interaction effectively prevent E. coli penetration into the brain during meningitis in rodents. IbeA interacts with extracellular domain of Caspr1 to activate focal adhesion kinase signaling causing E. coli internalization into the brain endothelial cells of BBB. E. coli can invade hippocampal neurons causing apoptosis dependent on IbeA–Caspr1 interaction. Our results indicate that E. coli exploits Caspr1 as a host receptor for penetration of BBB resulting in meningitis, and that Caspr1 might be a useful target for prevention or therapy of E. coli meningitis.

Feasibility of Neurapheresis™ as a Therapy for Multidrug Resistant Gram-negative Bacterial Meningitis

BackgroundThe World Health Organization has identified Pseudomonas, Acinetobacter and Klebsiella (PAK) as three multidrug resistant (MDR) gram-negative pathogens that pose a threat to human health. The greatest threat lies in hospitals, nursing homes, and patients with devices such as intravenous catheters and ventilators. Gram-negative bacterial meningitis (GBM) manifests when these bacteria invade the central nervous system. Due to the threat of increasing antibiotic resistance and the high mortality associated with MDR GBM, we have tested a closed-loop, extracorporeal cerebrospinal fluid (CSF) filtration system (NeurapheresisTM) for its applicability in this context. Here we demonstrate feasibility of Neurapheresis for MDR GBM and characterize system parameters for bacterial clearance.Methods PAK cultures were grown and diluted to 1 × 107 cells/mL in artificial CSF or Luria-Miller broth. Both single pass and closed loop filtration were performed with various tangential flow filtration (TFF) and dead-end filter paradigms. Samples were taken either immediately post-filter or after every full CSF volume cycle (150 mL) during a long-term closed loop experiment. Bacterial load, endotoxin and cytokines were quantified.ResultsIn single pass tests, 5kDa and 100kDa TFF filters and 0.2µm and 0.45µm dead-end filters excluded all PAK organisms completely. The 100kDa and 5kDa TFF filters significantly reduced endotoxin concentration by >95% and >99% of baseline, respectively. The 5 kDa TFF filters produced a 2-log (>99%) reduction in cytokines (IL-1ra, IL-6, TNF, CRP, and CXCL10). In closed-loop experiments, both TFF filters demonstrated a 1–2 Log CFU (90–99%) reduction of all PAK organisms over 4 filtration cycles.ConclusionNeurapheresis shows potential to be an efficient multi-modal tool for controlling and treating MDR GBM in this in vitro model. Extending closed loop filtration over time demonstrates capability for rapid sterilization of the CSF. Future iterations may include adjunctive intrathecal drug delivery to further accelerate elimination of bacteria. Reduction of both endotoxin and cytokines by Neurapheresis may have significant implications for controlling the damaging neuro-inflammatory response during MDR GBM.Disclosures B. Hedstrom, Minnetronix, Inc.: Employee, Salary; L. Zitella Verbick, Minnetronix, Inc.: Employee, Salary; A. Mccabe, Minnetronix, Inc.: Employee, Salary; S. P. Lad, Minnetronix, Inc.: Collaborator and Scientific Advisor, Licensing agreement or royalty, Research grant and Research support; V. Fowler Jr., Pfizer, Novartis, Galderma, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Cubist, Basilea, Affinergy, Janssen, xBiotech, Contrafect: Consultant, Consulting fee; NIH, MedImmune, Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius: Grant Investigator, Grant recipient; Green Cross, Cubist, Cerexa, Durata, Theravance; Debiopharm: Consultant, Consulting fee; UpToDate: Royalties, Royalties

The molecular characterisation of Escherichia coli K1 isolated from neonatal nasogastric feeding tubes.

