Treatment Of Meningitis Research Articles

Paradoxical reaction in the treatment of tuberculous meningitis – pitfalls and challenges

Paradoxical reaction during the treatment of tuberculous meningitis (TBM) poses both diagnostic and therapeutic challenge in the management. We report a patient with miliary tuberculosis and TBM who developed an enhanced paradoxical reaction and discuss the challenges of its management. A 22-year-old woman presented with fever and headache for two weeks with features of meningism on examination. Miliary tuberculosis with TBM was diagnosed based on positive cerebrospinal fluid (CSF) and sputum Gene-Xpert MTB/RIF. The chest radiograph showed a miliary pattern. Six weeks after starting antituberculosis treatment (ATT), she presented with worsening headache and repeat magnetic resonance imaging (MRI) showed increase in the number and size of tuberculomas. Prednisolone dose was increased. At 10 weeks after starting ATT, her symptoms persisted, and MRI showed further worsening of lesions. Intravenous dexamethasone was administered and gradually tapered with oral prednisolone. This resulted in resolution of symptoms and radiological lesions. Paradoxical reaction in TBM is a recognized phenomenon during the treatment of tuberculosis. Awareness of this complication and its treatment can prevent the morbidity associated with this reaction.

The use of intrathecal antibiotics for bacterial meningitis: what evidence do we have?

The treatment of meningitis is a complex issue when it comes to multi-resistant antibiotic (ATB) bacteria, limiting the drug options that can cross the blood-brain barrier and effectively reach the subarachnoid space. The impact on the effectiveness of the therapeutic arsenal available, due to the indiscriminate use of antibacterial on a global scale, increases the chances of therapeutic failure of the initial empirical treatment and a persistence of failure despite the culture of targeting the treatment at the pathogens, while not obtaining satisfactory results. Thus, the use of strategies to optimize the delivery of antibacterials to the pathology site involves using the pharmacokinetic mechanism in order to achieve the desired effect through intrathecal administration. During this review, we aimed to evaluate the use of intrathecal antibiotic therapy in patients infected with multidrug-resistant bacteria and analyze possible adverse effects.

Outcome of Bacterial Meningitis in Children age 1 Month – 12 Years in a Public st SectorHospital Treated with 1 line Antibiotics

Objective: To determine the effectiveness of using first line antibiotics for the treatment of acute bacterial meningitis in children admitted in a public sector hospital and assessing its outcome with the help of data by need for using second line antibiotics therapy and length of stay in hospital. Method: This Crosssectional study was conducted at department of Pediatrics, Pakistan Institute of Medical Sciences, Islamabad over a period of 6 months from January 2019 to July 2019. All children between the age of 1 month – 12 years, of both genders admitted in pediatric ward with acute bacterial meningitis, based on clinical features plus CSF findings, were enrolled in the study. These children were started with first line antibiotic therapy after admission in ward which included ceftriaxone alone or a combination of ampicillin and cefotaxime or cefotaxime plus amikacin depending on age specific recommendations for that age group. All children were closely observed in ward for improvement or deterioration of symptoms. If there was deterioration of symptoms, then second line antibiotics were started which in our case was vancomycin combined with ceftriaxone or meropenem combined with vancomycin. Duration of hospital stay was also noted. Data was analyzed by SPSS version 22. Results: A total of 51 patients were enrolled in the study. Mean age of children in the study was 3.23 ± 3.3 years. There were 33(65.1%) males and 18(34.9%) females. Only 30(58.6%) children were completely vaccinated, rest were either partially vaccinated or not vaccinated at all. ]In the first line antibiotics course, ceftriaxone was the most common antibiotic, which was prescribed to 32(61.3%) children, followed by a combination of cefotaxime with amikacin 13(23.7%) and ampicillin plus cefotaximeto 6(4.3%). Second line therapy was needed in only15(29%) children. The commonly prescribed was a combination of vancomycin and meropenem. The total duration of stay in hospital was for 10-14 days. Conclusion: Our study concluded that first line antibiotic therapy is still an effective treatment for acute bacterial meningitis. So, in the wake of emerging antibiotic resistance, irrational use of antibiotics should be avoided.

