rifampin and Tuberculosis--Meningeal

In September 2022, the World Health Organization (WHO) published a new guideline for the management of tuberculosis (TB) in children and adolescents. It included eight new recommendations. Xpert MTB/RIF Ultra (Xpert Ultra) has been designated as the preferred initial diagnostic test for pulmonary TB and detection of rifampicin resistance. But its place vis-à-vis the previously recommended GeneXpert has not been clarified. Further, the limited diagnostic accuracy of Xpert Ultra in some biological specimens like nasopharyngeal aspirates, and the inability to report the presence or absence of rifampicin resistance in 'trace' reports has not been addressed. The guideline also recommends a shortened 4-mo treatment regimen for non-severe drug-susceptible TB. This is based on a single trial having several methodological issues that limit its applicability and generalizability. Interestingly, the criteria for designating 'non-severe' TB in the trial is based on smear negativity, whereas the new WHO recommendation is to omit smear microscopy altogether. The guideline also recommends an alternative 6-mo intensive regimen for drug-susceptible TB meningitis, which needs more supportive evidence. The lower age limits for the use of bedaquiline and delamanid have been decreased to less than 6 and 3 y respectively. While this makes it feasible to treat drug resistant TB in children with oral medications, the resource implications need careful consideration. These concerns advocate caution before the WHO guideline recommendations can be universally implemented.

Topics: Adolescent; Antibiotics, Antitubercular; Child; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Meningeal

The GeneXpert MTB/RIF assay (Xpert) is a diagnostic tool that has been shown to significantly improve the accuracy of tuberculosis (TB) detection in clinical settings, with advanced sensitivity and specificity. Early detection of TB can be challenging, but Xpert has improved the efficacy of the diagnostic process. Nevertheless, the accuracy of Xpert varies according to different diagnostic specimens and TB infection sites. Therefore, the selection of adequate specimens is critical when using Xpert to identify suspected TB. As such, we have conducted a meta-analysis to evaluate the effectiveness of Xpert for diagnosis of different TB types using several specimens.. We conducted a comprehensive search of several electronic databases, including PubMed, Embase, the Cochrane Central Register of Controlled Trials, and the World Health Organization clinical trials registry center, covering studies published from Jan 2008 to July 2022. Data were extracted using an adapted version of the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies. Where appropriate, meta-analysis was performed using random-effects models. The risk of bias and level of evidence was assessed using the Quality in Prognosis Studies tool and a modified version of the Grading of Recommendations Assessment, Development, and Evaluation. RStudio was utilized to analyze the results, employing the. After excluding duplicates, a total of 2163 studies were identified, and ultimately, 144 studies from 107 articles were included in the meta-analysis based on predetermined inclusion and exclusion criteria. Sensitivity, specificity and diagnostic accuracy were estimated for various specimens and TB types. In the case of pulmonary TB, Xpert using sputum (0.95 95%CI 0.91-0.98) and gastric juice (0.94 95%CI 0.84-0.99) demonstrated similarly high sensitivity, surpassing other specimen types. Additionally, Xpert exhibited high specificity for detecting TB across all specimen types. For bone and joint TB, Xpert, based on both biopsy and joint fluid specimens, demonstrated high accuracy in TB detection. Furthermore, Xpert effectively detected unclassified extrapulmonary TB and tuberculosis lymphadenitis. However, the Xpert accuracy was not satisfactory to distinguish TB meningitis, tuberculous pleuritis and unclassified TB.. Xpert has exhibited satisfactory diagnostic accuracy for most TB infections, but the efficacy of detection may vary depending on the specimens analyzed. Therefore, selecting appropriate specimens for Xpert analysis is essential, as using inadequate specimens can reduce the ability to distinguish TB.. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=370111, identifier CRD42022370111.

Topics: Antibiotics, Antitubercular; Humans; Latent Tuberculosis; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis, Meningeal; Tuberculosis, Pulmonary

Tuberculous meningitis (TBM) is one of the most serious types of extrapulmonary tuberculosis and has caused distress to human. Effective treatment is particularly important. The aim of this meta-analysis is to compare the efficacy of high-dose and standard-dose rifampicin.. Databases including PubMed, Web of Science, Embase, Scopus and the Cochrane Library databases were electronically searched to identify randomized controlled trials that reported high-dose rifampicin in treatment of patients with TBM. The retrieval time is limited from inception to June 2021. Two reviewers independently screened literature, extracted data and assessed risk bias of included studies. Meta-analysis was performed by using STATA 12.0 software.. A total of 12 studies involving 1596 patients were included. The meta-analysis results showed no significant differences in 6-month mortality, 9-month mortality, Grade I-II AE, Grade III-V AE, hepatotoxicity, hepatotoxicity Grade I-II and cardiologic events between high-dose rifampicin (or high-dose rifampicin plus moxifloxacin or levofloxacin) and standard-dose groups. The log(C. High-dose rifampicin was not a protective factor for 6-month mortality, despite increased plasma C

Topics: Chemical and Drug Induced Liver Injury; Humans; Levofloxacin; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis, Meningeal

Despite its longstanding role in tuberculosis (TB) treatment, there continues to be emerging rifampicin research that has important implications for pediatric TB treatment and outstanding questions about its pharmacokinetics and optimal dose in children.. This review aims to summarize and discuss emerging data on the use of rifampicin for: 1) routine treatment of drug-susceptible TB; 2) special subpopulations such as children with malnutrition, HIV, or TB meningitis; 3) treatment shortening. We also highlight the implications of these new data for child-friendly rifampicin formulations and identify future research priorities.. New data consistently show low rifampicin exposures across all pediatric populations with 10-20 mg/kg dosing. Although clinical outcomes in children are generally good, rifampicin dose optimization is needed, especially given a continued push to shorten treatment durations and for specific high-risk populations of children who have worse outcomes. A pooled analysis of existing data using applied pharmacometrics would answer many of the important questions remaining about rifampicin pharmacokinetics needed to optimize doses, especially in special populations. Targeted clinical studies in children with TB meningitis and treatment shortening with high-dose rifampicin are also priorities.

Topics: Antitubercular Agents; Child; Humans; Rifampin; Tuberculosis, Meningeal

Tuberculous meningitis is a devastating brain infection that is caused by Mycobacterium tuberculosis and is notoriously difficult to diagnose and treat. New technologies characterising the transcriptome, proteome, and metabolome have identified new molecules and pathways associated with tuberculous meningitis severity and poor outcomes that could offer novel diagnostic and therapeutic targets. The next-generation GeneXpert MTB/RIF Ultra assay, when used on CSF, offers diagnostic sensitivity for tuberculous meningitis of approximately 70%, although it is not widely available and a negative result cannot rule out tuberculous meningitis. Small trials indicate that clinical outcomes might be improved with increased doses of rifampicin, the addition of linezolid or fluoroquinolones to standard antituberculosis therapy, or treatment with adjunctive aspirin combined with corticosteroids. Large phase 3 clinical trials are underway worldwide to address these and other questions concerning the optimal management of tuberculous meningitis; these studies also form a platform for studying pathogenesis and identifying novel diagnostic and treatment strategies, by allowing the implementation of new genomic, transcriptomic, proteomic, and metabolomic technologies in nested substudies.

Topics: Antitubercular Agents; Humans; Mycobacterium tuberculosis; Proteomics; Rifampin; Sensitivity and Specificity; Tuberculosis, Meningeal

Every year, an estimated one million children and young adolescents become ill with tuberculosis, and around 226,000 of those children die. Xpert MTB/RIF Ultra (Xpert Ultra) is a molecular World Health Organization (WHO)-recommended rapid diagnostic test that simultaneously detects Mycobacterium tuberculosis complex and rifampicin resistance. We previously published a Cochrane Review 'Xpert MTB/RIF and Xpert MTB/RIF Ultra assays for tuberculosis disease and rifampicin resistance in children'. The current review updates evidence on the diagnostic accuracy of Xpert Ultra in children presumed to have tuberculosis disease. Parts of this review update informed the 2022 WHO updated guidance on management of tuberculosis in children and adolescents.. To assess the diagnostic accuracy of Xpert Ultra for detecting: pulmonary tuberculosis, tuberculous meningitis, lymph node tuberculosis, and rifampicin resistance, in children with presumed tuberculosis. Secondary objectives To investigate potential sources of heterogeneity in accuracy estimates. For detection of tuberculosis, we considered age, comorbidity (HIV, severe pneumonia, and severe malnutrition), and specimen type as potential sources. To summarize the frequency of Xpert Ultra trace results.. We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, three other databases, and three trial registers without language restrictions to 9 March 2021.. Cross-sectional and cohort studies and randomized trials that evaluated Xpert Ultra in HIV-positive and HIV-negative children under 15 years of age. We included ongoing studies that helped us address the review objectives. We included studies evaluating sputum, gastric, stool, or nasopharyngeal specimens (pulmonary tuberculosis), cerebrospinal fluid (tuberculous meningitis), and fine needle aspirate or surgical biopsy tissue (lymph node tuberculosis). For detecting tuberculosis, reference standards were microbiological (culture) or composite reference standard; for stool, we also included Xpert Ultra performed on a routine respiratory specimen. For detecting rifampicin resistance, reference standards were drug susceptibility testing or MTBDRplus.. Two review authors independently extracted data and, using QUADAS-2, assessed methodological quality judging risk of bias separately for each target condition and reference standard. For each target condition, we used the bivariate model to estimate summary sensitivity and specificity with 95% confidence intervals (CIs). We stratified all analyses by type of reference standard. We summarized the frequency of Xpert Ultra trace results; trace represents detection of a very low quantity of Mycobacterium tuberculosis DNA. We assessed certainty of evidence using GRADE.. We identified 14 studies (11 new studies since the previous review). For detection of pulmonary tuberculosis, 335 data sets (25,937 participants) were available for analysis. We did not identify any studies that evaluated Xpert Ultra accuracy for tuberculous meningitis or lymph node tuberculosis. Three studies evaluated Xpert Ultra for detection of rifampicin resistance. Ten studies (71%) took place in countries with a high tuberculosis burden based on WHO classification. Overall, risk of bias was low. Detection of pulmonary tuberculosis Sputum, 5 studies Xpert Ultra summary sensitivity verified by culture was 75.3% (95% CI 64.3 to 83.8; 127 participants; high-certainty evidence), and specificity was 97.1% (95% CI 94.7 to 98.5; 1054 participants; high-certainty evidence). Gastric aspirate, 7 studies Xpert Ultra summary sensitivity verified by culture was 70.4% (95% CI 53.9 to 82.9; 120 participants; moderate-certainty evidence), and specificity was 94.1% (95% CI 84.8 to 97.8; 870 participants; moderate-certainty evidence). Stool, 6 studies Xpert Ultra summary sensitivity verified by culture was 56.1% (95% CI 39.1 to 71.7; 200 participants; moderate-certainty evidence), and specificity was 98.0% (95% CI 93.3 to 99.4; 1232 participants; high certainty-evidence). Nasopharyngeal aspirate, 4 studies Xpert Ultra summary sensitivity verified by culture was 43.7% (95% CI 26.7 to 62.2; 46 participants; very low-certainty evidence), and specificity was 97.5% (95% CI 93.6 to 99.0; 489 participants; high-certainty evidence). Xpert Ultra sensitivity was lower against a composite than a culture reference standard for all specimen types other than nasopharyngeal aspirate, while specificity was similar against both reference standards. Interpretation of results In theory, for a population of 1000 children: • where 100 have pulmonary tuberculosis in sputum (by culture): - 101 would be Xpert Ultra-positive, and of these, 26 (26%) would not have pulmonary tuberculosis (false positive); and - 899 would be Xpert Ultra-negative, and of these, 25 (3%) would have tuberculosis (false negative). • where 100 have pulmonary tuberculosis in gastric aspirate (by culture): - 123 would be Xpert Ultra-positive, and of these, 53 (43%) would not have pulmonary tuberculosis (false positive); and - 877 would be Xpert Ultra-negative, and of these, 30 (3%) would have tuberculosis (false negative). • where 100 have pulmonary tuberculosis in stool (by culture): - 74 would be Xpert Ultra-positive. We found Xpert Ultra sensitivity to vary by specimen type, with sputum having the highest sensitivity, followed by gastric aspirate and stool. Nasopharyngeal aspirate had the lowest sensitivity. Xpert Ultra specificity was high against both microbiological and composite reference standards. However, the evidence base is still limited, and findings may be imprecise and vary by study setting. Although we found Xpert Ultra accurate for detection of rifampicin resistance, results were based on a very small number of studies that included only three children with rifampicin resistance. Therefore, findings should be interpreted with caution. Our findings provide support for the use of Xpert Ultra as an initial rapid molecular diagnostic in children being evaluated for tuberculosis.

Topics: Adolescent; Antibiotics, Antitubercular; Child; Cross-Sectional Studies; HIV Infections; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Lymph Node; Tuberculosis, Meningeal; Tuberculosis, Pulmonary

This systematic review evaluated the diagnostic accuracy of Xpert MTB/RIF to detect tuberculous meningitis (TBM).. PubMed and five other databases were systematically searched through March 2019. All studies evaluating diagnostic accuracy of Xpert MTB/RIF on cerebrospinal fluid (CSF) samples were included. Reference standards were definitive or definite plus probable TBM. The quality of studies was assessed by the QUADAS-2 tool. We performed bivariate random-effects meta-analysis and calculated summary diagnostic statistics.. We identified 30 studies (n = 3972 participants), including 5 cohort studies and 25 cross-sectional studies. Reference standards were definite TB (n = 28 studies) or definite plus probable TBM (n = 6 studies). The pooled Xpert MTB/RIF sensitivity was 85% (95% CI, 70-93%), and specificity was 98% (95% CI, 97-99%) with a negative likelihood ratio of 0.15 (95% CI, 0.04-0.27) for definite TBM. For probable TBM cases, pooled sensitivity was 81% (95% CI, 66-90%), and specificity was 99% (95% CI, 97-99%). For both reference standard types, meta-analyses showed a C-statistic area under the curve of 0.98. The QUADAS-2 tool revealed low risk of bias as well as low concerns regarding applicability. Methodological heterogeneity was high among studies.. Xpert MTB/RIF showed high accuracy for TBM diagnosis, but a negative Xpert MTB/RIF test does not rule out TBM. Repeat Xpert testing may be necessary. In clinical practice, Xpert MTB/RIF adds speed and sensitivity when compared to classic TBM diagnostic methods or previous commercial nucleic acid amplification techniques. More studies and better strategies for rapidly confirming a diagnosis of TBM in children are urgently needed.. Cette revue systématique a évalué la précision diagnostique de Xpert MTB/RIF pour détecter la méningite tuberculeuse (MTB). MÉTHODES: PubMed et cinq autres bases de données ont fait l'objet d'une recherche systématique jusqu'en mars 2019. Toutes les études évaluant la précision du diagnostic de Xpert MTB/RIF sur des échantillons de liquide céphalo-rachidien (LCR) ont été incluses. Les étalons de référence étaient des MTB définitives ou définitives et probables. La qualité des études a été évaluée par l'outil QUADAS-2. Nous avons effectué une méta-analyse des effets aléatoires bivariés et calculé des statistiques de résumés diagnostiques. RÉSULTATS: Nous avons identifié 30 études (n = 3.972 participants), dont 5 études de cohorte et 25 études transversales. Les étalons de référence étaient la TB définitive (n = 28 études) ou la MTB définitive et probable (n = 6 études). La sensibilité poolée Xpert MTB/RIF était de 85% (IC95%: 70-93%) et la spécificité était de 98% (IC95%: 97-99%) avec un rapport de vraisemblance négatif de 0,15 (IC95%: 0,04-0,27) pour la MTB définitive. Pour les cas probables de la MTB, la sensibilité poolée était de 81% (IC95%: 66-90%) et la spécificité était de 99% (IC95%: 97-99%). Pour les deux types d'étalons de référence, les méta-analyses ont montré une aire statistique C sous la courbe de 0,98. L'outil QUADAS-2 a révélé un faible risque de biais ainsi que de faibles préoccupations concernant l'applicabilité. L'hétérogénéité méthodologique était élevée parmi les études.. Xpert MTB/RIF a montré une grande précision pour le diagnostic de la MTB, mais un test Xpert MTB/RIF négatif n'exclut pas la MTB. La répétition du tests Xpert peut être nécessaire. Dans la pratique clinique, Xpert MTB/RIF ajoute vitesse et sensibilité par rapport aux méthodes de diagnostic classiques de la MTB ou aux précédentes techniques d'amplification d'acide nucléique commerciales. Des études supplémentaires et de meilleures stratégies pour confirmer rapidement un diagnostic de MTB chez les enfants sont nécessaires d'urgence.