BackgroundThe most common cause of Gram-negative bacterial neonatal meningitis is E. coli K1. It has a mortality rate of 10–15 %, and neurological sequelae in 30–50 % of cases. Infections can be attributable to nosocomial sources, however the pre-colonisation of enteral feeding tubes has not been considered as a specific risk factor.MethodsThirty E. coli strains, which had been isolated in an earlier study, from the residual lumen liquid and biofilms of neonatal nasogastric feeding tubes were genotyped using pulsed-field gel electrophoresis, and 7-loci multilocus sequence typing. Potential pathogenicity and biofilm associated traits were determined using specific PCR probes, genome analysis, and in vitro tissue culture assays.ResultsThe E. coli strains clustered into five pulsotypes, which were genotyped as sequence types (ST) 95, 73, 127, 394 and 2076 (Achman scheme). The extra-intestinal pathogenic E. coli (ExPEC) phylogenetic group B2 ST95 serotype O1:K1:NM strains had been isolated over a 2 week period from 11 neonates who were on different feeding regimes. The E. coli K1 ST95 strains encoded for various virulence traits associated with neonatal meningitis and extracellular matrix formation. These strains attached and invaded intestinal, and both human and rat brain cell lines, and persisted for 48 h in U937 macrophages. E. coli STs 73, 394 and 2076 also persisted in macrophages and invaded Caco-2 and human brain cells, but only ST394 invaded rat brain cells. E. coli ST127 was notable as it did not invade any cell lines.ConclusionsRoutes by which E. coli K1 can be disseminated within a neonatal intensive care unit are uncertain, however the colonisation of neonatal enteral feeding tubes may be one reservoir source which could constitute a serious health risk to neonates following ingestion.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-015-1210-7) contains supplementary material, which is available to authorized users.

Neurosurgical Meningitis: Clinico-Microbiological Profile and Treatment Outcome from a Tertiary Care Center in India

Background Meningitis following neurosurgical procedure is a well-recognized and potentially fatal complication. The Indian literature on microbiological epidemiology is scarce. The aim of our study was to know clinical, microbiological profile and treatment outcomes of patients with neurosurgical meningitis at our center. Methods This was a retrospective observational cohort study of 25 culture-proven neurosurgical meningitis cases performed at the Apollo Speciality Hospital, Chennai, India, between January 2009 and May 2012. Results In our study, nine patients had skull fracture and cerebrospinal fluid leak, nearly 50% of the patients underwent craniotomy, and five patients had endoscopic surgery while 64% of the patients required shunt placement or drains. Only nine patients (36%) had definite clinical signs of meningitis and mean duration of onset of symptoms from surgery was 11.12 days. A total of 18 patients (72%) had gram-negative bacterial meningitis and majority (83.3%) was due to carbapenem-resistant organisms. Predominant isolate was Pseudomonas aeruginosa (44.4%), and the second most common isolate was Acinetobacter baumannii (33.3%). Among cases of gram-negative bacterial meningitis, patients who had carbapenem-resistant isolates were given combination antimicrobials (carbapenem/cefepime tazobactam with colistin/gentamicin) as per susceptibility via intravenous and intrathecal through the drain (extraventricular or lumbar). Only five patients (27.7%) had a complete cure. Conclusion Gram-negative organisms, mainly Pseudomonas and Acinetobacter , are predominant pathogen in neurosurgical meningitis in our center. While treating multidrug-resistant gram-negative meningitis, device removal and a combination of antimicrobial agents via both intravenous and intraventricular routes are crucial to achieve cure.

Intraperitoneal prophylaxis with CpG oligodeoxynucleotides protects neutropenic mice against intracerebral Escherichia coli K1 infection