Dynamic 18F-Pretomanid PET imaging in animal models of TB meningitis and human studies

Pretomanid is a nitroimidazole antimicrobial active against drug-resistant Mycobacterium tuberculosis and approved in combination with bedaquiline and linezolid (BPaL) to treat multidrug-resistant (MDR) pulmonary tuberculosis (TB). However, the penetration of these antibiotics into the central nervous system (CNS), and the efficacy of the BPaL regimen for TB meningitis, are not well established. Importantly, there is a lack of efficacious treatments for TB meningitis due to MDR strains, resulting in high mortality. We have developed new methods to synthesize 18F-pretomanid (chemically identical to the antibiotic) and performed cross-species positron emission tomography (PET) imaging to noninvasively measure pretomanid concentration-time profiles. Dynamic PET in mouse and rabbit models of TB meningitis demonstrates excellent CNS penetration of pretomanid but cerebrospinal fluid (CSF) levels does not correlate with those in the brain parenchyma. The bactericidal activity of the BPaL regimen in the mouse model of TB meningitis is substantially inferior to the standard TB regimen, likely due to restricted penetration of bedaquiline and linezolid into the brain parenchyma. Finally, first-in-human dynamic 18F-pretomanid PET in six healthy volunteers demonstrates excellent CNS penetration of pretomanid, with significantly higher levels in the brain parenchyma than in CSF. These data have important implications for developing new antibiotic treatments for TB meningitis.

Endoscopic lavage of the cerebral ventricular system for ventriculitis treatment in a patient with complicated new coronavirus infection (COVID‑19)

Introduction. The new coronavirus infection (COVID‑19) has a wide spectrum of complications. Frequency of neurological symptoms varies between 17.3 and 36.4 %. In 8 % of cases, COVID‑19 can be accompanied by bacterial or fungal infection. Since few descriptions of bacterial meningitis in adult patients with COVID‑19 and a single description of surgical treatment of purulent meningitis complicated by empyema of the 4th ventricle in a patient with COVID‑19 were found, and there are no meta‑analyses in this area, descriptions of such cases are of high scientific and practical value.Aim. The describe a case of surgical treatment of purulent ventriculitis in an adult (during treatment of the new coronavirus infection COVID‑19).Materials and methods. A man, 69 years old, with previously established diagnosis of the new coronavirus infection COVID‑19 and a comorbid pathology was admitted to the Moscow City Clinical Hospital No. 40 with newly diagnosed seizure disorder. Computed tomography imaging showed ventriculitis confirmed by MRI with obstructive hypertensive triventricular hydrocephalus.Results. The patient underwent treatment: three‑time endoscopic lavage of the ventricular system, removal of newly formed fibrin membranes with interventricular septostomy, removal of obstruction at the level of the Sylvian aqueduct; the surgery was concluded by external draining of the lateral ventricles, administration of an antibiotic intro the ventricular system and intravenously. Cerebrospinal fluid flow was restored, ventriculitis manifestations completely negated.Conclusion. Development of ventriculitis as one of the first signs of bacterial infection accompanying COVID‑19 is a very rare and life‑threatening complication requiring active surgical intervention. In was shown that endoscopic lavage of the ventricular system for ventriculitis treatment is an effective action against infection and cerebrospinal fluid flow disorders. Use of intraventricular endoscopy for ventriculitis treatment has several advantages compared to needle ventriculostomy. Further studies and analysis of treatment of bacterial ventriculitis using endoscopic surgical techniques in patients with and without the new coronavirus infection are needed.

Treatment of Herpes Simplex Virus Type 2 Meningitis: A Survey Among Infectious Diseases Specialists in France, Sweden, Australia, and Denmark.

We aimed to describe attitudes toward treatment of herpes simplex virus type 2 (HSV-2) meningitis and prioritize future trials. This was a self-administered online survey of HSV-2 meningitis treatment among infectious diseases (ID) specialists in France, Sweden, Australia, and Denmark. A total of 223 ID specialists (45% female) from France (36%), Denmark (24%), Sweden (21%), and Australia (19%) participated in the survey, primarily from university hospitals (64%). The estimated overall response rate was 11% and ranged from 6% (Australia) to 64% (Denmark). Intravenous (IV) acyclovir followed by oral valacyclovir was the favored treatment in 110 of 179 (61%), whereas monotherapy with either IV acyclovir or oral valacyclovir was used by 35 of 179 (20%) and 34 of 179 (19%), respectively. The median total duration was reported to be 7 days (interquartile range, 7-10 days) regardless of antiviral regimen. Immunocompromise influenced decisions on antiviral treatment in 110 of 189 (58%) of respondents, mainly by prolonged total duration of treatment (36/110 [33%]), prolonged IV administration (31/110 [28%]), and mandatory antiviral treatment (25/110 [23%]). Treatment with acyclovir/valacyclovir versus placebo and comparison of acyclovir versus valacyclovir were assigned the highest prioritization scores for future randomized controlled trials on HSV-2 meningitis. Perceptions of indications for as well as type and duration of antiviral treatment varied substantially among ID specialists.