Topics: Antibiotics, Antitubercular; Humans; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Predictive Value of Tests; Reproducibility of Results; Rifampin; Tuberculosis, Meningeal

Xpert MTB/RIF Ultra (Xpert Ultra) and Xpert MTB/RIF are World Health Organization (WHO)-recommended rapid nucleic acid amplification tests (NAATs) widely used for simultaneous detection of Mycobacterium tuberculosis complex and rifampicin resistance in sputum. To extend our previous review on extrapulmonary tuberculosis (Kohli 2018), we performed this update to inform updated WHO policy (WHO Consolidated Guidelines (Module 3) 2020).. To estimate diagnostic accuracy of Xpert Ultra and Xpert MTB/RIF for extrapulmonary tuberculosis and rifampicin resistance in adults with presumptive extrapulmonary tuberculosis.. Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature, Scopus, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number Registry, and ProQuest, 2 August 2019 and 28 January 2020 (Xpert Ultra studies), without language restriction.. Cross-sectional and cohort studies using non-respiratory specimens. Forms of extrapulmonary tuberculosis: tuberculous meningitis and pleural, lymph node, bone or joint, genitourinary, peritoneal, pericardial, disseminated tuberculosis. Reference standards were culture and a study-defined composite reference standard (tuberculosis detection); phenotypic drug susceptibility testing and line probe assays (rifampicin resistance detection).. Two review authors independently extracted data and assessed risk of bias and applicability using QUADAS-2. For tuberculosis detection, we performed separate analyses by specimen type and reference standard using the bivariate model to estimate pooled sensitivity and specificity with 95% credible intervals (CrIs). We applied a latent class meta-analysis model to three forms of extrapulmonary tuberculosis. We assessed certainty of evidence using GRADE.. 69 studies: 67 evaluated Xpert MTB/RIF and 11 evaluated Xpert Ultra, of which nine evaluated both tests. Most studies were conducted in China, India, South Africa, and Uganda. Overall, risk of bias was low for patient selection, index test, and flow and timing domains, and low (49%) or unclear (43%) for the reference standard domain. Applicability for the patient selection domain was unclear for most studies because we were unsure of the clinical settings. Cerebrospinal fluid Xpert Ultra (6 studies) Xpert Ultra pooled sensitivity and specificity (95% CrI) against culture were 89.4% (79.1 to 95.6) (89 participants; low-certainty evidence) and 91.2% (83.2 to 95.7) (386 participants; moderate-certainty evidence). Of 1000 people where 100 have tuberculous meningitis, 168 would be Xpert Ultra-positive: of these, 79 (47%) would not have tuberculosis (false-positives) and 832 would be Xpert Ultra-negative: of these, 11 (1%) would have tuberculosis (false-negatives). Xpert MTB/RIF (30 studies) Xpert MTB/RIF pooled sensitivity and specificity against culture were 71.1% (62.8 to 79.1) (571 participants; moderate-certainty evidence) and 96.9% (95.4 to 98.0) (2824 participants; high-certainty evidence). Of 1000 people where 100 have tuberculous meningitis, 99 would be Xpert MTB/RIF-positive: of these, 28 (28%) would not have tuberculosis; and 901 would be Xpert MTB/RIF-negative: of these, 29 (3%) would have tuberculosis. Pleural fluid Xpert Ultra (4 studies) Xpert Ultra pooled sensitivity and specificity against culture were 75.0% (58.0 to 86.4) (158 participants; very low-certainty evidence) and 87.0% (63.1 to 97.9) (240 participants; very low-certainty evidence). Of 1000 people where 100 have pleural tuberculosis, 192 would be Xpert Ultra-positive: of these, 117 (61%) would not have tuberculosis; and 808 would be Xpert Ultra-negative: of these, 25 (3%) would have tuberculosis. Xpert MTB/RIF (25 studies) Xpert MTB/RIF pooled sensitivity and specificity against culture were 49.5% (39.8 to 59.9) (644 participants; low-certainty evidence) and 98.9% (97.6 to 99.7) (2421 participants; high-certainty evidence). Of 1000 people where 100 have pleural tuberculosis, 60 would be Xpert MTB/RIF-positive: of these, 10 (17%) would not have tuberculosis; and 940 would be Xpert MTB/RIF-negative: of these, 50 (5%) would have tuberculosis. Lymph node aspirate Xpert Ultra (1 study) Xpert Ultra sensitivity and specificity (95% confidence interval) against composite reference standard we. Xpert Ultra and Xpert MTB/RIF may be helpful in diagnosing extrapulmonary tuberculosis. Sensitivity varies across different extrapulmonary specimens: while for most specimens specificity is high, the tests rarely yield a positive result for people without tuberculosis. For tuberculous meningitis, Xpert Ultra had higher sensitivity and lower specificity than Xpert MTB/RIF against culture. Xpert Ultra and Xpert MTB/RIF had similar sensitivity and specificity for rifampicin resistance. Future research should acknowledge the concern associated with culture as a reference standard in paucibacillary specimens and consider ways to address this limitation.

Topics: Adult; Antibiotics, Antitubercular; Bias; Drug Resistance, Bacterial; False Negative Reactions; False Positive Reactions; Humans; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Reagent Kits, Diagnostic; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Lymph Node; Tuberculosis, Meningeal; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pleural

Intensified antimicrobial treatment with higher rifampicin doses may improve outcome of tuberculous meningitis, but the desirable exposure and necessary dose are unknown. Our objective was to characterize the relationship between rifampicin exposures and mortality in order to identify optimal dosing for tuberculous meningitis.. An individual patient meta-analysis was performed on data from 3 Indonesian randomized controlled phase 2 trials comparing oral rifampicin 450 mg (~10 mg/kg) to intensified regimens including 750-1350 mg orally, or a 600-mg intravenous infusion. Pharmacokinetic data from plasma and cerebrospinal fluid (CSF) were analyzed with nonlinear mixed-effects modeling. Six-month survival was described with parametric time-to-event models.. Pharmacokinetic analyses included 133 individuals (1150 concentration measurements, 170 from CSF). The final model featured 2 disposition compartments, saturable clearance, and autoinduction. Rifampicin CSF concentrations were described by a partition coefficient (5.5%; 95% confidence interval [CI], 4.5%-6.4%) and half-life for distribution plasma to CSF (2.1 hours; 95% CI, 1.3-2.9 hours). Higher CSF protein concentration increased the partition coefficient. Survival of 148 individuals (58 died, 15 dropouts) was well described by an exponentially declining hazard, with lower age, higher baseline Glasgow Coma Scale score, and higher individual rifampicin plasma exposure reducing the hazard. Simulations predicted an increase in 6-month survival from approximately 50% to approximately 70% upon increasing the oral rifampicin dose from 10 to 30 mg/kg, and predicted that even higher doses would further improve survival.. Higher rifampicin exposure substantially decreased the risk of death, and the maximal effect was not reached within the studied range. We suggest a rifampicin dose of at least 30 mg/kg to be investigated in phase 3 clinical trials.

Topics: Anti-Infective Agents; Antitubercular Agents; Clinical Trials, Phase II as Topic; Humans; Indonesia; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis, Meningeal

Tuberculous meningitis (TBM) is one of the most serious types of extrapulmonary tuberculosis. However, low sensitivity of culture of cerebrospinal fluid (CSF) increases the difficulty in clinical diagnosis, leading to diagnostic delay, and misdiagnosis. Xpert MTB/RIF assay is a rapid and simple method to detect tuberculosis. However, the efficacy of this technique in diagnosing TBM remains unclear. Therefore, a meta-analysis was conducted to evaluate the diagnostic efficacy of Xpert MTB/RIF for TBM, which may enhance the development of early diagnosis of TBM.. Relevant studies in the PubMed, Embase, and Web of Science databases were retrieved using the keywords 'Xpert MTB/RIF', 'tuberculous meningitis (TBM)'. The pooled sensitivity, pooled specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, summary receiver operator characteristic curve, and area under the curve (AUC) of Xpert MTB/RIF were determined and analyzed.. A total of 162 studies were enrolled and only 14 met the criteria for meta-analysis. The overall pooled sensitivity of Xpert MTB/RIF was 63% [95% confidence interval (CI), 59-66%], while the overall pooled specificity was 98.1% (95% CI, 97.5-98.5%). The pooled values of positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 20.91% (12.71-52.82%), 0.40% (0.32-0.50%), and 71.49% (32.64-156.56%), respectively. The AUC was 0.76.. Xpert MTB/RIF exhibited high specificity in diagnosing TBM in CSF samples, but its sensitivity was relatively low. It is necessary to combine other high-sensitive detection methods for the early diagnosis of TBM. Moreover, the centrifugation of CSF samples was found to be beneficial in improving the sensitivity.

Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Predictive Value of Tests; Reproducibility of Results; Rifampin; Tuberculosis, Meningeal

Tubercular meningitis (TBM) continues to be a common cause of neuromorbidity in children. There is no single diagnostic method that can rapidly detect Mycobacterium tuberculosis (M.tb) in TBM patients with high sensitivity and specificity. Newer diagnostic modalities like Xpert/RIF assay and Loop mediated isothermal amplification assay (LAMP) have gained an essential stand in molecular diagnostics due to their high specificity, modest sensitivity in cerebrospinal fluid (CSF) and quick availability of results. Intensified drug regimens using high dose rifampicin, fluoroquinolone and aspirin appear to be useful adjunct therapy but more pediatric clinical trials on large scale are needed to determine their appropriate place in pediatric TBM. The emergence of multi and extreme drug resistant M.tb strains further challenges the standard therapy. In this review authors summarize challenges of the currently used diagnostic methods and treatment for TBM and discuss the recent advances.

Topics: Antitubercular Agents; Aspirin; Child; Drug Resistance, Bacterial; Fluoroquinolones; Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Rifampin; Sensitivity and Specificity; Tuberculosis, Meningeal

Tuberculosis is a global burden with an unacceptably high mortality rate, especially in low- and middle-income countries. We reported the case of 34-year-old Somali female with no significant risk factors who initially presented with headache and blurred vision. The patient subsequently developed altered mental status and significant vision changes. Initial lumbar puncture showed lymphocytic pleocytosis with negative gram stain, acid-fast bacilli stain, and culture. Initial polymerase chain reaction for tuberculosis was negative. The patient worsened despite receiving broad-spectrum antibiotics. The patient had a prolonged hospital course and eventually required lumbar drain placement for hydrocephalus. Repeated polymerase chain reactions for Mycobacterium tuberculosis from the lumbar drain samples was positive, and the diagnosis of tuberculous meningitis was confirmed. The patient improved after lumbar drain placement and treatment with isoniazid, rifampin, pyrazinamide, ethambutol and steroid tapering. This case illustrated the challenge of diagnosing tuberculous meningitis.

Topics: Adult; Antitubercular Agents; Asthma; Ethambutol; Female; Headache; Hospitalization; Humans; Hydrocephalus; Isoniazid; Leukocytosis; Magnetic Resonance Imaging; Polymerase Chain Reaction; Pyrazinamide; Rifampin; Somalia; Spinal Puncture; Tuberculosis, Meningeal; United States; Vision Disorders

Every year, at least one million children become ill with tuberculosis and around 200,000 children die. Xpert MTB/RIF and Xpert Ultra are World Health Organization (WHO)-recommended rapid molecular tests that simultaneously detect tuberculosis and rifampicin resistance in adults and children with signs and symptoms of tuberculosis, at lower health system levels. To inform updated WHO guidelines on molecular assays, we performed a systematic review on the diagnostic accuracy of these tests in children presumed to have active tuberculosis.. Primary objectives • To determine the diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra for (a) pulmonary tuberculosis in children presumed to have tuberculosis; (b) tuberculous meningitis in children presumed to have tuberculosis; (c) lymph node tuberculosis in children presumed to have tuberculosis; and (d) rifampicin resistance in children presumed to have tuberculosis - For tuberculosis detection, index tests were used as the initial test, replacing standard practice (i.e. smear microscopy or culture) - For detection of rifampicin resistance, index tests replaced culture-based drug susceptibility testing as the initial test Secondary objectives • To compare the accuracy of Xpert MTB/RIF and Xpert Ultra for each of the four target conditions • To investigate potential sources of heterogeneity in accuracy estimates - For tuberculosis detection, we considered age, disease severity, smear-test status, HIV status, clinical setting, specimen type, high tuberculosis burden, and high tuberculosis/HIV burden - For detection of rifampicin resistance, we considered multi-drug-resistant tuberculosis burden • To compare multiple Xpert MTB/RIF or Xpert Ultra results (repeated testing) with the initial Xpert MTB/RIF or Xpert Ultra result SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and the International Standard Randomized Controlled Trials Number (ISRCTN) Registry up to 29 April 2019, without language restrictions.. Randomized trials, cross-sectional trials, and cohort studies evaluating Xpert MTB/RIF or Xpert Ultra in HIV-positive and HIV-negative children younger than 15 years. Reference standards comprised culture or a composite reference standard for tuberculosis and drug susceptibility testing or MTBDRplus (molecular assay for detection of Mycobacterium tuberculosis and drug resistance) for rifampicin resistance. We included studies evaluating sputum, gastric aspirate, stool, nasopharyngeal or bronchial lavage specimens (pulmonary tuberculosis), cerebrospinal fluid (tuberculous meningitis), fine needle aspirates, or surgical biopsy tissue (lymph node tuberculosis).. Two review authors independently extracted data and assessed study quality using the Quality Assessment of Studies of Diagnostic Accuracy - Revised (QUADAS-2). For each target condition, we used the bivariate model to estimate pooled sensitivity and specificity with 95% confidence intervals (CIs). We stratified all analyses by type of reference standard. We assessed certainty of evidence using the GRADE approach.. For pulmonary tuberculosis, 299 data sets (68,544 participants) were available for analysis; for tuberculous meningitis, 10 data sets (423 participants) were available; for lymph node tuberculosis, 10 data sets (318 participants) were available; and for rifampicin resistance, 14 data sets (326 participants) were available. Thirty-nine studies (80%) took place in countries with high tuberculosis burden. Risk of bias was low except for the reference standard domain, for which risk of bias was unclear because many studies collected only one specimen for culture. Detection of pulmonary tuberculosis For sputum specimens, Xpert MTB/RIF pooled sensitivity (95% CI) and specificity (95% CI) verified by culture were 64.6% (55.3% to 72.9%) (23 studies, 493 participants; moderate-certainty evidence) and 99.0% (98.1% to 99.5%) (23 studies, 6119 participants; moderate-certainty evidence). For other specimen types (nasopharyngeal aspirate, 4 studies; gastric aspirate, 14 studies; stool, 11 studies), Xpert MTB/RIF pooled sensitivity ranged between 45.7% and 73.0%, and pooled specificity ranged between 98.1% and 99.6%. For sputum specimens, Xpert Ultra pooled sensitivity (95% CI) and specificity (95% CI) verified by culture were 72.8% (64.7% to 79.6%) (3 studies, 136 participants; low-certainty evidence) and 97.5% (95.8% to 98.5%) (3 studies, 551 participants; high-certainty evidence). For nasopharyngeal specimens, Xpert Ultra sensitivity (95% CI) and specificity (95% CI) were 45.7% (28.9% to 63.3%) and 97.5% (93.7% to 99.3%) (1 study, 195 participants). For all specimen types, Xpert MTB/RIF and Xpert Ultra sensitivity were lower against a composite reference standard than against culture. Detection of tuberculous meningitis For cerebrospinal fluid, Xpert MTB/RIF pooled sensitivity and specificity, verified by culture, were 54.0% (95% CI 27.8% to 78.2%) (6 studies, 28 participants; very low-certainty evidence) and 93.8% (95% CI 84.5% to 97.6%) (6 studies, 213 participants; low-certainty evidence). Detection of lymph node tuberculosis For lymph node aspirates or biopsies, Xpert MTB/RIF pooled sensitivity and specificity, verified by culture, were 90.4% (95% CI 55.7% to 98.6%) (6 studies, 68 participants; very low-certainty evidence) and 89.8% (95% CI 71.5% to 96.8%) (6 studies, 142 participants; low-certainty evidence). Detection of rifampicin resistance Xpert MTB/RIF pooled sensitivity and specificity were 90.0% (67.6% to 97.5%) (6 studies, 20 participants; low-certainty. We found Xpert MTB/RIF sensitivity to vary by specimen type, with gastric aspirate specimens having the highest sensitivity followed by sputum and stool, and nasopharyngeal specimens the lowest; specificity in all specimens was > 98%. Compared with Xpert MTB/RIF, Xpert Ultra sensitivity in sputum was higher and specificity slightly lower. Xpert MTB/RIF was accurate for detection of rifampicin resistance. Xpert MTB/RIF was sensitive for diagnosing lymph node tuberculosis. For children with presumed tuberculous meningitis, treatment decisions should be based on the entirety of clinical information and treatment should not be withheld based solely on an Xpert MTB/RIF result. The small numbers of studies and participants, particularly for Xpert Ultra, limits our confidence in the precision of these estimates.

Topics: Adolescent; Antibiotics, Antitubercular; Bias; Child; Feces; Gastrointestinal Contents; Humans; Molecular Typing; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Lymph Node; Tuberculosis, Meningeal; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Although the occurrence of tuberculous meningitis (TBM) in children is relatively rare, but it is associated with higher rates of mortality and severe morbidity. The peak incidence of TBM occurs in younger children who are less than five years of age, and most children present with late-stage disease. Confirmation of diagnosis is often difficult, and other infectious causes such as bacterial, viral and fungal causes must be ruled out. Bacteriological confirmation of diagnosis is ideal but is often difficult because of its paucibacillary nature as well as decreased sensitivity and specificity of diagnostic tests. Early diagnosis and management of the disease, though difficult, is essential to avoid death or neurologic disability. Hence, a high degree of suspicion and a combined battery of tests including clinical, bacteriological and neuroimaging help in diagnosis of TBM. Children diagnosed with TBM should be managed with antituberculosis therapy (ATT) and steroids. There are studies reporting low concentrations of ATT, especially of rifampicin and ethambutol in cerebrospinal fluid (CSF), and very young children are at higher risk of low ATT drug concentrations. Further studies are needed to identify appropriate regimens with adequate dosing of ATT for the management of paediatric TBM to improve treatment outcomes. This review describes the clinical presentation, investigations, management and outcome of TBM in children and also discusses various studies conducted among children with TBM.