BackgroundProphylaxis with unmethylated cytosine phosphate guanidine (CpG) oligodeoxynucleotides (ODN) protects against several systemic experimental infections. Escherichia coli is a major cause of Gram-negative neonatal bacterial meningitis and also causes meningitis and meningoencephalitis in older and immunocompromised patients.MethodsWild-type (wt) and Toll-like receptor 9 (TLR9)-deficient mice were rendered neutropenic by intraperitoneal administration of the anti-Ly-6G monoclonal antibody. Immunocompetent and neutropenic mice received intraperitoneal CpG ODN or vehicle 72 h prior to induction of E. coli K1 meningoencephalitis.ResultsPre-treatment with CpG ODN significantly increased survival of neutropenic wt mice from 33% to 75% (P = 0.0003) but did not protect neutropenic TLR9-/- mice. The protective effect of CpG ODN was associated with an enhanced production of interleukin (IL)-12/IL-23p40 with sustained increased levels in serum and spleen at least for 17 days after conditioning compared to buffer-treated animals. CpG-treated neutropenic wt mice showed reduced bacterial concentrations and increased recruitment of Ly6ChighCCR2+ monocytes in brain and spleen 42 h after infection. The levels of macrophage inflammatory protein 1α (MIP-1α) and interferon gamma (IFN-γ) in spleen were higher 42 h after infection in CpG-treated compared to buffer-treated neutropenic animals. In immunocompetent mice, prophylaxis with CpG ODN did not significantly increase survival compared to the buffer group (60% vs. 45%, P = 0.2).ConclusionsThese findings suggest that systemic administration of CpG ODN may help to prevent bacterial CNS infections in immunocompromised individuals.

Resistance of the Brain to Escherichia coli K1 Infection Depends on MyD88 Signaling and the Contribution of Neutrophils and Monocytes

Escherichia coli is the leading cause of Gram-negative neonatal bacterial meningitis and also causes meningitis and meningoencephalitis in older and immunocompromised patients. Here, we determined the contribution of granulocytes, monocytes, and TLR signaling cascades in the resistance of adult mice to Escherichia coli K1 brain infection. Deficiency in MyD88 (myd88(-/-)) but not in TRIF (trif(lps2)) adaptor proteins dramatically reduced the survival of animals. Depletion of CD11b(+) Ly-6G(+) Ly-6C(int) neutrophils by application of the anti-Ly-6G (1A8) monoclonal antibody (MAb) led to higher bacterial loads in cerebellum and spleen tissue and resulted in increased mortality compared to those of isotype-treated controls. Depletion of CD11b(+) Ly-6G(+) Ly-6C(int) neutrophils and CD11b(+) Ly-6G(-) Ly-6C(high) monocytes by administration of the anti-Gr-1 (RB6-8C5) MAb rendered mice even more susceptible to the infection, with higher central nervous system (CNS) and spleen bacterial burdens than anti-Ly-6G-treated animals. Depletion of ∼50% of CD11b(+) Ly-6G(-) Ly-6C(high) monocytes by injection of the anti-CCR2 (MC-21) MAb resulted in a trend toward higher mortality compared to that with isotype treatment. Production of interleukin 1β (IL-1β), IL-6, KC, and MIP-2 in the CNS strongly depended on the bacterial load: increased levels of these cytokines/chemokines were found after depletion of CD11b(+) Ly-6G(+) Ly-6C(int) neutrophils alone or together with CD11b(+) Ly-6G(-) Ly-6C(high) monocytes. These findings identify Toll-like receptor (TLR)-MyD88 signaling and neutrophil and monocyte activity as critical elements in the early host defense against E. coli meningitis.

Neonatal bacterial meningitis in Turkey: epidemiology, risk factors, and prognosis

We aimed to determine the incidence, etiology, risk factors and outcome of bacterial meningitis in neonates. Neonates who developed bacterial meningitis between 2003 and 2010 in a tertiary hospital in Turkey were included in the study. Patients born in our hospital were defined as Group 1 and patients referred from other centres were defined as Group 2. Patients with evidence of congenital infections or central nervous system malformations were excluded. Demographic features, delivery type, time of onset of meningitis, co-morbidities, clinical features, blood and cerebrospinal fluid (CSF) analysis, cranial sonographic findings, and outcome of patients were recorded. The study comprised 325 meningitis cases identified from 38,023 hospitalised patients in the neonatology unit among 11,8091 live births. Mean gestational age, birth weight, and hospital stay were 36.8 ± 3.7 weeks, 2.480 ± 924 g, and 26 ± 12.4 days, respectively. Almost half (48%) of the patients were diagnosed in the first seven postnatal days and 52% at 8-30 days after birth. CSF culture findings were positive in 59 (18%) patients (28 in Group 1 and 31 in Group 2). Gram-positive bacteria were the responsible agents in 30 (51%) patients, whereas 26 (44%) patients had Gram-negative bacterial meningitis and 3 (5%) had Candida meningitis. Gram-negative bacteria were predominant in Group 1 whereas Gram positive bacteria were predominant in Group 2. Transfontanel ultrasonography revealed pathologic findings in 17.5% of patients. The total mortality rate was 2.5%. This large-scale study provides essential information about the etiology, characteristics, and outcome of neonatal bacterial meningitis in Turkey.