Oral GSH Exerts a Therapeutic Effect on Experimental Salmonella Meningitis by Protecting BBB Integrity and Inhibiting Salmonella-induced Apoptosis.

Bacterial meningitis (BM) is the main cause of the central nervous system (CNS) infection and continues to be an important cause of mortality and morbidity. Glutathione (GSH), an endogenous tripeptide antioxidant, has been proved to exert crucial role in reducing superoxide radicals, hydroxyl radicals and peroxynitrites. The purpose of this study is to expand the application scope of GSH via exploring its therapeutic effect on BM caused by Salmonella typhimurium SL1344 and then provide a novel approach for the treatment of BM. The results suggested that intragastric administration of GSH could significantly increase median survival and improve experimental autoimmune encephalomyelitis score of BM model mice. However, exogenous GSH did not affect the adhesion, invasion and cytotoxicity of SL1344 to C6, BV2 and primary microglia. Due to the contradiction between the therapeutic and bactericidal effects of GSH, the effect of GSH on blood-brain barrier (BBB) was investigated to explore its action target for the treatment of meningitis. GSH was found to repair the damage of BBB and then prevent the leakage of SL1344 from the brain to the blood circulation. The repaired BBB could also effectively reduce the entry of macrophages and neutrophils into the brain, and significantly reverse the microglia activation induced by SL1344. More importantly, exogenous GSH was proved to reduce mouse brain cell apoptosis by inhibiting the activation of caspase-8 followed by caspase-3, and reversing the up-regulation of ICAD and PARP-1 caused by SL1344.

Cost-effectiveness of liposomal amphotericin B for HIV-associated cryptococcal meningitis

A single high dose of liposomal amphotericin B deoxycholate (L-AmB) given alongside 14 days of flucytosine and fluconazole offers equivalent efficacy and superior safety over the previous WHO-recommended treatment for HIV-associated cryptococcal meningitis (ie, 1 week of AmB plus flucytosine followed by 1 week of high-dose fluconazole).1 Despite being more expensive than the WHO-recommended regimen, the analysis conducted by David Lawrence and colleagues in The Lancet Global Health2 shows that the new regimen is a cost-effective advancement in several countries in sub-Saharan Africa.

LBSAT313 Hashimoto Encephalitis Presenting With Stroke-like Symptoms In An Adult Male

Abstract Hashimoto encephalopathy (HE) is a term used to describe an encephalopathy of presumed autoimmune origin characterized by high titers of antithyroid peroxidase antibodies, an essential feature of this disorder. Pertinent laboratory findings include an elevated serum level of antithyroid peroxidase antibody (TPOAb) and/or antithyroglobulin antibody (TgAb) and negative autoimmune markers of encephalitis in cerebrospinal fluid (CSF). The analysis of CSF may show increased cellularity due to lymphocytic pleocytosis. However, there is no clear relationship between the severity of neurologic symptoms and the type or serum concentration of antibodies. Approximately two-thirds of patients of HE will experience seizures. Patients can present with a recurrence/remission or a diffuse, progressive pattern characterized by slowly progressive cognitive impairment with dementia, confusion, or hallucinations. We present a rare case of Hashimoto's encephalopathy associated with hyperthyroidism in a 61-year-old man evaluated for left facial droop and right upper extremity weakness, successfully treated with corticosteroids and methimazole. We conclude that the diagnosis of HE should be suspected early and be on the differential in patients who present with encephalopathy, which workup shows positive anti-thyroid antibodies and CSF with lymphocytosis. Treatment for meningitis or other life-threatening conditions should never be postponed, as HE is a diagnosis of exclusion that usually requires an extensive laboratory and diagnostic workup. Early diagnosis has an excellent outcome once treatment is started as it is a steroid-responsive encephalopathy associated with autoimmune thyroiditis. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

New Drugs and Regimens for Tuberculosis Disease Treatment in Children and Adolescents.