Topics: Antitubercular Agents; Child; Child, Preschool; Ethambutol; Humans; Mycobacterium tuberculosis; Rifampin; Steroids; Treatment Outcome; Tuberculosis, Meningeal

Tuberculous meningitis (TBM) is a commonly encountered central nervous system infection. Characteristic clinical, imaging and cerebrospinal fluid parameters help clinicians to make a prompt presumptive diagnosis that enables them to start empirical anti-tuberculosis treatment. There are several close mimic to TBM, such as partially treated pyogenic meningitis, fungal meningitis, sarcoidosis, meningeal metastases and meningeal lymphomatosis. Microbiological confirmation instils a sense of confidence amongst treating physicians. With conventional phenotypic methods (cerebrospinal fluid microscopy and culture), in more than 50 per cent patients, microbiological confirmation is not achieved. Moreover, these methods take a long time before providing conclusive results. Negative result does not rule out Mycobacterium tuberculosis infection of the brain. Genotypic methods, such as IS 6110 polymerase chain reaction and automated Xpert M. tuberculosis/rifampicin (MTB/RIF) assay system improved the TBM diagnostics, as results are rapidly available. Xpert MTB/RIF assay, in addition, detects rifampicin resistance. Xpert MTB/RIF Ultra is advanced technology which has higher (60-70%) sensitivity and is being considered a game-changer in the diagnostics of TBM. A large number of TBM cases remain unconfirmed. The situation of TBM diagnostics will remain grim, if low-cost technologies are not widely available. Till then, physicians continue to rely on their clinical acumen to start empirical anti-tuberculosis treatment.

Topics: Antibiotics, Antitubercular; Diagnostic Tests, Routine; Genotype; Humans; Mycobacterium tuberculosis; Phenotype; Rifampin; Tuberculosis, Meningeal

Tuberculous meningitis carries a high rate of mortality and morbidity despite of an adequate treatment. Newer agents are being searched to improve outcome of these patients. Fluoroquinolones might be useful in the management of tuberculous meningitis in view of good cerebrospinal fluid penetration and good in-vitro activity against the mycobacterium. This review summarizes the effects of fluoroquinolone in first line regimens in tuberculous meningitis.. A systematic search of literature was performed using PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) and LILACS for articles published till march 2017. We also searched meta-register of controlled trials and bibliography of relevant studies. Randomized controlled trials (RCTs) where a fluoroquinolone was administered in addition or substitution of standard antituberculosis drugs formed the basis of selection criteria. Data was extracted on a pre-specified format. Risk ratio (RR) for dichotomous data was calculated and fixed effect model was used to combined the data if no heterogeneity was found. Death was taken as the primary outcome measure.. Five trials including 1115 patients of tuberclous meningitis were included. Addition of a fluoroquinolone to a standard regimen was not found to significantly reduce mortality [RR = 0.68 (0.30-1.52)] (low-quality evidence). Addition of a fluoroquinolone to an intensified regimen (containing high dose rifampicin) was not found to significantly reduce mortality [RR = 0.97 (0.78-1.20)] (low-quality evidence). Substitution of fluoroquinolone for ethambutol [RR = 1.17 (0.67-2.07)] (moderate-quality evidence, risk of harm cannot be ruled out) or for rifampicin [RR = 0.57 (0.32-1.01)] (low-quality evidence) in the standard regimen in terms of mortality did not show any benefit. There was no significant difference in the distribution of overall adverse events except for a higher incidence of vision loss and seizures in the fluoroquinolone arm.. Routine addition or substitution of a fluroquinolone in the standard regimen can not be recommended at present. As most of the evidence driven in this review was of moderate- to low-quality, further research in this area is expected to make a significant impact in formulating a directive.

Topics: Antibiotics, Antitubercular; Antitubercular Agents; Disease Management; Drug Therapy, Combination; Fluoroquinolones; Humans; Mycobacterium tuberculosis; Randomized Controlled Trials as Topic; Rifampin; Treatment Outcome; Tuberculosis, Meningeal

To determine the diagnostic accuracy of Xpert a) for extrapulmonary TB by site of disease in people presumed to have extrapulmonary TB; and b) for rifampicin resistance in people presumed to have extrapulmonary TB.. We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature (LILACS), Scopus, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number (ISRCTN) Registry, and ProQuest up to 7 August 2017 without language restriction.. We included diagnostic accuracy studies of Xpert in people presumed to have extrapulmonary TB. We included TB meningitis and pleural, lymph node, bone or joint, genitourinary, peritoneal, pericardial, and disseminated TB. We used culture as the reference standard. For pleural TB, we also included a composite reference standard, which defined a positive result as the presence of granulomatous inflammation or a positive culture result. For rifampicin resistance, we used culture-based drug susceptibility testing or MTBDRplus as the reference standard.. Two review authors independently extracted data, assessed risk of bias and applicability using the QUADAS-2 tool. We determined pooled predicted sensitivity and specificity for TB, grouped by type of extrapulmonary specimen, and for rifampicin resistance. For TB detection, we used a bivariate random-effects model. Recognizing that use of culture may lead to misclassification of cases of extrapulmonary TB as 'not TB' owing to the paucibacillary nature of the disease, we adjusted accuracy estimates by applying a latent class meta-analysis model. For rifampicin resistance detection, we performed univariate meta-analyses for sensitivity and specificity separately to include studies in which no rifampicin resistance was detected. We used theoretical populations with an assumed prevalence to provide illustrative numbers of patients with false positive and false negative results.. We included 66 unique studies that evaluated 16,213 specimens for detection of extrapulmonary TB and rifampicin resistance. We identified only one study that evaluated the newest test version, Xpert MTB/RIF Ultra (Ultra), for TB meningitis. Fifty studies (76%) took place in low- or middle-income countries. Risk of bias was low for patient selection, index test, and flow and timing domains and was high or unclear for the reference standard domain (most of these studies decontaminated sterile specimens before culture inoculation). Regarding applicability, in the patient selection domain, we scored high or unclear concern for most studies because either patients were evaluated exclusively as inpatients at tertiary care centres, or we were not sure about the clinical settings.Pooled Xpert sensitivity (defined by culture) varied across different types of specimens (31% in pleural tissue to 97% in bone or joint fluid); Xpert sensitivity was > 80% in urine and bone or joint fluid and tissue. Pooled Xpert specificity (defined by culture) varied less than sensitivity (82% in bone or joint tissue to 99% in pleural fluid and urine). Xpert specificity was ≥ 98% in cerebrospinal fluid, pleural fluid, urine, and peritoneal fluid.Xpert testing in cerebrospinal fluidXpert pooled sensitivity and specificity (95% credible interval (CrI)) against culture were 71.1% (60.9% to 80.4%) and 98.0% (97.0% to 98.8%), respectively (29 studies, 3774 specimens; moderate-certainty evidence).For a population of 1000 people where 100 have TB meningitis on culture, 89 would be Xpert-positive: of these, 18 (20%) would not have TB (false-positives); and 911 would be Xpert-negative: of these, 29 (3%) would have TB (false-negatives).For TB meningitis, ultra sensitivity and specificity against culture (95% confidence interval (CI)) were 90% (55% to 100%) and 90% (83% to 95%), respectively (one study, 129 participants).Xpert testing in pleural fluidXpert pooled sensitivity and specificity (95% CrI) against culture were 50.9% (39.7% to 62.8%) and 99.2% (98.2% to 99.7%), respectively (27 studies, 4006 specimens; low-certainty evidence).For a population of 1000 people where 150 have pleural TB on culture, 83 would be Xpert-positive: of these, seven (8%) would not have TB (false-positives); and 917 would be Xpert-negative: of these, 74 (8%) would have TB (false-negatives).Xpert testing in urineXpert pooled sensitivity and specificity (95% CrI) against culture were 82.7% (69.6% to 91.1%) and 98.7% (. In people presumed to have extrapulmonary TB, Xpert may be helpful in confirming the diagnosis. Xpert sensitivity varies across different extrapulmonary specimens, while for most specimens, specificity is high, the test rarely yielding a positive result for people without TB (defined by culture). Xpert is accurate for detection of rifampicin resistance. For people with presumed TB meningitis, treatment should be based on clinical judgement, and not withheld solely on an Xpert result, as is common practice when culture results are negative.

Topics: Antibiotics, Antitubercular; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; False Negative Reactions; False Positive Reactions; Humans; Mycobacterium tuberculosis; Reagent Kits, Diagnostic; Reference Standards; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Meningeal

Tuberculous meningitis (TBM) is the most severe form of infection caused by Mycobacterium tuberculosis, causing death or disability in more than half of those affected. The aim of this review is to examine recent advances in our understanding of TBM, focussing on the diagnosis and treatment of this devastating condition.. Papers on TBM published between 1891 and 2014 and indexed in the NCBI Pubmed. The following search terms were used: TBM, diagnosis, treatment and outcome.. The diagnosis of TBM remains difficult as its presentation is non-specific and may mimic other causes of chronic meningoencephalitis. Rapid recognition of TBM is crucial, however, as delays in initiating treatment are associated with poor outcome. The laboratory diagnosis of TBM is hampered by the low sensitivity of cerebrospinal fluid microscopy and the slow growth of M. tuberculosis in conventional culture systems. The current therapy of TBM is based on the treatment of pulmonary tuberculosis, which may not be ideal. The combination of TBM and HIV infection poses additional management challenges because of the need to treat both infections and the complications associated with them.. The pathogenesis of TBM remains incompletely understood limiting the development of interventions to improve outcome. The optimal therapy of TBM has not been established in clinical trials, and increasing antimicrobial resistance threatens successful treatment of this condition. The use of adjunctive anti-inflammatory agents remains controversial, and their mechanism of action remains incompletely understood. The role of surgical intervention is uncertain and may not be available in areas where TBM is common.. Laboratory methods to improve the rapid diagnosis of TBM are urgently required. Clinical trials of examining the use of high-dose rifampicin and/or fluoroquinolones are likely to report in the near future.. The use of biomarkers to improve the rapid diagnosis of TBM warrants further investigation. The role of novel antituberculosis drugs, such as bedaquiline and PA-824, in the treatment of TBM remains to be explored. Human genetic polymorphisms may explain the heterogeneity of response to anti-inflammatory therapies and could potentially be used to tailor therapy.

Topics: Antitubercular Agents; Drug Therapy, Combination; Host-Pathogen Interactions; Humans; Isoniazid; Mycobacterium tuberculosis; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Meningeal

Early diagnosis and treatment of tuberculous meningitis (TBM) saves lives, but current laboratory diagnostic tests lack sensitivity and the best treatment regimens are uncertain. This article reviews the advances towards better TBM diagnosis and treatments made over the last 2 years.. A modified Ziehl-Neelsen stain, interferon-gamma release assays and Mycobacterium tuberculosis antigen detection assays have all shown promise as new TBM diagnostic tests. HIV-associated TBM carries an especially grave prognosis and there are new data describing the optimal timing of antiretroviral treatment initiation and the clinical predictors of TBM immune reconstitution inflammatory syndrome. The pharmacokinetic and pharmacodynamic properties of different fluoroquinolones for TBM treatment have been compared, and there are intriguing new data to suggest higher doses of rifampicin given intravenously may improve the survival. Finally, there are preliminary data to suggest that the beneficial effect of adjunctive corticosteroids on TBM survival may be augmented by aspirin and predicted by a polymorphism in a gene responsible for eicosanoid synthesis.. Much remains to be done to improve the outcome from TBM. There have been important advances in the treatment, which may influence treatment guidelines in the near future, but there remains an urgent need for better diagnostic tests.

Topics: Antibiotics, Antitubercular; Antigens, Bacterial; HIV Infections; Humans; Prognosis; Rifampin; Tuberculosis, Meningeal

Tuberculous (TB) meningitis is common in resource-poor communities but also occurs in developed countries where the diagnosis is frequently delayed because of unfamiliarity with the disease. TB meningitis develops whenever a small intracranial tuberculoma (Rich focus) ruptures causing predominantly basal meningitis. This results in hydrocephalus, cranial nerve palsies, and ischemic brain injury secondary to tuberculous vasculitis. The primary source of TB is usually the lung. Early diagnosis is difficult because patients tend to present subacutely with nonspecific symptoms such as fever, cough, vomiting, listlessness, and failure to thrive. Lumbar puncture typically shows clear and colorless CSF with a low, predominantly lymphocytic, leukocytosis and raised protein and low glucose levels. Decision to treat is mostly clinical because of difficulty in demonstrating TB bacilli on routine smear and time needed for culture. A positive TB contact, Mantoux skin test, chest radiograph, CT/MRI brain scan, PCR for tuberculosis on CSF, and demonstration of TB bacilli from extraneural sources are invaluable in supporting a diagnosis of TB meningitis. Current World Health Organization guidelines recommend treatment with a four-drug regimen for 2 months, followed by a two-drug regimen for 10 months, the total duration of treatment being 12 months. Corticosteroids reduce mortality without changing neurological morbidity. Outcome relates closely to age and stage of disease.

Topics: Antitubercular Agents; Child; Humans; Isoniazid; Magnetic Resonance Imaging; Prognosis; Rifampin; Treatment Outcome; Tuberculosis, Meningeal

Tuberculous meningitis (TBM) causes a devastating morbidity and mortality in adults and children. Even in patients presenting at an early stage of disease, deterioration may occur despite apparently adequate therapy. The literature relating to cerebrospinal fluid penetration of antituberculosis agents is reviewed. Amongst the essential antituberculosis agents isoniazid has the best CSF pharmacokinetics reaching peak concentrations (C(max)) only slightly less than in blood. Pyrazinamide also has good CSF penetration and in children receiving dosages of 40 mg/kg the CSF C(max) exceeds the proposed minimal inhibitory concentration of 20 μg/ml. Streptomycin other aminoglycosides and ethambutol have poor CSF penetration and cannot be agents of first choice for TBM treatment. Rifampicin at dosages used in adults seldom reaches CSF concentrations exceeding MIC, but does so more frequently in children when dosages of up to 20 mg/kg are used. The non-essential agents ethionamide, the fluoroquinolones, with the exception of ciprofloxacin, and cycloserine (terizadone) have relatively good CSF penetration and are recommended for TBM treatment. The dosages of the essential agents recommended for the treatment of TBM in children are INH 10 mg/kg (range 6-15 mg/kg bodyweight), rifampicin 15 mg/kg (range 10-20 mg/kg), pyrazinamide 35 mg/kg (range 30-40 mg/kg), ethambutol 20 mg/kg (range 15-25 mg/kg) and streptomycin 15 mg/kg (range 12-18 mg/kg). Amongst second-line agents ofloxacin, levofloxacin and moxifloxacin should be used in dosages of 15-20 mg/kg, ethionamide 20 mg/kg in a single dose, if tolerated, and for cycloserine (terizadone) 15 mg/kg. Antituberculous chemotherapy should be started as soon as the diagnosis of TBM is considered.

Topics: Adult; Antitubercular Agents; Child; Dose-Response Relationship, Drug; Female; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Tuberculosis, Meningeal

Literature dealing with antituberculosis chemotherapy of tuberculous meningitis (TBM) in adults and children is reviewed and recommendations made for the chemotherapy of TBM. Publications relating to the chemotherapy of TBM were reviewed which contribute to understanding the efficacy of different drugs and regimens in TBM treatment. The established classification of disease severity into stages I (no neurological signs and fully conscious), II (patients conscious but with neurological signs) and III (comatose or stuporous or with severe pareses) was used to compare regimens of isoniazid (INH), para-amino salicylic acid and streptomycin (INH regimens) used up to approximately 1970 with those using INH and rifampicin (RMP), supported by pyrazinamide and ethambutol or streptomycin (RMP regimens). Mortality in studies at all disease stages in adults or adults and children, with the children not distinguished, following INH regimens (12.4%, 25.2% and 55% at stages I, II and III respectively) did not differ significantly from that following introduction of RMP regimens (9.7%, 22.2% and 56% at stages I, II and III respectively), In studies of children only, mortality fell significantly following the introduction of RMP to 0%, 5.9% and 28.2% in children at stage I, II and III having been 10.2%, 22.3% and 49.4% respectively with INH regimens (P = 0.006). Following RMP regimens of 6 months duration, only 2 (1%) relapses occurred amongst 197 patients, after RMP regimens of 9-24 months only 1 (0.16%) relapse was recorded amongst 632 patients. Where INH resistance rates are <4% a directly observed INH, RMP, pyrazinamide and ethambutol for 2-months followed by INH and RMP for 4 months is recommended. If directly observed therapy cannot be practiced treatment duration should be extended to at least 9 months; if the risk of INH resistance or multidrug resistance is higher, the use of ethionamide and a fluoroquinolone and possibly cycloserine is recommended and pyrazinamide should be continued for full treatment duration. The penetration of RMP, ethambutol and streptomycin into cerebrospinal fluid is poor; higher dosages of RMP should be considered.

Topics: Adult; Aminosalicylic Acid; Antibiotics, Antitubercular; Antitubercular Agents; Child; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; History, 18th Century; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Severity of Illness Index; Streptomycin; Tuberculosis, Meningeal

Diffuse pachymeningitis is an uncommon presentation of tuberculous meningitis (TBM). We present a 78-year-old woman patient with a 1-year history of progressive headache and MRI of the brain compatible with diffuse pachymeningitis. Without strong evidence to support a diagnosis, she subsequently underwent dural biopsy which revealed caseous granulomatous inflammation and was positive for Mycobacterium tuberculosis complex by PCR. The dura tissue culture subsequently confirmed the diagnosis of TBM. Successful treatment with antituberculous drugs and corticosteroid was observed without complications. Literature review on characteristics, diagnoses and treatment of central nervous system tuberculosis was also performed.