Klebsiella Meningitis

Acute bacterial meningitis is a severe CNS infection occurring mostly in infants and older children. Bacterial meningitis caused by gram-negative bacteria is usually fatal. Klebsiella pneumoniae is an uncommon gram-negative bacteria causing meningitis with a poor outcome. Though the commonest presentation of bacterial meningitis is fever, patients usually seek medical attention for uncontrolled seizure and features of raised ICP. The commonest complications of gram-negative bacterial meningitis including Klebsiella meningitis are subdural hygroma / empyema, hydrocephalus, infarcts (both arterial and venous) and cortical blindness due to hypoxic ischaemic insult. MRI is the best modality for evaluating these patients for early diagnosis. Early institution of treatment significantly reduces the mortality and morbidity. We describe a case of acute bacterial meningitis caused by Klebsiella pneumoniae with MR evidence of sinus thrombosis, venous infarcts and subdural hygroma.

Targeting neutrophil collagenase/matrix metalloproteinase-8 and gelatinase B/matrix metalloproteinase-9 with a peptidomimetic inhibitor protects against endotoxin shock

Gram-negative sepsis, bacterial meningitis and endotoxin shock are life-threatening disorders, associated with the rapid release of neutrophil enzymes. Neutrophil collagenase/matrix metalloproteinase-8 (MMP-8) and gelatinase B/matrix metalloproteinase-9 (MMP-9) are contained in granules, are quickly exocytosed upon granulocyte activation and efficiently cleave intact and denatured collagens, respectively. Genetic ablation of gelatinase B protects against endotoxin-induced mortality. Therefore, we designed and synthesized a peptidomimetic gelatinase B inhibitor Regasepin1, and compared the selectivity for the collagenases MMP-1, MMP-8 and MMP-13. Regasepin1 was found to inhibit, almost to the same degree, the neutrophil enzymes MMP-8 and MMP-9 and the monocytic tumor necrosis factor-α (TNF-α) converting enzyme (TACE/ADAM-17) in vitro. With the use of mass spectrometry analysis, the plasma half-life of inhibitor levels was determined after an intraperitoneal bolus injection in mice. Plasma peak levels of the inhibitor were reached at 50 min after intraperitoneal injection and the subsequent half-life in the circulation exceeded 40 min. Regasepin1 protected mice against lethal endotoxinemia by intraperitoneal and intravenous injection routes. This proofs the principle that early neutrophil MMP inhibition followed by TACE blockade may become a treatment strategy of gram-negative sepsis, endotoxinemia and other life-threatening inflammatory reactions.

Treatment of Salmonella meningitis: two case reports and a review of the literature