After almost 30 years of relative stagnation, research over the past decade has led to remarkable advances in the treatment of both drug-susceptible (DS) and drug-resistant (DR) tuberculosis (TB) disease in children and adolescents. Compared with the previous standard therapy of at least 6 months, 2 new regimens lasting for only 4 months for the treatment of DS-TB have been studied and are recommended by the World Health Organization (WHO), along with a shortened 6-month regimen for treatment of DS-TB meningitis. In addition, the 18- to 24-month regimens previously used for DR-TB that included painful injectable drugs with high rates of adverse effects have been replaced with shorter, safer all-oral regimens. Advances that have improved treatment include development of new TB drugs (bedaquiline, delamanid, pretomanid), reapplication of older TB drugs (rifampicin and rifapentine), and repurposing of other drugs (clofazimine and linezolid). The development of child-friendly formulations for many of these drugs has further enhanced the ability to safely and effectively treat DS- and DR-TB in children and adolescents. The characteristics and use of these drugs, regimens, and formulations are reviewed.

Case study on Tuberculous Meningitis (TBM)

Tuberculous Meningitis (TBM) is an inflammation of the meninges (membrane) around the brain or spinal cord and it’s caused by Mycobacterium tuberculosis. The clinical features are headaches, behavioral changes, Fever, stiff neck, vomiting and for older children and adults progress from irritability to confusion, drowsiness and stupor. It’s diagnosed by Examination of the Mycobacterium tuberculosis, blood culture, chest X-ray, CT scan of the head and skin test for tuberculosis (PPD skin test. TB meningitis treatment includes isoniazid, rifampin, pyrazinamide and moxifloxacin or levofloxacin and Corticosteroids.

Pharmacogenetic variability and the probability of site of action target attainment during tuberculosis meningitis treatment: A physiologically based pharmacokinetic modeling and simulations study

Objective and methodsOur objective was to investigate the role of patient pharmacogenetic variability in determining site of action target attainment during tuberculous meningitis (TBM) treatment. Rifampin and isoniazid PBPK model that included SLCO1B1 and NAT2 effects on exposures respectively were obtained from literature, modified, and validated using available cerebrospinal-fluid (CSF) concentrations. Population simulations of isoniazid and rifampin concentrations in brain interstitial fluid and probability of target attainment according to genotypes and M. tuberculosis MIC levels, under standard and intensified dosing, were conducted. ResultsThe rifampin and isoniazid model predicted steady-state drug concentration within brain interstitial fluid matched with the observed CSF concentrations. At MIC level of 0.25 mg/L, 57% and 23% of the patients with wild type and heterozygous SLCO1B1 genotype respectively attained the target in CNS with rifampin standard dosing, improving to 98% and 91% respectively with 35 mg/kg dosing. At MIC level of 0.25 mg/L, 33% of fast acetylators attained the target in CNS with isoniazid standard dosing, improving to 90% with 7.5 mg/kg dosing. ConclusionIn this study, the combined effects of pharmacogenetic and M. tuberculosis MIC variability were potent determinants of target attainment in CNS. The potential for genotype-guided dosing during TBM treatment should be further explored in prospective clinical studies.

Risk Factors for Severe Cutaneous Anthrax in a Retrospective Case Series and Use of a Clinical Algorithm to Identify Likely Meningitis and Evaluate Treatment Outcomes, Kyrgyz Republic, 2005-2012.