Topics: Adrenal Cortex Hormones; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Ethambutol; Female; Humans; Isoniazid; Meningitis; Mycobacterium tuberculosis; Prednisone; Pyrazinamide; Rifampin; Tuberculosis, Meningeal

The British Thoracic Society and the American Thoracic Society advise 12 months treatment for tuberculous meningitis, with at least isoniazid (H), rifampicin (R) and pyrazinamide (Z).. To establish whether a 6-month treatment regimen for tuberculous meningitis is equally as effective as longer treatment.. Medline search for papers published between 1978 and 1999.. study populations of patients with tuberculous meningitis in whom the diagnosis was confirmed with clinical, cerebrospinal fluid and epidemiological findings; a treatment regimen with at least HRZ and at least 12 months of follow-up after the completion of treatment.. the number of relapses.. There were four 6-month treatment regimens (G6) and seven longer treatment regimens (G>6); 160/197 (81%) patients completed the 6-month treatment regimens, while 577/675 (85%) completed the longer-term regimens. The clinical stage of patients in the G6 group was poorer than in the G>6 group. Relapse occurred in two out of 131 (1.5%) G6 and in 0 out of 591 G>6 patients.. Although no studies have compared 6-month treatment regimens with longer treatment, it can be concluded on the basis of this literature review that 6-month treatment is sufficient for tuberculous meningitis with fully susceptible mycobacteria.

Topics: Adult; Antitubercular Agents; Child; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Recurrence; Rifampin; Tuberculosis, Meningeal

Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Drug Therapy, Combination; Female; Hepatic Encephalopathy; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis, Meningeal

Tuberculous meningitis is a rare, treatable neurologic disorder, in which early recognition is paramount because outcome depends greatly on the speed with which therapy is initiated. Patients with meningitis and CSF findings of low glucose, elevated protein and pleocytosis with evidence of tuberculosis elsewhere in the body (chest radiographs, positive tuberculin skin test), or a history of exposure to tuberculosis should be treated immediately with antituberculous medication. When the diagnosis remains uncertain, serial examination of the CSF for tuberculous organisms will often yield positive results. The CT scan may show hydrocephalus, a basilar arachnoiditis, or intraparenchymal lesions: tuberculomas. Hydrocephalus may respond to early shunting. Tuberculomas are best treated medically. Therapy should include INH and rifampin; ethambutol and pyrazinamide are suggested for the first 2 months of therapy. Steroids may be useful in diminishing the inflammatory response when altered consciousness or focal neurologic signs are present.

Topics: Biopsy; Cerebral Ventricles; Cerebrospinal Fluid; Ethambutol; Humans; Hyaluronoglucosaminidase; Isoniazid; Nervous System Diseases; Prognosis; Pyrazinamide; Rifampin; Streptomycin; Tomography, X-Ray Computed; Tuberculoma; Tuberculosis, Meningeal

In the United States, an increasing proportion of all forms of reactivation tuberculosis occurs in patients over the age of 60 years. Atypical presentations and presence of chronic illness obscure the diagnosis of tuberculosis in the elderly. Prompt diagnosis requires a high index of suspicion and aggressive procedures for diagnostic microbiology. Short-course (9 months) chemotherapy with isoniazid and rifampin is the treatment of choice for elderly patients with uncomplicated pulmonary tuberculosis. Isoniazid chemoprophylaxis is recommended for selected elderly patients.

Topics: Aged; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Pyridoxine; Rifampin; Streptomycin; Tuberculosis, Meningeal; Tuberculosis, Miliary; Tuberculosis, Osteoarticular; Tuberculosis, Pulmonary; Tuberculosis, Urogenital; United States

Topics: Aminosalicylic Acid; Antitubercular Agents; Blood-Brain Barrier; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Humans; Injections, Spinal; Isoniazid; Optic Neuritis; Rifampin; Streptomycin; Tuberculosis, Meningeal

Topics: Adrenal Cortex Hormones; Antitubercular Agents; Child; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis, Meningeal

Topics: Aminosalicylic Acids; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Thioacetazone; Tuberculosis; Tuberculosis, Lymph Node; Tuberculosis, Meningeal; Tuberculosis, Miliary; Tuberculosis, Osteoarticular; Tuberculosis, Pulmonary; Tuberculosis, Urogenital

Topics: Aminosalicylic Acids; Ethambutol; Female; Humans; Hypersensitivity, Delayed; Isoniazid; Male; Mycobacterium tuberculosis; Recurrence; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Cardiovascular; Tuberculosis, Female Genital; Tuberculosis, Lymph Node; Tuberculosis, Male Genital; Tuberculosis, Meningeal; Tuberculosis, Osteoarticular; Tuberculosis, Pulmonary; Tuberculosis, Renal; United States

Topics: Adrenal Cortex Hormones; Brain Edema; Cerebral Angiography; Developing Countries; Ethambutol; Humans; India; Isoniazid; Male; Mycobacterium tuberculosis; Rifampin; Streptomycin; Thailand; Tuberculosis, Meningeal

Topics: Acute Disease; Antitubercular Agents; Child; Diagnosis, Differential; Drug Therapy, Combination; Female; Humans; Isoniazid; Lung; Middle Aged; Mycobacterium tuberculosis; Peritonitis, Tuberculous; Pneumonia; Radiography; Rifampin; Sputum; Tuberculosis; Tuberculosis, Cardiovascular; Tuberculosis, Meningeal; Tuberculosis, Miliary

Drug regimens that include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in tuberculous meningitis (TBM). Safety data on their use in combination and in the context of human immunodeficiency virus (HIV) are needed to inform clinical trial design.. We conducted a phase 2, open-label, parallel-design, randomized, controlled trial to assess the safety of high-dose rifampicin, linezolid, and high-dose aspirin in HIV-associated TBM. Participants were randomized (1.4:1:1) to 3 treatment arms (1, standard of care [SOC]; 2, SOC + additional rifampicin [up to 35 mg/kg/d] + linezolid 1200 mg/d reducing after 28 days to 600 mg/d; 3, as per arm 2 + aspirin 1000 mg/d) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed.. A total of 52 participants with HIV-associated TBM were randomized; 59% had mild disease (British Medical Research Council (MRC) grade 1) vs 39% (grade 2) vs 2% (grade 3). AESI or death occurred in 10 of 16 (63%; arm 3) vs 4 of 14 (29%; arm 2) vs 6 of 20 (30%; arm 1; P = .083). The cumulative proportion of AESI or death (Kaplan-Meier) demonstrated worse outcomes in arm 3 vs arm 1 (P = .04); however, only 1 event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (modified Rankin scale) between arms.. High-dose rifampicin and adjunctive linezolid can safely be added to the standard of care in HIV-associated TBM. Larger studies are required to determine whether potential toxicity associated with these interventions, particularly high-dose aspirin, is outweighed by mortality or morbidity benefit.. NCT03927313.

Topics: Antitubercular Agents; Aspirin; HIV; HIV Infections; Humans; Linezolid; Rifampin; Treatment Outcome; Tuberculosis, Meningeal

Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM.. TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL).. Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and expressive language domains (P < .01).. In a pediatric TBM trial, functional outcomes were excellent overall. The trend toward higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial.. NCT02958709.

Topics: Adult; Antitubercular Agents; Child; Ethambutol; Humans; Levofloxacin; Rifampin; Standard of Care; Tuberculosis, Meningeal

Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis (TB), particularly in sub-Saharan Africa. Current anti-TB treatment is poorly effective since TBM mortality reaches 40% in HIV-negative patients and up to 70% in HIV-co-infected patients. To reduce TBM-induced morbidity and mortality, the INTENSE-TBM trial evaluates two interventions in both HIV-infected and uninfected patients: an anti-TB treatment intensification using oral high-dose rifampicin (35 mg/kg daily) and linezolid (1200 mg daily and then 600 mg daily) during the first 8 weeks of the anti-TB treatment and the use of adjunctive aspirin (200 mg daily).. This is a randomized controlled, phase III, multicenter, 2 × 2 factorial plan superiority trial. The trial has four arms, combining the two experimental treatments (intensified TBM regimen and aspirin) with the two reference treatments (WHO standard TB treatment and placebo), and is open-label for anti-TB treatment and double-blind placebo-controlled for aspirin treatment. This trial is conducted in adults or adolescents of age ≥15 years with TBM defined as "definite," "probable," or "possible" using Tuberculosis Meningitis International Research Consortium criteria, in four African countries: Ivory Coast, Madagascar, Uganda, and South Africa. The primary outcome is all-cause death between inclusion and week 40.. The INTENSE-TBM trial represents a key opportunity to enhance TBM treatment with widely available existing drugs notably in high-incidence settings of both TB and HIV. The trial design is pragmatic and the results will permit early and effective applications in TBM patient care, in both HIV and TB high-incidence countries.. ClinicalTrials.gov NCT04145258. Registered on October 30, 2019.

Topics: Adolescent; Adult; Antitubercular Agents; Aspirin; Clinical Trials, Phase III as Topic; HIV Infections; Humans; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Rifampin; South Africa; Tuberculosis, Meningeal

High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in human immunodeficiency virus (HIV) coinfection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity.. In this phase II open-label trial, Ugandan adults with suspected TBM were randomized to standard-of-care control (PO-10, rifampicin 10 mg/kg/day), intravenous rifampicin (IV-20, 20 mg/kg/day), or high-dose oral rifampicin (PO-35, 35 mg/kg/day). We performed PK sampling on days 2 and 14. The primary outcomes were total exposure (AUC0-24), maximum concentration (Cmax), CSF concentration, and grade 3-5 adverse events.. We enrolled 61 adults, 92% were living with HIV, median CD4 count was 50 cells/µL (interquartile range [IQR] 46-56). On day 2, geometric mean plasma AUC0-24hr was 42.9·h mg/L with standard-of-care 10 mg/kg dosing, 249·h mg/L for IV-20 and 327·h mg/L for PO-35 (P < .001). In CSF, standard of care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0-24hr 0.27 mg/L, compared with 1.74 mg/L (95% confidence interval [CI] 1.2-2.5) for IV-20 and 2.17 mg/L (1.6-2.9) for PO-35 regimens (P < .001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (P = .34).. Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe and respectively resulted in exposures ~6- and ~8-fold higher than standard of care, and CSF levels above the MIC.

Topics: Adult; Antitubercular Agents; HIV; HIV Infections; Humans; Rifampin; Tuberculosis, Meningeal; Uganda

The most effective antituberculosis drug treatment regimen for tuberculous meningitis is uncertain. We conducted a randomized controlled trial comparing standard treatment with a regimen intensified by rifampin 15 mg/kg and levofloxacin for the first 60 days. The intensified regimen did not improve survival or any other outcome. We therefore conducted a nested pharmacokinetic/pharmacodynamic study in 237 trial participants to define exposure-response relationships that might explain the trial results and improve future therapy. Rifampin 15 mg/kg increased plasma and cerebrospinal fluid (CSF) exposures compared with 10 mg/kg: day 14 exposure increased from 48.2 hour·mg/L (range 18.2-93.8) to 82.5 hour·mg/L (range 8.7-161.0) in plasma and from 3.5 hour·mg/L (range 1.2-9.6) to 6.0 hour·mg/L (range 0.7-15.1) in CSF. However, there was no relationship between rifampin exposure and survival. In contrast, we found that isoniazid exposure was associated with survival, with low exposure predictive of death, and was linked to a fast metabolizer phenotype. Higher doses of isoniazid should be investigated, especially in fast metabolizers.

Topics: Adult; Antitubercular Agents; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levofloxacin; Male; Rifampin; Treatment Outcome; Tuberculosis, Meningeal

Drug-resistant tuberculous meningitis (TBM) is difficult to diagnose and treat. Mortality is high and optimal treatment is unknown. We compared clinical outcomes of drug-resistant and -susceptible TBM treated with either standard or intensified antituberculosis treatment.. We analyzed the influence of Mycobacterium tuberculosis drug resistance on the outcomes of patients with TBM enrolled into a randomized controlled trial comparing a standard, 9-month antituberculosis regimen (containing rifampicin 10 mg/kg/day) with an intensified regimen with higher-dose rifampicin (15 mg/kg/day) and levofloxacin (20 mg/kg/day) for the first 8 weeks. The primary endpoint of the trial was 9-month survival. In this subgroup analysis, resistance categories were predefined as multidrug resistant (MDR), isoniazid resistant, rifampicin susceptible (INH-R), and susceptible to rifampicin and isoniazid (INH-S + RIF-S). Outcome by resistance categories and response to intensified treatment were compared and estimated by Cox regression.. Of 817 randomized patients, 322 had a known drug resistance profile. INH-R was found in 86 (26.7%) patients, MDR in 15 (4.7%) patients, rifampicin monoresistance in 1 patient (0.3%), and INH-S + RIF-S in 220 (68.3%) patients. Multivariable regression showed that MDR (hazard ratio [HR], 5.91 [95% confidence interval {CI}, 3.00-11.6]), P < .001), was an independent predictor of death. INH-R had a significant association with the combined outcome of new neurological events or death (HR, 1.58 [95% CI, 1.11-2.23]). Adjusted Cox regression, corrected for treatment adjustments, showed that intensified treatment was significantly associated with improved survival (HR, 0.34 [95% CI, .15-.76], P = .01) in INH-R TBM.. Early intensified treatment improved survival in patients with INH-R TBM. Targeted regimens for drug-resistant TBM should be further explored.. ISRCTN61649292.

Topics: Adult; Antitubercular Agents; Drug Resistance, Bacterial; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Rifampin; Treatment Outcome; Tuberculosis, Meningeal

Tuberculous meningitis is often lethal. Early antituberculosis treatment and adjunctive treatment with glucocorticoids improve survival, but nearly one third of patients with the condition still die. We hypothesized that intensified antituberculosis treatment would enhance the killing of intracerebral Mycobacterium tuberculosis organisms and decrease the rate of death among patients.. We performed a randomized, double-blind, placebo-controlled trial involving human immunodeficiency virus (HIV)-infected adults and HIV-uninfected adults with a clinical diagnosis of tuberculous meningitis who were admitted to one of two Vietnamese hospitals. We compared a standard, 9-month antituberculosis regimen (which included 10 mg of rifampin per kilogram of body weight per day) with an intensified regimen that included higher-dose rifampin (15 mg per kilogram per day) and levofloxacin (20 mg per kilogram per day) for the first 8 weeks of treatment. The primary outcome was death by 9 months after randomization.. A total of 817 patients (349 of whom were HIV-infected) were enrolled; 409 were randomly assigned to receive the standard regimen, and 408 were assigned to receive intensified treatment. During the 9 months of follow-up, 113 patients in the intensified-treatment group and 114 patients in the standard-treatment group died (hazard ratio, 0.94; 95% confidence interval, 0.73 to 1.22; P=0.66). There was no evidence of a significant differential effect of intensified treatment in the overall population or in any of the subgroups, with the possible exception of patients infected with isoniazid-resistant M. tuberculosis. There were also no significant differences in secondary outcomes between the treatment groups. The overall number of adverse events leading to treatment interruption did not differ significantly between the treatment groups (64 events in the standard-treatment group and 95 events in the intensified-treatment group, P=0.08).. Intensified antituberculosis treatment was not associated with a higher rate of survival among patients with tuberculous meningitis than standard treatment. (Funded by the Wellcome Trust and the Li Ka Shing Foundation; Current Controlled Trials number, ISRCTN61649292.).

Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Double-Blind Method; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; HIV Infections; Humans; Kaplan-Meier Estimate; Levofloxacin; Male; Middle Aged; Mycobacterium tuberculosis; Proportional Hazards Models; Rifampin; Tuberculosis, Meningeal

Levofloxacin is an effective bactericidal category III antitubercular drug. There is paucity of studies comparing the role of additional levofloxacin to standard antitubercular regimen in the patients with tuberculous meningitis (TBM).. To compare the safety and efficacy of adding levofloxacin to standard four drug ATT regimen (RHZE).. The patients with TBM diagnosed on the basis of clinical, cerebrospinal fluid (CSF) and MRI criteria were included. Children below 15 years, patients with pregnancy, seizures, liver failure, kidney failure and malignancy were excluded. The baseline clinical, CSF and MRI characteristics were noted and consciousness was evaluated by Glasgow Coma Scale (GCS). The patients were randomized to RHZE (rifampicin, isoniazid, pyrazinamide and ethambutol) and RHZEL (RHZE and levofloxacin) groups. Outcome was defined at 6 months. Primary outcome was death and secondary outcomes were disability as assess by Barthel Index score and adverse events.. Out of 110 TBM patients screened, 57 fulfilled the inclusion criteria. Their median age was 35 (15-75) years. 29 patients received RHZEL and 28 RHZE. The baseline clinical, biochemical and MRI characteristics were similar in the two groups. At 6 months, 11 (19.3%) patients died, 38 (66.7%) had good and 7 (12.3%) poor outcome. There was insignificant survival benefit in RHZEL group compared to RHZE (HR-2.61, 95% CI 0.73-9.36, P = 0.14), 25% patients died in RHZE where as 13.8% in RHZEL group. The disability was not significantly different between the two groups. The composite side effects were also similar between the two groups except for a higher frequency of seizure in RHZEL group (5 Vs 0) which resulted in withdrawal of levofloxacin.. There was insignificant survival benefit in RHZEL which was associated with high frequency of seizures.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Disability Evaluation; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Levofloxacin; Male; Middle Aged; Pilot Projects; Proportional Hazards Models; Pyrazinamide; Rifampin; Seizures; Time Factors; Treatment Outcome; Tuberculosis, Meningeal; Young Adult

High-dose intravenous (i.v.) rifampicin improved the outcome of tuberculous meningitis (TBM) in a previous study. Unfortunately, i.v. rifampicin is not available in many high-endemic settings. This study examined exposures to and safety of higher oral rifampicin doses compared with i.v. rifampicin. Thirty adult Indonesian TBM patients were randomised to rifampicin 750 mg (ca. 17 mg/kg) orally, 900 mg (ca. 20 mg/kg) orally or 600 mg (ca. 13 mg/kg, as used previously) i.v. over 1.5 h for 14 days, combined with other TB drugs. The pharmacokinetics of rifampicin was assessed in the critical phase of TBM treatment (≤3 days after treatment initiation) and at ≥9 days. In the first days of treatment, the geometric mean (range) plasma AUC0-24 values following rifampicin 750 mg orally, 900 mg orally and 600 mg i.v. were 131.4 (38.1-275.1), 164.8 (66.9-291.2) and 145.7 (77.7-430.2) mg⋅h/L, respectively; Cmax values were 14.3 (6.1-22.2), 16.2 (5.7-28.3) and 24.7 (13.9-37.8) mg/L. CSF concentrations correlated with plasma exposures. After ≥9 days, AUC0-24 values had decreased to 100.1, 101.2 and 94.9 mg⋅h/L. Transient grade 3 ALT increases (8/30 patients) and one grade 4 ALT increase occurred, not related to rifampicin exposure. Higher oral rifampicin doses resulted in approximately similar plasma AUC0-24 but lower plasma Cmax values compared with 600 mg i.v. over 1.5 h. Exposures to rifampicin varied substantially and decreased due to autoinduction. Liver function disturbances occurred in this severely ill population. Future studies should examine even higher rifampicin doses in TBM treatment.

Topics: Administration, Intravenous; Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Chemical and Drug Induced Liver Injury; Female; Humans; Indonesia; Male; Middle Aged; Plasma; Random Allocation; Rifampin; Time Factors; Tuberculosis, Meningeal; Young Adult

Recent data suggest that intensified antimicrobial treatment may improve the outcome of tuberculous meningitis (TBM). Considering that drug exposure is the intermediate link between dose and effect, we examined the concentration-response relationship for rifampicin and moxifloxacin in TBM patients. In an open-label, phase 2 clinical trial performed in Indonesia (ClinicalTrials.gov NCT01158755), 60 TBM patients were randomised to receive standard-dose (450mg oral) or high-dose rifampicin (600mg intravenous) plus either oral moxifloxacin (400mg or 800mg) or ethambutol (750mg). After 14 days, all patients continued with standard tuberculosis treatment. Pharmacokinetic sampling was performed once in every patient during the first three critical days. Differences in exposure between patients who died or survived were tested with independent samples t-tests. The relationship between drug exposure and mortality was examined using Cox regression. Compared with patients who died during the 2 weeks of intensified treatment, surviving patients had significantly higher rifampicin plasma AUC0-6h, plasma Cmax and CSF Chighest. Additionally, patients had a 32-43% lower relative likelihood of dying with an interquartile range increase in rifampicin exposure. Moxifloxacin exposure did not show a clear relationship with survival. From exposure-response curves, a rifampicin plasma AUC0-6h of ∼70mg·h/L (AUC0-24h of ∼116mgh/L) and a Cmax of ∼22mg/L were deduced as minimum target values for treatment. A strong concentration-effect relationship was found, with higher rifampicin exposure leading to better TBM survival. The current treatment dose of rifampicin is suboptimal; higher doses of rifampicin should be evaluated.

Topics: Adolescent; Adult; Antitubercular Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fluoroquinolones; Humans; Indonesia; Male; Middle Aged; Moxifloxacin; Plasma; Rifampin; Survival Analysis; Tuberculosis, Meningeal; Young Adult

We report the efficacy and safety of levofloxacin versus rifampicin in tuberculous meningitis (TBM).. In this open-label, randomized controlled trial from India, patients with TBM diagnosed on the basis of clinical, MRI and CSF findings were included. Patients with hepatic or renal dysfunction, organ transplantation, malignancy, pregnancy, lactation, allergy, seizure, age <15 years and antitubercular treatment ≥1 month were excluded. Sixty patients each were randomized to levofloxacin (10 mg/kg, maximum 500 mg) or rifampicin (10 mg/kg, maximum 450 mg). They also received isoniazid, pyrazinamide, ethambutol, prednisolone and aspirin. The primary outcome was death and secondary outcome measures were 6 month disability, repeat MRI changes and serious adverse events (SAEs).. The median age of the patients was 34.5 (16-75) years. The baseline clinical and MRI findings were similar between the two groups. At 6 months, 13 out of 60 (21.7%) patients in the levofloxacin arm and 23 out of 60 (38.3%) patients in the rifampicin arm had died (P = 0.07). On Cox regression analysis, survival in the levofloxacin group was significantly better than in the rifampicin group (hazard ratio 2.13, 95% CI 1.04-4.34, P = 0.04). The functional outcome (P = 0.47) was, however, not significantly different between the two groups. On intention-to-treat analysis, 10 out of 47 (21.3%) in the levofloxacin arm and 5 out of 37 (13.5%) in the rifampicin arm had poor recovery. Repeat MRI findings did not differ between the groups. Levofloxacin was discontinued more frequently than rifampicin due to SAEs (16 versus 4, P = 0.01).. Levofloxacin is superior to rifampicin in reducing 6 month death in TBM but not disability. Levofloxacin may be used in TBM especially in those patients with hepatotoxicity and without seizure.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Aspirin; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Levofloxacin; Male; Middle Aged; Prednisolone; Pyrazinamide; Radiography; Rifampin; Treatment Outcome; Tuberculosis, Meningeal; Young Adult

Intensified antibiotic treatment might improve the outcome of tuberculous meningitis. We assessed pharmacokinetics, safety, and survival benefit of several treatment regimens containing high-dose rifampicin and moxifloxacin in patients with tuberculous meningitis in a hospital setting.. In an open-label, phase 2 trial with a factorial design in one hospital in Indonesia, patients (aged >14 years) with tuberculous meningitis were randomly assigned to receive, according to a computer-generated schedule, first rifampicin standard dose (450 mg, about 10 mg/kg) orally or high dose (600 mg, about 13 mg/kg) intravenously, and second oral moxifloxacin 400 mg, moxifloxacin 800 mg, or ethambutol 750 mg once daily. All patients were given standard-dose isoniazid, pyrazinamide, and adjunctive corticosteroids. After 14 days of treatment all patients continued with standard treatment for tuberculosis. Endpoints included pharmacokinetic analyses of the blood and cerebrospinal fluid, adverse events attributable to tuberculosis treatment, and survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01158755.. 60 patients were randomly assigned to receive rifampicin standard dose (12 no moxifloxacin, ten moxifloxacin 400 mg, and nine moxifloxacin 800 mg) and high dose (ten no moxifloxacin, nine moxifloxacin 400 mg, and ten moxifloxacin 800 mg). A 33% higher dose of rifampicin, intravenously, led to a three times higher geometric mean area under the time-concentration curve up to 6 h after dose (AUC(0-6); 78·7 mg.h/L [95% CI 71·0-87·3] vs 26·0 mg.h/L [19·0-35·6]), maximum plasma concentrations (C(max); 22·1 mg/L [19·9-24·6] vs 6·3 mg/L [4·9-8·3]), and concentrations in cerebrospinal fluid (0·60 mg/L [0·46-0·78] vs 0·21 mg/L [0·16-0·27]). Doubling the dose of moxifloxacin resulted in a proportional increase in plasma AUC(0-6) (31·5 mg.h/L [24·1-41·1] vs 15·1 mg.h/L [12·8-17·7]), C(max) (7·4 mg/L [5·6-9·6] vs 3·9 mg/L [3·2-4·8]), and drug concentrations in the cerebrospinal fluid (2·43 mg/L [1·81-3·27] vs 1·52 mg/L [1·28-1·82]). Intensified treatment did not result in increased toxicity. 6 month mortality was substantially lower in patients given high-dose rifampicin intravenously (ten [35%] vs 20 [65%]), which could not be explained by HIV status or severity of disease at the time of presentation (adjusted HR 0·42; 95% CI 0·20-0·91; p=0·03).. These data suggest that treatment containing a higher dose of rifampicin and standard-dose or high-dose moxifloxacin during the first 2 weeks is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease.. Royal Dutch Academy of Arts and Sciences, Netherlands Foundation for Scientific Research, and Padjadjaran University, Bandung, Indonesia.

Topics: Adolescent; Adult; Anti-Infective Agents; Antibiotics, Antitubercular; Antitubercular Agents; Aza Compounds; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluoroquinolones; Follow-Up Studies; Humans; Indonesia; Male; Middle Aged; Moxifloxacin; Quinolines; Rifampin; Tuberculosis, Meningeal; Young Adult

HIV-associated tuberculous meningitis (TBM) has high mortality. Aside from the devastating impact of multidrug resistance (MDR) on survival, little is understood about the influence of other bacterial factors on outcome. This study examined the influence of Mycobacterium tuberculosis drug resistance, bacterial lineage, and host vaccination status on outcome in patients with HIV-associated TBM. Mycobacterium tuberculosis isolates from the cerebrospinal fluid of 186 patients enrolled in two studies of HIV-associated TBM in Ho Chi Minh City, Vietnam, were tested for resistance to first-line antituberculosis drugs. Lineage genotyping was available for 122 patients. The influence of antituberculosis drug resistance and M. tuberculosis lineage on 9-month mortality was analyzed using Kaplan-Meier survival analysis and Cox multiple regression models. Isoniazid (INH) resistance without rifampin resistance was associated with increased mortality (adjusted hazard ratio [HR], 1.78, 95% confidence interval [CI], 1.18 to 2.66; P = 0.005), and multidrug resistance was uniformly fatal (n = 8/8; adjusted HR, 5.21, 95% CI, 2.38 to 11.42; P < 0.0001). The hazard ratio for INH-resistant cases was greatest during the continuation phase of treatment (after 3 months; HR, 5.05 [95% CI, 2.23 to 11.44]; P = 0.0001). Among drug-susceptible cases, patients infected with the "modern" Beijing lineage strains had lower mortality than patients infected with the "ancient" Indo-Oceanic lineage (HR, 0.29 [95% CI, 0.14 to 0.61]; P = 0.001). Isoniazid resistance, multidrug resistance, and M. tuberculosis lineage are important determinants of mortality in patients with HIV-associated TBM. Interventions which target these factors may help reduce the unacceptably high mortality in patients with TBM.

Topics: Adult; Antitubercular Agents; Female; Genotype; HIV Infections; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Meningeal; Tuberculosis, Multidrug-Resistant; Young Adult

Tuberculous meningitis is the most severe form of tuberculosis. Mortality for untreated tuberculous meningitis is 100%. Despite the introduction of antibiotic treatment for tuberculosis the mortality rate for tuberculous meningitis remains high; approximately 25% for HIV-negative and 67% for HIV positive patients with most deaths occurring within one month of starting therapy. The high mortality rate in tuberculous meningitis reflects the severity of the condition but also the poor antibacterial activity of current treatment regimes and relatively poor penetration of these drugs into the central nervous system. Improving the antitubercular activity in the central nervous system of current therapy may help improve outcomes. Increasing the dose of rifampicin, a key drug with known poor cerebrospinal fluid penetration may lead to higher drug levels at the site of infection and may improve survival. Of the second generation fluoroquinolones, levofloxacin may have the optimal pharmacological features including cerebrospinal fluid penetration, with a ratio of Area Under the Curve (AUC) in cerebrospinal fluid to AUC in plasma of >75% and strong bactericidal activity against Mycobacterium tuberculosis. We propose a randomized controlled trial to assess the efficacy of an intensified anti-tubercular treatment regimen in tuberculous meningitis patients, comparing current standard tuberculous meningitis treatment regimens with standard treatment intensified with high-dose rifampicin and additional levofloxacin.. A randomized, double blind, placebo-controlled trial with two parallel arms, comparing standard Vietnamese national guideline treatment for tuberculous meningitis with standard treatment plus an increased dose of rifampicin (to 15 mg/kg/day total) and additional levofloxacin. The study will include 750 patients (375 per treatment group) including a minimum of 350 HIV-positive patients. The calculation assumes an overall mortality of 40% vs. 30% in the two arms, respectively (corresponding to a target hazard ratio of 0.7), a power of 80% and a two-sided significance level of 5%. Randomization ratio is 1:1. The primary endpoint is overall survival, i.e. time from randomization to death during a follow-up period of 9 months. Secondary endpoints are: neurological disability at 9 months, time to new neurological event or death, time to new or recurrent AIDS-defining illness or death (in HIV-positive patients only), severe adverse events, and rate of treatment interruption for adverse events.. Currently very few options are available for the treatment of TBM and the mortality rate remains unacceptably high with severe disabilities seen in many of the survivors. This trial is based on the hypothesis that current anti-mycobacterial treatment schedules for TBM are not potent enough and that outcomes will be improved by increasing the CSF penetrating power of this regimen by optimising dosage and using additional drugs with better CSF penetration.. International Standard Randomised Controlled Trial Number ISRCTN61649292.

Topics: Adult; Antitubercular Agents; Disability Evaluation; Double-Blind Method; Drug Therapy, Combination; HIV Infections; Humans; Levofloxacin; Neurologic Examination; Ofloxacin; Research Design; Rifampin; Sample Size; Time Factors; Treatment Outcome; Tuberculosis, Meningeal; Vietnam

In certain diseases clinical experts may judge that the intervention with the best prospects is the addition of two treatments to the standard of care. This can either be tested with a simple randomized trial of combination versus standard treatment or with a 2 x 2 factorial design.. We compared the two approaches using the design of a new trial in tuberculous meningitis as an example. In that trial the combination of 2 drugs added to standard treatment is assumed to reduce the hazard of death by 30% and the sample size of the combination trial to achieve 80% power is 750 patients. We calculated the power of corresponding factorial designs with one- to sixteen-fold the sample size of the combination trial depending on the contribution of each individual drug to the combination treatment effect and the strength of an interaction between the two.. In the absence of an interaction, an eight-fold increase in sample size for the factorial design as compared to the combination trial is required to get 80% power to jointly detect effects of both drugs if the contribution of the less potent treatment to the total effect is at least 35%. An eight-fold sample size increase also provides a power of 76% to detect a qualitative interaction at the one-sided 10% significance level if the individual effects of both drugs are equal. Factorial designs with a lower sample size have a high chance to be underpowered, to show significance of only one drug even if both are equally effective, and to miss important interactions.. Pragmatic combination trials of multiple interventions versus standard therapy are valuable in diseases with a limited patient pool if all interventions test the same treatment concept, it is considered likely that either both or none of the individual interventions are effective, and only moderate drug interactions are suspected. An adequately powered 2 x 2 factorial design to detect effects of individual drugs would require at least 8-fold the sample size of the combination trial.. Current Controlled Trials ISRCTN61649292.

Topics: Anti-Bacterial Agents; Antitubercular Agents; Data Interpretation, Statistical; Drug Synergism; Drug Therapy, Combination; Humans; Ofloxacin; Research Design; Rifampin; Sample Size; Tuberculosis, Meningeal

Tuberculous meningitis (TBM) is the most lethal form of tuberculosis, and new treatments that improve outcomes are required. We randomly assigned adults with TBM to treatment with standard antituberculosis treatment alone or in combination with ciprofloxacin (750 mg/12 h), levofloxacin (500 mg/12 h), or gatifloxacin (400 mg/24 h) for the first 60 days of therapy. Fluoroquinolone concentrations were measured with plasma and cerebrospinal fluid (CSF) specimens taken at predetermined, randomly assigned times throughout treatment. We aimed to describe the pharmacokinetics of each fluoroquinolone during TBM treatment and evaluate the relationship between drug exposure and clinical response over 270 days of therapy (Controlled Trials number ISRCTN07062956). Sixty-one patients with TBM were randomly assigned to treatment with no fluoroquinolone (n = 15), ciprofloxacin (n = 16), levofloxacin (n = 15), or gatifloxacin (n = 15). Cerebrospinal fluid penetration, measured by the ratio of the plasma area under the concentration-time curve from 0 to 24 h (AUC(0-24)) to the cerebrospinal fluid AUC(0-24), was greater for levofloxacin (median, 0.74; range, 0.58 to 1.03) than for gatifloxacin (median, 0.48; range, 0.47 to 0.50) or ciprofloxacin (median, 0.26; range, 0.11 to 0.77). Univariable and multivariable analyses of fluoroquinolone exposure against a range of different treatment responses revealed worse outcomes among patients with lower and higher plasma and CSF exposures than for patients with intermediate exposures (a U-shaped exposure-response). TBM patients most likely to benefit from fluoroquinolone therapy were identified, along with exposure-response relationships associated with improved outcomes. Fluoroquinolones add antituberculosis activity to the standard treatment regimen, but to improve outcomes of TBM, they must be started early, before the onset of coma.