Background: Salmonella species now represent a leading cause of Gram-negative bacterial meningitis in the developing world. Various drugs have been used for the treatment of Salmonella meningitis over the past decades, but mortality, neurologic sequelae and relapse rates remain high. In this report we describe two children aged 8 and 9 months who presented within a week to our hospital with Salmonella meningitis. They were treated with penicillin and chloramphenicol but progressed rapidly to death within 48 h. Aim: The aim of this article is to review all published English literature on the treatment of Salmonella meningitis and identify the best drug option for its treatment. This was done by comparing the outcomes such as cure, failure, relapse, and death rates. Method: A Medline electronic search was carried out to find and retrieve articles that have been published since 1987, when the last review of Salmonella meningitis was done. Results: Salmonella typhimurium was the commonest organism reported, and 89.7% of infections occurred in children less than 1 year old. Fluoroquinolones had a cure rate of 88.9%, while the third-generation cephalosporins had a cure rate of 84.6%. Conventional antibiotics (chloramphenicol, ampicillin, and cotrimoxazole) had a cure rate of 41.2%, a relapse rate of 11.8%, and an associated mortality of 44.7%. Treatment with fluoroquinolone and imipenem resulted in no deaths. There were, however, only two cases that were treated with imipenem. Conclusion: When Salmonella meningitis is suspected, third-generation cephalosporins, with or without a fluoroquinolone, may be the best option for treatment.

C-Reactive Protein Concentrations in Cerebral Spinal Fluid in Gram-positive and Gram-negative Bacterial Meningitis

Several reports have shown an ability of C-reactive protein (CRP) to discriminate between patients with bacterial meningitis and patients with aseptic (viral) meningitis (1)(2). Although a recent metaanalysis suggested that a negative CRP test in either cerebrospinal fluid (CSF) or serum can be used with a very high probability to rule out bacterial meningitis (3), a more recent report (4) suggested that serum concentrations are a better screening tool for this differential diagnosis. To assess the ability of CSF CRP to differentiate gram-positive from gram-negative meningitis, we compared CRP concentrations in the blood and CSF, along with CSF nitric oxide (NO), protein, glucose, and leukocyte count, in 17 consecutive patients (age range, 2 months to 47 years) with suspected bacterial meningitis and in noninfected controls. The two patient groups had comparable CSF leukocyte counts and protein and glucose concentrations, and were not considerably different with respect to dispersion of gender and age. …

Facteurs de virulence associés à E. coli responsable de méningite néonatale

Escherichia coli K1 is the leading cause of gram-negative bacterial meningitis in neonates. It is associated with a mortality rate as high as 40%, and more than half of the survivors have neurologic sequelae. Bacterial meningitis is the result of bacterial translocation from gastrointestinal tract to the blood and from blood to the central nervous system. Succeful crossing of the BBB by E. coli K1 requires (a) a high degree of bacteremia and (b) several E. coli determinants contributing to invasion of BMEC such as the K1 capsule, Sfa, Ibe proteins, and CNF1. A better understanding for the molecular basis of E. coli K1 penetration of the BBB could potentially lead to the development of novel therapeutic and preventative strategies for E. coli K1 meningitis.

Application of Signature-Tagged Mutagenesis for Identification of Escherichia coli K1 Genes That Contribute to Invasion of Human Brain Microvascular Endothelial Cells

Escherichia coli K1 is the leading cause of gram-negative bacterial meningitis in neonates. It is principally due to our limited understanding of the pathogenesis of this disease that the morbidity and mortality rates remain unacceptably high. To identify genes required for E. coli K1 penetration of the blood-brain barrier (BBB), we used the negative selection strategy of signature-tagged transposon mutagenesis (STM) to screen mutants for loss or decreased invasion of human brain microvascular endothelial cells (HBMEC) which comprise the BBB. A total of 3,360 insertion mutants of E. coli K1 were screened, and potential HBMEC invasion mutants were subjected to a secondary invasion screen. Those mutants that failed to pass the serial invasion screens were then tested individually. Seven prototrophic mutants were found to exhibit significantly decreased invasive ability in HBMEC. We identified traJ and five previously uncharacterized loci whose gene products are necessary for HBMEC invasion by E. coli K1. In addition, cnf1, a gene previously shown to play a role in bacterial invasion, was identified. More importantly, a traJ mutant was attenuated in penetration of the BBB in the neonatal rat model of experimental hematogenous meningitis. This is the first in vivo demonstration that traJ is involved in the pathogenesis of E. coli K1 meningitis.