US Centers for Disease Control and Prevention guidelines currently recommend triple-therapy antimicrobial treatment for anthrax meningitis. In the Kyrgyz Republic, a country with endemic anthrax, cutaneous anthrax patients are routinely hospitalized and treated successfully with only monotherapy or dual therapy. Clinical algorithms have been developed to identify patients with likely anthrax meningitis based on signs and symptoms alone. We sought to retrospectively identify likely meningitis patients in the Kyrgyz Republic using a clinical algorithm and evaluate risk factors and their outcomes by type of treatment. We conducted a retrospective chart review of cutaneous anthrax patients in the Kyrgyz Republic from 2005 through 2012. Using previous methods, we developed a highly specific algorithm to categorize patients by meningitis status. We then evaluated patient risk factors, treatments, and outcomes by disease severity and meningitis status. We categorized 37 of 230 cutaneous anthrax patients as likely having meningitis. All 37 likely meningitis patients survived, receiving only mono- or dual-therapy antimicrobials. We identified underlying medical conditions, such as obesity, hypertension, and chronic obstructive pulmonary disease, and tobacco and alcohol use, as potential risk factors for severe anthrax and anthrax meningitis. Based on our analyses, treatment of anthrax meningitis may not require 3 antimicrobials, which could impact future anthrax treatment recommendations. In addition, chronic comorbidities may increase risk for severe anthrax and anthrax meningitis. Future research should further investigate potential risk factors for severe anthrax and their impact on laboratory-confirmed meningitis and evaluate mono- and dual-therapy antimicrobial regimens for anthrax meningitis.

Persistent meningeal signs despite previous treatment for cryptococcal meningitis – a case report

Cryptococcal meningitis continues to be a life-threatening fungal infection in patients with HIV. Treatment involves a year of antifungal therapy, and persistent meningeal signs months after treatment initiation are uncommon. We report a case of a 29-year-old male with HIV who was diagnosed with cryptococcal meningitis ten months earlier and underwent induction, maintenance, and consolidation therapy and ART. Subsequently, he continued to have persistent headaches and developed severe meningeal signs with leptomeningeal enhancement on imaging. This case discusses the importance of keeping both immune reconstitution inflammatory syndrome and a cryptococcal meningitis relapse in the differential diagnosis for patients with persistent meningeal signs.

Alpha7 Nicotinic Acetylcholine Receptor Antagonists Prevent Meningitic Escherichia coli-Induced Blood-Brain Barrier Disruptions by Targeting the CISH/JAK2/STAT5b Axis.

Despite the availability of antibiotics over the last several decades, excessive antibiotic treatments for bacterial sepsis and meningitis (BSM) in children may result in several adverse outcomes. Hematogenous pathogens may directly induce permeability increases in human brain microvascular endothelial cells (HBMECs) and blood–brain barrier (BBB) dysfunctions. Our preliminary studies demonstrated that the alpha7 nicotinic acetylcholine receptor (α7nAChR) played an important role in the pathogenesis of BSM, accompanied by increasing cytokine-inducible SH2-containing protein (CISH) at the transcriptome level, but it has remained unclear how α7nAChR-CISH works mechanistically. The study aims to explore the underlying mechanism of α7nAChR and CISH during E. coli-induced BSM in vitro (HBMECs) and in vivo (α7nAChR-KO mouse). We found that in the stage of E. coli K1-induced BBB disruptions, α7nAChR functioned as the key regulator that affects the integrity of HBMECs by activating the JAK2–STAT5 signaling pathway, while CISH inhibited JAK2–STAT5 activation and exhibited protective effects against E. coli infection. Notably, we first validated that the expression of CISH could be regulated by α7nAChR in HBMECs. In addition, we determined the protective effects of MLA (methyllycaconitine citrate) and MEM (memantine hydrochloride) (functioning as α7nAChR antagonists) on infected HBMECs and suggested that the α7nAChR–CISH axis could explain the protective effects of the two small-molecule compounds on E. coli-induced HBMECs injuries and BBB disruptions. In conclusion, we dissected the α7nAChR/CISH/JAK2/STAT5 axis as critical for the pathogenesis of E. coli-induced brain microvascular leakage and BBB disruptions and provided novel evidence for the development of α7nAChR antagonists in the prevention of pediatric E. coli BSM.

Comprehensive chemical profiling of volatile constituents of Angong Niuhuang Pill in vitro and in vivo based on gas chromatography coupled with mass spectrometry