Topics: Administration, Oral; Adolescent; Adult; Aged; Ciprofloxacin; Ethambutol; Female; Fluoroquinolones; Gatifloxacin; Humans; Injections, Intramuscular; Isoniazid; Levofloxacin; Male; Middle Aged; Multivariate Analysis; Ofloxacin; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Meningeal; Young Adult

Three recent studies found that corticosteroids improve clinical outcome and mortality in tuberculous meningitis (TBM), although the exact mechanism of action of the drug remains speculative. A number of reports on the effect of corticosteroids on cerebrospinal fluid (CSF) findings in TBM have been published, often with conflicting results regarding serial cell counts and protein levels. As part of a controlled, randomized trial on the effect of oral prednisone on outcome in childhood TBM at our institution, CSF was collected and analysed weekly during the 1st month of treatment. We found no significant difference in serial CSF cell counts between the steroid and non-steroid groups in the study. However, the steroid group had significantly lower CSF protein and globulin levels after the 1st month of treatment, and a more steady rise in CSF glucose levels than the non-steroid group. Knowledge of the different CSF responses during the course of anti-tuberculosis therapy is important in clinical decision-making.

Topics: Adenylate Kinase; Antitubercular Agents; Cerebrospinal Fluid Proteins; Child; Child, Preschool; Drug Interactions; Drug Therapy, Combination; Female; Globulins; Glucocorticoids; Glucose; Humans; Infant; Lactic Acid; Lymphocyte Count; Male; Neutrophils; Prednisone; Rifampin; Statistics, Nonparametric; Tuberculosis, Meningeal

Chemotherapy studies were undertaken in 180 patients with tuberculous meningitis. They were treated for 12 months with 1 of 3 regimens: the first consisted of streptomycin, isoniazid and rifampicin daily for the first 2 months, followed by ethambutol plus isoniazid for 10 months; in the second, pyrazinamide was added for the first 2 months, and in the third, rifampicin was reduced to twice weekly in the first 2 months. Steroids were prescribed for all the patients in the initial weeks of treatment. Approximately 50% of the patients were aged less than 3 years. On admission, 13% of the patients were classified as stage I, 77% as stage II and 9% as stage III. Cerebrospinal fluid (CSF) culture results were available for all the 180 patients and M. tuberculosis was isolated in 59 (33%). CSF smear results for acid fast bacilli were available only for the 103 patients admitted to the second and the third studies, and of these in 60 (58%) the CSF was positive either by smear or culture. The response to therapy was similar in the 3 studies. Despite administration of rifampicin for 2 months, the mortality was high. In all, 27% of the patients died of tuberculous meningitis, 39% had neurological sequelae and 34% recovered completely. There was a strong association between the stage on admission and the mortality rate, the deaths being highest in stage III. In the first study, when isoniazid was prescribed daily in a dosage of 20 mg/kg, 39% of the patients developed jaundice; however, when the dosage was reduced to 12 mg/kg, the incidence fell to 16%. In the third study, where rifampicin was administered twice a week, the incidence of jaundice was much lower (5%).

Topics: Antitubercular Agents; Child; Child, Preschool; Drug Therapy, Combination; Ethambutol; Female; Humans; India; Infant; Isoniazid; Male; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Meningeal

Seventy-one patients diagnosed to have tuberculous meningitis were treated with isoniazid, streptomycin plus either rifampicin (36 patients or ethambutol (35 patients). Results of therapy were identical in both treatment-groups (approximately 50 per cent mortality). Rifampicin appears to be as effective as ethambutol in the treatment of this infection.

Topics: Adolescent; Adult; Child; Child, Preschool; Drug Therapy, Combination; Ethambutol; Female; Humans; Infant; Male; Middle Aged; Rifampin; Tuberculosis, Meningeal

Eighty tuberculous meningitis patients who were seen in the neurological clinics in Surabaya between the January 1971 and January 1975 were asked to cooperate in a double blind clinical trial. One group was given isoniazid, streptomycin and p-aminosalicylic acid, the other group was given isioniazid, rifampicin, ethambutol and a protease. The outcome after the treatment with isoniazid, rifampicin and ethambutol was significantly better than that with isoniazed, streptomycin and p-aminosalicylic acid. The clinical and laboratory symptoms and signs are reviewed in detail.

Topics: Adolescent; Adult; Aged; Aminosalicylic Acid; Child; Child, Preschool; Drug Therapy, Combination; Ethambutol; Female; Humans; Indonesia; Infant; Isoniazid; Male; Middle Aged; Rifampin; Streptomycin; Tuberculosis, Meningeal

Hematogenous disseminated tuberculosis predisposes to concurrent tuberculous meningitis (TBM), the most devastating and disabling form of tuberculosis. However, children often have atypical clinical symptoms, difficulty in specimen collection, low specimen content, and an increasing incidence of drug-resistant tuberculosis. Thus, the accurate diagnosis and timely treatment of childhood tuberculosis face monumental challenges.. The 14-year-old female presented to the hospital with intermittent fever, headache, and blurred vision. Her cerebrospinal fluid (CSF) showed a lymphocytic pleocytosis, an elevated protein level, and a decreased chloride level. And her CSF tested positive for TB-RNA. Xpert MTB/RIF detected Mycobacterium tuberculosis in her CSF, but the rifampin resistance test was unknown. Subsequently, her CSF culture was positive for Mycobacterium tuberculosis. The drug sensitivity test (DST) revealed resistance to isoniazid, rifampin, and fluoroquinolones. A computed tomography (CT) of the chest showed diffuse miliary nodules in both lungs. Intracranial enhanced magnetic resonance imaging (MRI) showed "multiple intensified images of the brain parenchyma, cisterns, and part of the meninges." The final diagnosis is miliary pulmonary tuberculosis and pre-extensive drug-resistant TBM. After 19 months of an oral, individualized antituberculosis treatment, she recovered with no significant neurological sequelae.. For patients with miliary pulmonary tuberculosis, especially children, even if there are no typical clinical symptoms, it is necessary to know whether there is TBM and other conditions. Always look for the relevant aetiological basis to clarify whether it is drug-resistant tuberculosis. Only a rapid and accurate diagnosis and timely and effective treatment can improve the prognosis and reduce mortality and disability rates.

Topics: Adolescent; Child; Female; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis, Meningeal; Tuberculosis, Miliary; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Limited knowledge is available on the pharmacokinetics of rifampicin in children with tuberculous meningitis (TBM) and its penetration into brain tissue, which is the site of infection. In this analysis, we characterize the distribution of rifampicin in cerebrospinal fluid (CSF), lumbar (LCSF) and ventricular (VCSF), and brain extracellular fluid (ECF). Children with TBM were included in this pharmacokinetic analysis. Sparse plasma, LCSF, and VCSF samples were collected opportunistically, as clinically indicated. Brain ECF was sampled using microdialysis (MD). Rifampicin was quantified with liquid chromatography with tandem mass spectrometry in all samples, and 25-desacetyl rifampicin in the plasma samples. The data were interpreted with nonlinear mixed-effects modeling, with the CSF and brain ECF modeled as "effect compartments." Data were available from 61 children, with median (min-max) age of 2 (0.3 to 10) years and weight of 11.0 (4.8 to 49.0) kg. A one-compartment model for parent and metabolite with first-order absorption and elimination via saturable hepatic clearance described the data well. Allometric scaling, maturation, and auto-induction of clearance were included. The pseudopartition coefficient between plasma and LCSF/VCSF was ~5%, while the value for ECF was only ~0.5%, possibly reflecting low recovery of rifampicin using MD. The equilibration half-life between plasma and LCSF/VCSF was ~4 h and between plasma and ECF ~2 h. Our study confirms previous reports showing that rifampicin concentrations in the LCSF are lower than in plasma and provides novel knowledge about rifampicin in the VCSF and the brain tissue. Despite MD being semiquantitative because the relative recovery cannot be quantified, our study presents a proof-of-concept that rifampicin reaches the brain tissue and that MD is an attractive technique to study site-of-disease pharmacokinetics in TBM.

Topics: Brain; Child; Child, Preschool; Extracellular Fluid; Humans; Rifampin; South Africa; Tuberculosis, Meningeal

Nucleic acid amplification techniques like GeneXpert and GeneXpert Ultra (Xpert Ultra), the first-line tests for diagnosing Tuberculous meningitis (TBM), are expensive and depend on sophisticated equipment.. The diagnostic potential of multitargeted loop-mediated isothermal assay (MLAMP), a low-cost simple test using novel gene combination, was evaluated for TBM.. 300 CSF specimen (200 TBM patients, 100 controls) processed between January 2017 and December 2021 were subjected to MLAMP (using sdaA, IS1081 and IS6110 gene targets), sdaA PCR and Xpert Ultra. The performance was evaluated against uniform case definition as per Marais criteria, and against culture.. Uniform case definition classified 50 as definite TBM and 150 as probable or definite TBM. Against this uniform case definition, the sensitivity and specificity of MLAMP was 88% and 100%, respectively. The sensitivity was 96% against culture-positive cases and 85.3% against culture-negative cases. The sensitivity of sdaA-LAMP, IS1081-LAMP, IS6110-LAMP, Xpert Ultra and sdaA-PCR was 82.5%, 80.5%, 85.3%, 67% and 71%, respectively against uniform case definition. sdaA-LAMP detected additional two cases and IS1081-LAMP detected nine. 11 of 134 (8.2%) cases were reported rifampicin resistant by Xpert Ultra.. MLAMP, incorporating sdaA and IS1081, is a cheap, easy and accurate first-line diagnostic test for TBM.

Topics: Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Tuberculosis, Meningeal

Tuberculous meningitis (TB meningitis) is the most severe form of tuberculosis (TB), requiring 12 months of multidrug treatment for cure, and is associated with high morbidity and mortality. High-dose rifampin (35 mg/kg/d) is safe and improves the bactericidal activity of the standard-dose (10 mg/kg/d) rifampin-containing TB regimen in pulmonary TB. However, there are conflicting clinical data regarding its benefit for TB meningitis, where outcomes may also be associated with intracerebral inflammation. We conducted cross-species studies in mice and rabbits, demonstrating that an intensified high-dose rifampin-containing regimen has significantly improved bactericidal activity for TB meningitis over the first-line, standard-dose rifampin regimen, without an increase in intracerebral inflammation. Positron emission tomography in live animals demonstrated spatially compartmentalized, lesion-specific pathology, with postmortem analyses showing discordant brain tissue and cerebrospinal fluid rifampin levels and inflammatory markers. Longitudinal multimodal imaging in the same cohort of animals during TB treatment as well as imaging studies in two cohorts of TB patients demonstrated that spatiotemporal changes in localized blood-brain barrier disruption in TB meningitis are an important driver of rifampin brain exposure. These data provide unique insights into the mechanisms underlying high-dose rifampin in TB meningitis with important implications for developing new antibiotic treatments for infections.

Topics: Animals; Antitubercular Agents; Humans; Inflammation; Mice; Models, Animal; Rabbits; Rifampin; Tuberculosis, Meningeal

Our 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.. The 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.. In 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.

Topics: Antitubercular Agents; Arylamine N-Acetyltransferase; Humans; Isoniazid; Liver-Specific Organic Anion Transporter 1; Mycobacterium tuberculosis; Pharmacogenetics; Probability; Prospective Studies; Rifampin; Tuberculosis, Meningeal

The morbidity of rifampicin/multidrug-resistant tuberculous meningitis (RR/MDR-TBM) has shown an increasing trend globally. Its mortality rate is significantly higher than that of non-rifampicin/multidrug-resistant tuberculous meningitis (NRR/MDR-TBM). This article aimed to explore risk factors related to RR/MDR-TBM, and compare therapeutic effects of linezolid (LZD)- and non-linezolid-containing regimen for RR/MDR-TB patients in Shenzhen city. Furthermore, we aimed to find a better therapy for pathogen-negative TBM with RR/MDR-TBM related risk factors.. We conducted a retrospective study enrolling 137 hospitalized cases with confirmed TBM from June 2014 to March 2020. All patients were divided into RR/MDR-TBM group (12 cases) and NRR/MDR-TBM group (125 cases) based on GeneXpert MTB/RIF and (or) phenotypic drug susceptibility test results using cerebral spinal fluid (CSF). The risk factors related to RR/MDR-TBM were investigated through comparing clinical and examination features between the two groups. The mortality rate of RR/MDR-TBM patients treated with different regimens was analyzed to compare their respective therapeutic effects. A difference of P < 0.05 was considered statistically significant.. Most patients (111/137, 81%) were from southern or southwestern China, and a large proportion (72/137, 52.55%) belonged to migrant workers. 12 cases were RR/MDR-TBM (12/137, 8.8%) while 125 cases were NRR/MDR-TBM (125/137, 91.2%). The proportion of patients having prior TB treatment history in the RR/MDR-TBM group was significantly higher than that of the NRR/MDR-TBM group (6/12 vs. 12/125, 50% vs. 10.5%, P < 0.01). No significant difference was observed on other clinical and examination features between the two groups. Mortality was significantly lower in RR/MDR-TBM patients on linezolid-containing treatment regimen than those who were not (0/7 versus 3/5, 0% versus 60%, P = 0.045).. The main related risk factor of RR/MDR-TBM is the history of anti-tuberculosis treatment. Linezolid-containing regimen appears to lower mortality rate of RR/MDR-TBM significantly in our study. We think Linezolid should be evaluated prospectively in the treatment of RR/MDR-TBM.

Topics: Antitubercular Agents; China; Humans; Linezolid; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Tuberculosis, Meningeal; Tuberculosis, Multidrug-Resistant

Tuberculous meningitis (TBM) is an incurable disease with high mortality. It is an extrapulmonary tuberculosis caused by mycobacterium tuberculosis which penetrated the blood-brain barrier and infected the meninges. Mycobacterium tuberculosis lurking in the body mainly reside in macrophages. Anti-tuberculous drugs usually can not target the blood-brain barrier and macrophages, the drug concentration in the lesion is low, which cannot effectively kill mycobacterium tuberculosis, making TBM difficult to treat. Targeted drug delivery systems can target drugs to specific nidus. In the study, we constructed a drug delivery system, which was a cell penetrate peptide B6 and phosphatidylserine (PS) modified polyethylene glycol (PEG) nanomaterial to target the blood-brain barrier and to target macrophages. This nanomaterial was a combined anti-tuberculosis drug delivery system encapsulating antituberculosis drugs rifampicin and pyrazinamide, designed to target macrophages in the brain and kill mycobacterium tuberculosis lurking in the macrophages. We have physically characterized the drug delivery system, and verified the bactericidal ability at cellular and animal level. Results have shown that the targeted drug delivery system had a remarkable efficacy to treat TBM in mice.

Topics: Animals; Antitubercular Agents; Blood-Brain Barrier; Mice; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Meningeal

A comparative performance evaluation of the novel Xpert MTB/RIF Ultra (Xpert Ultra) and MTB/RIF Xpert (Xpert) for tuberculous meningitis (TBM) diagnosis was performed. The cerebrospinal fluids of suspected TBM patients were collected consecutively and subjected to smear microscopy, culture, Xpert, and Xpert Ultra. In total, 160 patients were recruited. Xpert Ultra produced a higher sensitivity (45%, 34 of 76) than Xpert (28%, 21 of 76; P = 0.001) and culture (18%, 14 of 76; P < 0.001), respectively. Inclusion of Xpert Ultra outcomes increased the percentage of definite TBM case from 36% (27 of 76) to 51% (39 of 76). Both Xpert Ultra and Xpert accurately identified the one rifampicin (RIF)-resistant and the 5 RIF-sensitive cases defined by phenotypic drug sensitivity test. The specificities of all of the culture, Xpert and Xpert Ultra were 100% (45 of 45). Xpert Ultra outperformed both Xpert and culture for TBM diagnosis, which may speed up the appropriate treatment of patients in clinical practice.

Topics: Adult; Antibiotics, Antitubercular; China; DNA, Bacterial; Drug Resistance, Bacterial; Female; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Rifampin; Sensitivity and Specificity; Tuberculosis, Meningeal; Young Adult

Tuberculous meningitis (TBM) is now uncommon in high-income countries. It is the most severe form of extrapulmonary tuberculosis with high rates of mortality and morbidity if diagnosis and treatment are delayed. An 8-month-old girl with TBM who was treated with high-dose intravenous anti-tuberculous drugs (ATD) is reported. Therapeutic drug monitoring (TDM) of isoniazid and rifampicin was undertaken by measuring serial drug concentrations in serum and cerebrospinal fluid (CSF). There was rapid eradication of

Topics: Antitubercular Agents; Drug Monitoring; Female; Humans; Infant; Isoniazid; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Meningeal

On analyzing the drug susceptibility profile of 151 clinical isolates collected from patients of tuberculous meningitis (TBM) over 10 years, we reflect on few lessons learnt from the trend of susceptibility profile - drug resistance was not uncommon, fluoroquinolone resistance was observed even among otherwise susceptible isolates and hetero-resistance was observed against rifampicin, isoniazid and also fluoroquinolones. In the midst of widening gap between incidence of drug resistant TBM and availability of effective drugs, our data suggests that universal testing for drug resistance, careful choice of drugs having optimal penetration and individualized therapy should form important pillars of TBM management.