BackgroundAngong Niuhuang Pill (ANP), a renowned precious traditional Chinese medicine prescription, is extensively utilized for the clinical treatment of stroke, meningitis and encephalorrhagia in China. As a classic resuscitation-inducing aromatic prescription, ANP has been investigated for its pharmacological effects in recent years, while the volatile composition in ANP still lacks comprehensive elucidation.MethodTo better explore the volatile constituents in ANP, a qualitative analysis method was developed based on gas chromatography coupled with mass spectrometry. Furthermore, a validated quantitative method was established to determine 21 main compounds in 8 batches of commercially available ANP samples by gas chromatography-tandem mass spectrometry. The quantitative data were successively subjected to Pearson correlation coefficient analysis. Additionally, the absorbed volatile constituents in rat plasma after single oral administration of ANP have also been characterized.ResultsA total of 93 volatile constituents including 29 sesquiterpenoids, 28 monoterpenoids, 13 fatty acids and their esters, 7 alkanes, 6 ketones, 3 phenols, 3 aldehydes, 2 benzoate esters, and 2 other types, were preliminarily characterized, which primarily originated from Borneolum, Moschus, Curcumae Radix, and Gardeniae Fructus. d-Borneol, isoborneol and muscone were the top three abundant ingredients (> 600 μg/g) in 8 batches of ANP samples. Subsequently, the average Pearson correlation coefficient of the contents of 21 analytes was 0.993, inferring the high batch-to-batch similarity among 8 batches. After oral administration of ANP, d-borneol, isoborneol, muscone and camphor were the main volatile constituents absorbed in the rat plasma.ConclusionThis research may be helpful for the comprehensive quality control study of ANP, and provide for guarantee the clinical efficacy of ANP.

Exploring the Factors Affecting the Transferability of Vancomycin to Cerebrospinal Fluid in Postoperative Neurosurgical Patients with Bacterial Meningitis.

Vancomycin (VCM) is a standard treatment for bacterial meningitis. However, little is known about the transferability of VCM to cerebrospinal fluid (CSF), thus evidence of the transferability of VCM to CSF during bacterial meningitis is needed. In this study, we evaluated the concentration of VCM in the plasma and CSF of postoperative neurosurgical patients with bacterial meningitis and evaluated the factors that affect the transferability of VCM to CSF. The concentrations of VCM in plasma (trough) and CSF were determined in eight patients (four males and four females) with bacterial meningitis who were treated with VCM using HPLC. The ratio of the VCM concentrations in CSF/plasma was also calculated by estimating the blood VCM concentration at the same time as the VCM concentration in CSF was measured. The results showed that the VCM concentration in CSF was 0.9-12.7 µg/mL and the CSF/plasma VCM concentration ratio was 0.02-0.62. We examined the effect of drainage on the transferability of VCM to CSF, which showed that the VCM concentration in CSF and the CSF/plasma VCM concentration ratio were significantly higher in patients not undergoing drainage than in patients who were undergoing drainage. The CSF protein and glucose concentrations, which are diagnostic indicators of meningitis, were positively correlated with the VCM concentration in CSF and the CSF/plasma VCM concentration ratio. Thus, VCM transferability to CSF may be affected by changes in the status of the blood-brain barrier and blood-cerebrospinal fluid barrier due to drainage or meningitis.

Non-steroidal anti-inflammatory drugs ketorolac and etodolac can augment the treatment against pneumococcal meningitis by targeting penicillin-binding proteins.

Streptococcus pneumoniae is the principal etiological agent of acute bacterial meningitis (ABM) which has fatal outcome in children and elderly. Due to poor blood-brain barrier (BBB) permeation, conventional β-lactam antibiotics fail to establish the requisite bactericidal concentration in central nervous system leading to resistance in meningeal infections. The present study intended to identify potential therapeutic alternatives against Streptococcal meningitis. Virtual screening, pharmacokinetics/pharmacodynamics (PK/PD) and anti-bacterial evaluations were employed to screen potential drugs. Molecular docking and structural dynamics simulations were performed to analyze the binding affinity and interaction stability of the drugs against the conventional Penicillin binding protein (PBP) targets. Screened drugs were also checked for interactions with other possible Streptococcal targets and relevant host targets. Non-steroidal anti-inflammatory drugs (NSAIDs) ketorolac and etodolac exhibiting high BBB-permeation and anti-bacterial potency were identified. Ketorolac and etodolac possessed uniform binding affinities against PBP1A, PBP2X, PBP2B and PBP3 with low inhibition constants (<50μM). Against PBP2B and PBP3, higher binding affinities were observed for ketorolac (-6.45 and -6Kcal/mol respectively) and etodolac (-6.36 and -6.55Kcal/mol respectively) than penicillin (-5.95 and -5.85Kcal/mol respectively) and cefotaxime (-5.08 and -5.07Kcal/mol respectively). The binding affinities were contributed by conventional H-bonds and non-canonical interactions with active site residues of PBPs. Structural dynamics simulations further indicated the overall stability of the drug-bound complexes through minimal overall average root-mean square fluctuations (RMSFs) (<1.0Å). The average binding affinities of Ketorolac and Etodolac with PBPs were marginally higher than other Streptococcal targets and comparable to their conventional inflammatory targets. Pharmacological and structural profiles indicated that ketorolac and etodolac can potentially subdue the cause and effects of streptococcal meningitis and hence encourage experimental validations.