Topics: Antitubercular Agents; Fluoroquinolones; Humans; Isoniazid; Mycobacterium tuberculosis; Patient-Centered Care; Rifampin; Tuberculosis, Meningeal; Tuberculosis, Multidrug-Resistant

Topics: Antibiotics, Antitubercular; Delayed Diagnosis; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis, Meningeal

Tuberculosis (TB) is a disease of diverse manifestations. In children, neurotuberculosis is the severest form, which when left untreated can have deleterious consequences. There has been reports on pediatric TB meningitis manifesting with fever and seizures, altered sensorium or focal deficits. There are reports on TB meningitis presenting with cognitive decline in adults. We are reporting a eleven month old girl child who presented with acute regression of attained developmental milestones of one month duration as the only presenting complaint and MRI brain revealed basal exudates with hydrocephalus which nailed the diagnosis of tuberculous meningitis. CSF (Cerebro Spinal Fluid) tested by CBNAAT (Cartridge Based Nucleic Acid Amplification Testing) for TB was negative, but gastric aspirate tested for the same, came positive. Tuberculin skin testing was also positive. Chest X-ray was normal. The child had not received BCG (Bacillus Calmette Guerin)vaccine, thereby increasing her risk of complicated TB. The contact couldn't be traced. The child was started on ATT (Anti Tubercular Treatment) as soon as the diagnosis was made and she improved, thus signifying the better outcome with early initiation of ATT. This case reporting is intended to highlight the unusual presentation of TB meningitis in children, which when clinicians are aware of will lead to early treatment and better prognosis.

Topics: Acetazolamide; Antitubercular Agents; Carbonic Anhydrase Inhibitors; Cerebrospinal Fluid; Early Medical Intervention; Ethambutol; Female; Glucocorticoids; Humans; Hydrocephalus; Infant; Isoniazid; Magnetic Resonance Imaging; Neurodevelopmental Disorders; Nucleic Acid Amplification Techniques; Prednisolone; Pyrazinamide; Rifampin; Stomach; Treatment Outcome; Tuberculosis, Meningeal

Topics: Antitubercular Agents; Brain; Ethambutol; Horner Syndrome; Humans; Immunocompetence; Isoniazid; Male; Nucleic Acid Amplification Techniques; Pyrazinamide; Pyridoxine; Rifampin; Tomography, X-Ray Computed; Tuberculosis, Meningeal; Uganda; Young Adult

Patients with tuberculous meningitis (TBM) in any stage of the British Medical Research Council (BMRC) scale, if requiring mechanical ventilation (MV), are likely to have a poor outcome. We report the usefulness of BMRC, BMRC-MV, and BMRC-hydrocephalus (BMRC-HC) staging, and Haydarpasa Meningitis Severity Index (HAMSI) scoring in predicting the outcome of TBM. One hundred ninety-seven TBM patients were analyzed from a prospectively maintained TBM registry. The severity of meningitis was categorized using BMRC (stages I-III), BMRC-MV (I-IV [MV patients were grouped as stage IV]), and BMRC-HC (I-IV [BMRC stage III patients with hydrocephalus were grouped as stage IV]). Haydarpasa Meningitis Severity Index scoring was categorized as < 6 and ≥ 6. The outcome was defined at 6 months using the modified Rankin Scale (mRS) as death, poor (mRS score > 2), or good (mRS score ≤ 2). Forty-nine (25%) patients died. BMRC-mechanical ventilation stage IV had the highest predictive value for defining death, with a sensitivity of 88% and a specificity of 86%. About 81.7% of surviving patients had a good outcome at 6 months. BMRC-mechanical ventilation stages I-III had the highest predictive value for defining good outcome, with a sensitivity of 93% and a specificity of 61%. In TBM, BMRC-MV staging has the best predictive value for defining death and disability.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Antitubercular Agents; Child; Child, Preschool; Consciousness Disorders; Ethambutol; Female; Humans; Hydrocephalus; India; Isoniazid; Magnetic Resonance Imaging; Male; Middle Aged; Prognosis; Pyrazinamide; Registries; Respiration, Artificial; Rifampin; Seizures; Severity of Illness Index; Tomography, X-Ray Computed; Tuberculosis, Meningeal; Ventriculoperitoneal Shunt; Young Adult

BACKGROUND Rifampicin-induced pneumonitis is an infrequent occurrence, with only a few cases reported in the literature. Furthermore, this condition constitutes a diagnostic challenge, particularly in the era of COVID-19 infection. Here, we report a case of rifampicin-induced pneumonitis with clinical, imaging, and histological features of acute respiratory distress syndrome (ARDS), which required severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing to exclude a diagnosis of coronavirus disease 2019 (COVID-19) pneumonia. CASE REPORT A 43-year-old man on anti-TB treatment for TB meningitis developed new-onset fever, fatigue, hypoxemic respiratory failure, and bilateral pulmonary opacities. His clinical, chest X-ray, and CT thorax findings of ARDS were similar to both rifampicin-induced pneumonitis and severe COVID-19 pneumonia. However, reverse transcription polymerase chain reaction (RT-PCR) testing from a nasopharyngeal swab and bronchoalveolar lavage (BAL) via the GeneXpert system was negative for SARS-CoV-2. A detailed workup, including lung biopsy, revealed drug-induced pneumonitis as the cause of his presentation. His pneumonitis improved after discontinuation of rifampicin and recurred following the rifampicin challenge. CONCLUSIONS This case highlights the importance of early, rapid, and accurate testing for SARS-CoV-2 during the COVID-19 pandemic for patients presenting with acute respiratory symptoms, so that accurate diagnosis and early patient management are not delayed for patients with treatable causes of acute and severe lung diseases. Timely identification of rifampicin-induced pneumonitis via a high clinical suspicion, detailed workup, and histopathological analysis is required to avoid permanent damage to the lungs.

Topics: Adult; Antibiotics, Antitubercular; Betacoronavirus; Coronavirus Infections; COVID-19; Humans; Male; Pandemics; Pneumonia; Pneumonia, Viral; Rifampin; SARS-CoV-2; Tomography, X-Ray Computed; Tuberculosis, Meningeal

Tuberculous meningitis (TBM) is the most severe form of Mycobacterium tuberculosis (Mtb) infection in humans and is a public health concern worldwide. We evaluated the performance of GeneXpert MTB/RIF (GeneXpert) for the diagnosis of TBM. In addition, genetic diversity and drug susceptibility profiling of Mtb strains isolated from TBM patients were also investigated. A total of 293 TBM suspected cerebrospinal fluid (CSF) samples were collected and subjected to GeneXpert and Mycobacterial Growth Indicator Tube (MGIT 960) culture, respectively. Sensitivity and specificity of GeneXpert was 72.7% and 98.5%, respectively by using MGIT 960 as a gold standard (GeneXpert (n = 20, 6.8%) vs MGIT 960 (n = 22, 7.5%)). All Mtb positive cultures were subjected to 24-locus Mycobacterial Interspersed Repetitive Unit Variable Number Tandem Repeat (MIRU-VNTR) typing, Line probe assay (LPA) and MGIT 960- Drug Susceptibility Testing (DST). The rpoB gene was amplified and sequenced for selected isolates. Among our TBM patients, East African Indian (EAI) lineage (n = 16, 72.7%) was most predominant followed by Beijing (n = 3, 13.6%), S-family (n = 2, 9.1%) and Delhi/CAS (n = 1, 4.5%). Three Mtb strains were found to be Isoniazid (INH) resistant by MGIT 960; however LPA revealed that two strains were INH resistant and one strain was multi drug resistant (MDR) (Resistant to Isoniazid and Rifampicin (RIF)). We identified rifampicin resistant isolate with the mutation D516F in rifampicin resistance-determining region (RRDR) and observed discordant results between LPA, GeneXpert and MGIT 960. In addition, GeneXpert showing false RIF resistance was identified (no mutation in RRDR). We conclude that GeneXpert is useful for the diagnostic confirmation of TBM; however a GeneXpert negative sample should be subjected to MGIT 960 culture or LPA to rule out TBM. EAI lineage was the most predominant among TBM patients in South India and associated with drug resistance. The discordance between GeneXpert, MGIT 960 and LPA with respect to rifampicin resistance has to be ruled out to avoid TB treatment failure or relapse.

Topics: Antitubercular Agents; Bacterial Proteins; DNA-Directed RNA Polymerases; Genetic Variation; Humans; India; Isoniazid; Microbial Sensitivity Tests; Multiplex Polymerase Chain Reaction; Pathology, Molecular; Rifampin; Tertiary Care Centers; Tuberculosis, Meningeal

The timely diagnosis of tuberculous meningitis (TBM) is challenging. Molecular diagnostic tools are necessary for TBM, particularly in low- and middle-income countries.. We aimed to calculate the diagnostics characteristics of Xpert MTB/RIF for the detection of Mycobacterium tuberculosis in the cerebrospinal fluid (CSF) and the frequency of rifampicin (RIF)-resistance in the CSF samples.. A total of 313 consecutive CSF samples were studied and categorized into TBM definite, probable, possible, or not TBM cases based on the clinical, laboratory, and imaging data.. For the definite TBM cases (n=7), the sensitivity, specificity, efficiency, and positive likelihood ratio were 100, 97, 97, and 38%, respectively. However, for the TBM definite associated with the probable cases (n=24), the sensitivity decreased to 46%. All CSF samples that were Xpert MTB/RIF-positive were RIF susceptible.. Xpert MTB/RIF showed high discriminating value among the microbiology-proven TBM cases, although the values for the probable and possible TBM cases were reduced. Xpert MTB/RIF contributes significantly to the diagnosis of TBM, mainly when coupled with the conventional microbiological tests and clinical algorithms.

Topics: Brazil; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis, Meningeal

Topics: Anticonvulsants; Antitubercular Agents; Cross-Sectional Studies; Disease Management; Drug Therapy, Combination; Duration of Therapy; Ethambutol; Humans; India; Isoniazid; Levetiracetam; Neurologists; Practice Patterns, Physicians'; Pyrazinamide; Rifampin; Streptomycin; Surveys and Questionnaires; Tuberculosis, Meningeal

Topics: Anti-Bacterial Agents; Antitubercular Agents; Brain; Diagnosis, Differential; Electroencephalography; Emigrants and Immigrants; Ethambutol; Female; Glucocorticoids; Humans; Infant; Isoniazid; Magnetic Resonance Imaging; Prednisone; Pyrazinamide; Rifampin; Romania; Texas; Tuberculosis, Meningeal

Topics: Adult; HIV; Humans; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Tuberculosis, Meningeal

Central nervous system tuberculosis (CNS-TB) is a devastating manifestation of TB. The most common form of CNS-TB is tuberculous meningitis. Drug-resistant TB poses a major threat to the control of TB worldwide. Timely treatment dramatically improves the outcome. Colorimetric techniques for drug susceptibility testing based on the oxidation-reduction principle give results quick and are less expensive. The objectives of this study were to compare the susceptibility of Mycobacterium tuberculosis isolated from cerebrospinal fluid to four first-line drugs using the MGIT automated mycobacterial detection system and the resazurin assay (RA) as well as to estimate the minimum inhibitory concentrations (MICs) by RA.. A total of 42 M. tuberculosis isolates were analysed for their susceptibilities by MGIT and RA.. Of the 42 isolates, 35 gave concordant results with both methods. Agreement between the two tests for streptomycin and rifampicin was 100% with a Fleiss' kappa (κ) value of 1, whereas for isoniazid and ethambutol agreement was 92.86% and 90.48%, respectively, with κ values of 0.853 and 0.738.. The RA appears to be a good alternative to the automated MGIT technique in resource-limited settings.

Topics: Antitubercular Agents; Cerebrospinal Fluid; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxazines; Rifampin; Streptomycin; Tuberculosis, Meningeal; Xanthenes

Heteroresistant Mycobacterium tuberculosis (mixture of susceptible and resistant subpopulations) is thought to be a preliminary stage to full resistance and timely detection, initiation of correct treatment is vital for successful anti tubercular therapy. The aim of this study was to detect multi drug resistant (MDR) and heteroresistant M. tuberculosis with the associated gene mutations from patients of tuberculous meningitis.. A total of 197 M. tuberculosis isolates from 478 patients of TBM were isolated from July 2012 to July 2015 and subjected to drug susceptibility testing (DST) by BACTEC MGIT and Genotype MTBDR line probe assay (LPA). Heteroresistance was defined as presence of both WT and mutant genes in LPA.. Of 197 M. tuberculosis isolates, 11 (5.6%) were MDR, 23 (11.6%), 1 (0.5%) were mono resistant to isoniazid (INH) and rifampicin (RMP) respectively. Heteroresistance was detected in 8 (4%), 2 (1%) isolates to INH and RMP respectively. INH heteroresistant strains had WT bands with mutation band S315T1 whereas RMP heteroresistant strains had WT bands with mutation band S531L.. The prevalence of MDR M. tuberculosis was 5.6% in TBM patients with the most common mutation being ΔWT band with S315T1 for INH and ΔWT band with S531T for RMP. MGIT DST was found to be more sensitive for detecting overall resistance in M. tuberculosis but inclusion of LPA not only reduced time for early initiation of appropriate treatment but also enabled detection of heteroresistance in 8 (4%), 2 (1%) isolates for INH and RMP respectively.

Topics: Antitubercular Agents; Female; Humans; Incidence; India; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Tuberculosis, Meningeal; Tuberculosis, Multidrug-Resistant

Tuberculomas optoquiasmaticos como reaccion paradojica al tratamiento de tuberculosis meningea.

Topics: Adult; Antitubercular Agents; Brain Infarction; Diagnostic Errors; Disease Progression; Drug Resistance, Microbial; Drug Substitution; Ethambutol; Female; Host-Pathogen Interactions; Humans; Isoniazid; Magnetic Resonance Imaging; Meningitis, Viral; Moxifloxacin; Mycobacterium tuberculosis; Neuroimaging; Optic Chiasm; Paresis; Prednisone; Pyrazinamide; Rifampin; Thalamus; Tuberculoma; Tuberculosis, Meningeal; Vision Disorders

Meningitis caused by Mycobacterium tuberculosis is a major cause of morbidity and mortality worldwide. We evaluated the performance of cerebrospinal fluid (CSF) testing with the GeneXpert MTB/RIF assay versus traditional approaches for diagnosing tuberculosis meningitis (TBM).. Patients were adults (n = 37) presenting with suspected TBM to the Hospital Nacional Dos de Mayo, Lima, Peru, during 12 months until 1st January 2015. Each participant had a single CSF specimen that was divided into aliquots that were concurrently tested for M. tuberculosis using GeneXpert, Ziehl-Neelsen smear and culture on solid and liquid media. Drug susceptibility testing used Mycobacteria Growth Indicator Tube (MGIT 960) and the proportions method.. 81% (30/37) of patients received a final clinical diagnosis of TBM, of whom 63% (19/30, 95% confidence intervals, CI: 44-80%) were HIV-positive. 22% (8/37, 95%CI: 9.8-38%), of patients had definite TBM. Because definite TBM was defined by positivity in any laboratory test, all laboratory tests had 100% specificity. Considering the 30 patients who had a clinical diagnosis of TBM: diagnostic sensitivity was 23% (7/30, 95%CI: 9.9-42%) for GeneXpert and was the same for all culture results combined; considerably greater than 7% (2/30, 95%CI: 0.82-22%) for microscopy; whereas all laboratory tests had poor negative predictive values (20-23%). Considering only the 8 patients with definite TBM: diagnostic sensitivity was 88% (7/8, 95%CI: 47-100%) for GeneXpert; 75% (6/8, 95%CI: 35-97%) for MGIT culture or LJ culture; 50% (4/8, 95%CI 16-84) for Ogawa culture and 25% (2/8, 95%CI: 3.2-65%) for microscopy. GeneXpert and microscopy provided same-day results, whereas culture took 20-56 days. GeneXpert provided same-day rifampicin-susceptibility results, whereas culture-based testing took 32-71 days. 38% (3/8, 95%CI: 8.5-76%) of patients with definite TBM with data had evidence of drug-resistant TB, but 73% (22/30) of all clinically diagnosed TBM (definite, probable, and possible TBM) had no drug-susceptibility results available.. Compared with traditional culture-based methods of CSF testing, GeneXpert had similar yield and faster results for both the detection of M. tuberculosis and drug-susceptibility testing. Including use of the GeneXpert has the capacity to improve the diagnosis of TBM cases.

Topics: Adolescent; Adult; Antitubercular Agents; Autoanalysis; Cerebrospinal Fluid; Clinical Laboratory Techniques; Drug Resistance, Bacterial; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Reproducibility of Results; Rifampin; Sensitivity and Specificity; Tuberculosis, Meningeal; Tuberculosis, Multidrug-Resistant; Young Adult

Rapid and specific diagnosis of tuberculous meningitis (TBM) is of paramount importance to decrease morbidity and mortality. Therefore, the present study was undertaken to compare the efficacy of Xpert MTB/RIF assay (GXpert) and multiplex PCR (MPCR) using three targets (IS6110, MPB64 and protein B) for diagnosing tuberculous meningitis.. GXpert and MPCR were performed on cerebrospinal fluid samples of 225 patients out of which 80 were culture-positive confirmed cases of TBM, 100 were 'suspected' cases of TBM and 45 were non-TBM controls. rpoB gene sequencing was done for diagnosing rifampicin (Rif) resistance in all positive cases.. GXpert and MPCR were positive in 91/180 (50.5%) and 157/180 (87.2%) confirmed or suspected TBM patients respectively. Both the tests were negative in all 45 controls. Rif resistance was detected in 14 cases by GXpert and in 13 cases by MPCR. Rif resistance was confirmed in 13 cases with rpoB gene sequencing. There was one case of false Rif resistance detected by GXpert which was Rif susceptible on rpoB gene sequencing. Cost of doing MPCR was less than USD1 whereas GXpert required USD10 per isolate.. MPCR has a higher sensitivity than GXpert for diagnosing TBM. MPCR is a robust and cost effective method for diagnosis of TBM in low-resource and high-endemic countries.