Comparison of amphotericin B deoxycholate in combination with either flucytosine or fluconazole, and voriconazole plus flucytosine for the treatment of HIV-associated cryptococcal meningitis: a prospective multicenter study in China

BackgroundThe most appropriate alternative to induction therapy for HIV-associated cryptococcal meningitis (CM) remains unclear when standard treatment is unavailable, inaccessible, intolerable, or ineffective.MethodsA prospective, multi-centre cohort study was conducted to analyze the data of 156 HIV-infected patients with CM who were treated with amphotericin B deoxycholate (AmB-D) + flucytosine (5FC), voriconazole (VCZ) + 5FC, or AmB-D + Fluconazole (Flu) as induction regimens. Clinical efficacy, cumulative mortality, and adverse effects were compared among the three treatment groups.ResultsFewer deaths occurred by week 4 and week 10 among patients receiving AmB-D + 5FC than among those receiving AmB-D + Flu [4 (5.1%) vs. 8 (16.0%) deaths by week 4; hazard ratio, 1.8; 95% confidence interval [CI], 1.0 to 3.3; p = 0.039; and 8 (10.3%) vs. 14 (28.0%) deaths by week 10; hazard ratio, 1.8; 95% CI, 1.1 to 2.7; p = 0.008, respectively]. AmB-D plus 5FC was found to result in significantly higher rates of cerebrospinal fluid (CSF) culture sterility (57.6% vs. 34% by week 2; 87.9% vs. 70% by week 10; p < 0.05 for both comparisons). However, the differences in CSF culture sterility and mortality between the VCZ + 5FC group and the AmB-D + 5FC group were not statistically significant. VCZ plus 5FC had a significantly advantageous effect on the incidence of new AIDS-defining illness and length of hospital stay, compared with AmB-D plus 5FC. Laboratory adverse events (grade 3 or 4), such as severe anemia, were less frequent with VCZ + 5FC use than with AmB-D combined with 5FC or Flu use.ConclusionOur results suggest that AmB-D combined with 5FC remains the more efficacious induction regimen compared to AmB-D plus Flu, and that VCZ + 5FC might be a potential alternative when the standard regimen is not readily available, accessible, tolerated, or effective.Clinical Trials: Registration number, ChiCTR1900021195. Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362.

Identification of protein biomarkers in host cerebrospinal fluid for differential diagnosis of tuberculous meningitis and other meningitis.

Background and purposeThe diagnosis of tuberculous meningitis (TBM) is difficult due to the lack of sensitive methods. Identification of TBM-specific biomarkers in the cerebrospinal fluid (CSF) may help diagnose and improve our understanding of TBM pathogenesis.Patients and methodsOf the 112 suspected patients with TBM prospectively enrolled in the study, 32 patients with inconclusive diagnosis, non-infectious meningitis, and long-term treatment with hormones and immunosuppressants were excluded. The expression of 8 proteins in the CSF was analyzed using ELISA in 22 patients with definite TBM, 18 patients with probable TBM, and 40 patients with non-TBM.ResultsSignificant differences in the expression of 7 proteins were detected between the TBM and non-TBM groups (P < 0.01). Unsupervised hierarchical clustering (UHC) analysis revealed a disease-specific profile consisting of 7 differentially expressed proteins for TBM diagnosis, with an accuracy of 82.5% (66/80). Logistic regression with forward stepwise analysis indicated that a combination of 3 biomarkers (APOE_APOAI_S100A8) showed a better ability to discriminate TBM from patients with non-TBM [area under the curve (AUC) = 0.916 (95%CI: 0.857–0.976)], with a sensitivity of 95.0% (95%CI: 83.1–99.4%) and a specificity of 77.5% (95%CI: 61.5–89.2%).ConclusionOur results confirmed the potential ability of CSF proteins to distinguish TBM from patients with non-TBM and provided a useful panel for the diagnosis of TBM.