Topics: Antibiotics, Antitubercular; Antigens, Bacterial; Bacterial Proteins; Bacteriological Techniques; Case-Control Studies; Cerebrospinal Fluid; Cost Savings; Cost-Benefit Analysis; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Health Care Costs; Humans; Multiplex Polymerase Chain Reaction; Mycobacterium tuberculosis; Predictive Value of Tests; Reproducibility of Results; Rifampin; Tuberculosis, Meningeal

Rifampicin (RFP) and pyrazinamide (PZA) are the primary anti-tubercular drugs with a considerably safe profile. However, none of the drugs are without adverse reactions. They both can lead to a variety of adverse effects including life-threatening anaphylaxis. We report an interesting and possibly the first case of concurrent hypersensitivity to two primary anti-tubercular treatment (ATT) drugs. Hypersensitivity to RFP and PZA was confirmed in this patient by drug provocation and intradermal skin testing. He improved on alternative ATT regime withdrawing RFP and PZA.

Topics: Anaphylaxis; Antitubercular Agents; Child; Drug Hypersensitivity; Humans; Male; Pyrazinamide; Rifampin; Tuberculosis, Meningeal

Topics: Antibiotics, Antitubercular; Brain; Humans; Limit of Detection; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Neuroimaging; Nucleic Acid Amplification Techniques; Point-of-Care Testing; Predictive Value of Tests; Rifampin; Tomography, X-Ray Computed; Tuberculoma, Intracranial; Tuberculosis, Meningeal

Tuberculous meningitis (TBM) is the most devastating clinical presentation of infection with Mycobacterium tuberculosis; delayed initiation of effective antituberculosis therapy is associated with poor treatment outcomes. Our objective was to determine the relationship between drug resistance and 10-year mortality among patients with TBM.. We conducted a retrospective cohort study of 324 patients with culture-confirmed TBM, susceptibility results reported for isoniazid and rifampin, and initiation of at least 2 antituberculosis drugs, reported to the tuberculosis registry in New York City between 1 January 1992 and 31 December 2001. Date of death was ascertained by matching the tuberculosis registry with death certificate data for 1992-2012 from the New York Office of Vital Statistics. Human immunodeficiency virus (HIV) status was ascertained by medical records review, matching with the New York City HIV Surveillance registry, and review of cause of death.. Among 257 TBM patients without rifampin-resistant isolates, isoniazid resistance was associated with mortality after the first 60 days of treatment when controlling for age and HIV infection (adjusted hazard ratio, 1.94 [95% confidence interval, 1.08-3.94]). Death occurred before completion of antituberculosis therapy in 63 of 67 TBM patients (94%) with rifampin-resistant disease.. Among patients with culture-confirmed TBM, we observed rapid early mortality in patients with rifampin-resistant isolates, and an independent association between isoniazid-resistant isolates and death after 60 days of therapy. These findings support the continued evaluation of rapid diagnostic techniques and the empiric addition of second-line drugs for patients with clinically suspected drug-resistant TBM.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Drug Resistance, Bacterial; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; New York City; Retrospective Studies; Rifampin; Time Factors; Tuberculosis, Meningeal; Young Adult

Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Female; Humans; Levofloxacin; Male; Rifampin; Tuberculosis, Meningeal

It is not always possible to administer antituberculosis pharmacotherapy orally for reasons that may be a direct consequence of tuberculosis itself. To our knowledge, no published literature is available regarding antituberculosis drug absorption via feeding tube. We present the case of a patient with tuberculosis meningitis who required medication administration via percutaneous endoscopic jejunostomy (PEJ) tube. Blood samples were collected during the continuation phase of antituberculosis therapy, immediately before dose administration, and then at 1, 2, 4, and 6 hours after dose administration for quantification of serum rifampin concentrations. Assaying these concentrations by high-pressure liquid chromatography demonstrated a peak serum rifampin level (C(max)) of 18 μg/ml and total rifampin exposure (area under the curve from 0-6 hours [AUC(0-6)]) of 50.1 μg/ml. These are high compared with rifampin C(max) and AUC(0-6) values reported in patients after oral rifampin administration; C(max) tends to range between 4.0-10.5 μg/ml and AUC(0-6) 7.0-52.9 μg/ml after oral administration of 600 mg at steady state. Based on our patient's results, therefore, rifampin administered by PEJ tube appears to be well absorbed, with preservation of adequate C(max) and AUC values. It is worth noting that this was in the context of drug administration in the fasted state. In the absence of any published evidence of adequate absorption via jejunal feeding tube in the nonfasted state, it would seem prudent to ensure that patients are fasted when rifampin is administered via PEJ tube, just as patients are when oral rifampin is administered. This report represents the first documented evidence, to our knowledge, of adequate rifampin absorption when administered via PEJ tube and provides important reassurance for health care providers, patients, and families facing similar clinical scenarios.

Topics: Administration, Mucosal; Antibiotics, Antitubercular; Deglutition Disorders; Endoscopy, Gastrointestinal; Humans; Intestinal Absorption; Intestinal Mucosa; Jejunostomy; Jejunum; Male; Middle Aged; Rifampin; Tuberculosis, Meningeal

Among the various forms of TB, tuberculous meningitis (TBM) is the most severe, with about 30% mortality and 50% of survivors left with neurological sequelae. Children suffer more frequently from TBM than adults and outcomes are often poor due to difficulties in making the diagnosis and uncertainty regarding the best anti-tuberculosis drug regimen. The aim of this prospective study was to describe the pharmacokinetics of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of children with tuberculous meningitis treated with the standard TBM regimen.. We performed a prospective observational study of 100 consecutively treated children (≤ 15 years of age) with tuberculous meningitis in Ho Chi Minh City, Vietnam. Children were treated according to the 2006 WHO recommended pediatric treatment regimen consisting of isoniazid (5 mg/kg), rifampicin (10 mg/kg) and ethambutol (15 mg/kg) for 8 months, with the addition of pyrazinamide (25 mg/kg) for the first 3 months and streptomycin (15 mg/kg) for the first 2 months. Pyrazinamide, isoniazid and rifampicin concentrations were measured in plasma at day 14 and in cerebrospinal fluid (CSF) at 1 month by HPLC-UV. A naïve-pooled non-compartmental data analysis was used to describe the pharmacokinetic properties of drugs in the two-age groups of children ≤ 4 years or > 4 years of age.. Younger children, when compared to older children, presented a higher body weight-normalized clearance and volume of distribution, and lower median total plasma exposures for the three studied drugs with -14%, -22% and -16% for Pyrazinamide, Isoniazid and Rifampicin, respectively. In CSF, individual concentrations of isoniazid and pyrazinamide were comparable to that in plasma in both age groups; but rifampicin concentrations were lower than the minimum inhibitory concentration of susceptible bacteria in all but two children.. There is an age-dependent variation in the plasma and cerebrospinal fluid pharmacokinetics of rifampicin, isoniazid and pyrazinamide. The safety and efficacy of higher doses of rifampicin should be investigated for the treatment of childhood tuberculous meningitis.

Topics: Adolescent; Antitubercular Agents; Arylamine N-Acetyltransferase; Asian People; Child; Child, Preschool; Female; Genotype; Half-Life; Humans; Infant; Isoniazid; Male; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis, Meningeal; Vietnam

Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Female; Humans; Levofloxacin; Male; Rifampin; Tuberculosis, Meningeal

Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Female; Humans; Levofloxacin; Male; Rifampin; Tuberculosis, Meningeal

Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Female; Humans; Levofloxacin; Male; Rifampin; Tuberculosis, Meningeal

Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Female; Humans; Levofloxacin; Male; Rifampin; Tuberculosis, Meningeal

To explore the application value of GeneXpert MTB/RIF for detection of extra-pulmonary tuberculosis and resistance to rifampin.. A total of 150 samples were collected, including 33 needle aspirates from lymphoid tuberculosis, 23 needle aspirates from spinal tuberculosis, 49 from tuberculous pleural effusions, 24 from cerebrospinal fluid of tuberculous cephalomeningitis, and 21 urinary sediment samples from renal tuberculosis. Smear microscopy, mycobacterium tuberculosis culture and the MTB/RIF method were used to examine these samples and their positive rates were compared. Rifampin susceptibility tests was performed for culture-positive strains using proportion method, which was compared with the result from GeneXpert MTB/RIF method.. Of the 150 cases of extra-pulmonary tuberculosis, 17 samples were smear-positive, with a sensitivity of 11.3% (17/150); 30 were culture-positive with a sensitivity of 20.0% (30/150); and 96 were positive by MTB/RIF method with a sensitivity of 64.0% (96/150). There was a significant difference between MTB/RIF method and the culture method (χ(2)=59.61, P<0.01). The differences were also significant when the MTB/RIF method was compared with the smear method (χ(2)=88.60, P<0.01) or compared with culture plus smear methods (χ(2)=4.26, P<0.05). Separately, the differences were statistically significant between GeneXpert MTB/RIF method and other 2 methods for diagnosis of lymphoid tuberculosis (n=33, χ(2)=20.56, P<0.01 vs. culture method; χ(2)=27.13, P<0.01 vs. smear results) while no difference was found between culture and smear method (χ(2)=0.67, P>0.05), spinal tuberculosis (n=23, χ(2)=12.74, P<0.01 vs. culture method; χ(2)=14.81, P< 0.01 vs. smear method), tuberculous pleurisy (n=49, χ(2)=32.34, P<0.01 vs.culture method; χ(2)=49.69, P<0.01 vs. smear method) and renal tuberculosis (n=21, χ(2)=4.20, P<0.05 vs. culture method; χ(2) =8.40, P<0.01 vs. smear results). The sensitivity for tuberculous meningitis had no difference among these 3 methods (n=24, P>0.05). Rifampicin-resistance of the strains from the 30 culture-positive cases of extra-pulmonary tuberculosis (20.0%, 6/30) exhibited agreement with GeneXpert MTB/RIF test.. The simplicity and high sensitivity of GeneXpert MTB/RIF technology make it a good diagnostic test for rapid detection of extra-pulmonary tuberculosis and resistance to rifampin.

Topics: Antitubercular Agents; Humans; Microbial Sensitivity Tests; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Needles; Pleural Effusion; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Lymph Node; Tuberculosis, Meningeal; Tuberculosis, Renal; Tuberculosis, Spinal

BACKGROUND Tuberculous meningitis is very rare in the United States in immunocompetent hosts. Risk factors are similar to those of pulmonary tuberculosis, including poverty, malnutrition, overcrowding, a compromised immune system, and coming from an endemic area. Meningeal tuberculosis mortality and other outcomes have changed little over time despite effective therapies due to delay in diagnosis because of its rarity, variable presentation, and often indolent course. CASE REPORT We describe a case of a 57-year-old male immigrant from Senegal with no significant past medical history and no previous history of tuberculosis or evidence of immune compromise. He presented to the hospital with headache and altered mental status and was subsequently diagnosed with tuberculous meningitis. CONCLUSIONS This is a rare case of tuberculous meningitis in an immunocompetent host, questioning the conventional view that tuberculous meningitis is a disease of immunocompromised individuals. It emphasizes the importance of maintaining a strong clinical suspicion of tuberculous meningitis even in an immunocompetent patient in a geographical area with low prevalence if the patient has risk factors. Missed or delayed diagnosis is commonly fatal.

Topics: Antitubercular Agents; Cerebrospinal Fluid; Drug Therapy, Combination; Emigrants and Immigrants; Humans; Immunocompetence; Isoniazid; Levofloxacin; Male; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Senegal; Treatment Outcome; Tuberculosis, Meningeal; United States

Topics: Adult; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antitubercular Agents; Dexamethasone; Ethambutol; Female; Humans; Infliximab; Isoniazid; Middle Aged; Prednisolone; Pyrazinamide; Rifampin; Tuberculoma, Intracranial; Tuberculosis, Meningeal; Tumor Necrosis Factor-alpha

Multiple drug hypersensitivity (MDH) is an allergy to two or more chemically unrelated drugs. We present a case of MDH caused by antituberculosis agents during the treatment of tuberculous meningitis (TBM). A 64-year-old man without a history of drug allergy developed fever and severe headache. Examination of cerebrospinal fluid showed lymphocytosis, a low glucose level, and a high ADA activity, suggestive of TBM. The patient was treated with isoniazid, rifampicin, pyrazinamide, and ethambutol, and his symptoms resolved quickly. However, 20 days after the initiation of therapy, he developed remittent fever without mucocutaneous lesions. A drug-induced lymphocyte stimulation test was positive for isoniazid, rifampicin, and pyrazinamide, which was consistent with a diagnosis of MDH. All the antituberculosis drugs were replaced with levofloxacin and ethionamide, both of which have excellent cerebrospinal fluid penetration, and the fever subsided. The patient made a full recovery from TBM. Because standard antituberculosis regimens include three or four antituberculosis drugs, it is difficult to determine the culprit drug when hypersensitivity occurs. Moreover, there can be multiple causative drugs as illustrated by the present case. During a time-consuming desensitization therapy, TBM could flare up, leading to permanent neurological damage. Thus, treatment with suitable alternative drugs should be started immediately.

Topics: Antitubercular Agents; Drug Hypersensitivity; Drug Therapy, Combination; Ethambutol; Ethionamide; Humans; Immunologic Tests; Isoniazid; Levofloxacin; Lymphocyte Activation; Male; Middle Aged; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Meningeal

Pediatric tuberculous meningitis (TBM) is a highly morbid, often fatal disease. Standard treatment includes isoniazid, rifampin, pyrazinamide, and ethambutol. Current rifampin dosing achieves low cerebrospinal fluid (CSF) concentrations, and CSF penetration of ethambutol is poor. In adult trials, higher-dose rifampin and/or a fluoroquinolone reduced mortality and disability. To estimate optimal dosing of rifampin and levofloxacin for children, we compiled plasma and CSF pharmacokinetic (PK) and outcomes data from adult TBM trials plus plasma PK data from children. A population PK/pharmacodynamic (PD) model using adult data defined rifampin target exposures (plasma area under the curve (AUC)0-24 = 92 mg*h/L). Levofloxacin targets and rifampin pediatric drug disposition information were literature-derived. To attain target rifampin exposures, children require daily doses of at least 30 mg/kg orally or 15 mg/kg intravenously (i.v.). From our pediatric population PK model, oral levofloxacin doses needed to attain exposure targets were 19-33 mg/kg. Our results provide data-driven guidance to maximize pediatric TBM treatment while we await definitive trial results.

Topics: Administration, Intravenous; Administration, Oral; Adolescent; Adult; Age Factors; Antitubercular Agents; Body Weight; Child; Child, Preschool; Clinical Trials, Phase II as Topic; Computer Simulation; Drug Dosage Calculations; Humans; Infant; Levofloxacin; Models, Biological; Mycobacterium tuberculosis; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis, Meningeal

Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder characterised by conjugated hyperbilirubinemia resulting from mutations of ABCC2/MRP2 gene. The beneficial effects of ursodeoxycholic acid (UDCA) and rifampicin were found to be complementary in the treatment of cholestatic liver disease secondary to DJS. We present a case of a young woman with tubercular meningitis. She was started on modified antitubercular therapy in view of conjugated hyperbilirubinemia. However, reinitiation of rifampicin resulted in redevelopment of jaundice. Liver biopsy was suggestive of DJS. The patient was started on rifampicin along with UDCA. There was improvement in hyperbilirubinemia and a full course of antituberculous therapy without further worsening of the disorder was possible. This is a rare case of DJS with tuberculosis, showing beneficial effects of rifampicin and UDCA combination therapy, which so far has been considered doubtful. It is uncertain what the level of efficacy of therapy is in various MRP2 gene mutations.

Topics: Adult; Antitubercular Agents; Cholagogues and Choleretics; Drug Therapy, Combination; Female; Humans; Isoniazid; Jaundice, Chronic Idiopathic; Multidrug Resistance-Associated Protein 2; Rifampin; Tuberculosis, Meningeal; Ursodeoxycholic Acid

Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Microbiological confirmation is rare, and treatment is often delayed, increasing mortality and morbidity. The GeneXpert MTB/RIF test was evaluated in a large cohort of patients with suspected tuberculous meningitis. Three hundred seventy-nine patients presenting with suspected tuberculous meningitis to the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, between 17 April 2011 and 31 December 2012 were included in the study. Cerebrospinal fluid samples were tested by Ziehl-Neelsen smear, mycobacterial growth indicator tube (MGIT) culture, and Xpert MTB/RIF. Rifampin (RIF) resistance results by Xpert were confirmed by an MTBDR-Plus line probe assay and all positive cultures were tested by phenotypic MGIT drug susceptibility testing. Overall, 182/379 included patients (48.0%) were diagnosed with tuberculous meningitis. Sensitivities of Xpert, smear, and MGIT culture among patients diagnosed with TBM were 59.3% (108/182 [95% confidence interval {CI}, 51.8 to 66.5%]), 78.6% (143/182 [95% CI, 71.9 to 84.3%]) and 66.5% (121/182 [95% CI, 59.1 to 73.3%]), respectively. There was one false-positive Xpert MTB/RIF test (99.5% specificity). Four cases of RIF resistance (4/109; 3.7%) were identified by Xpert, of which 3 were confirmed to be multidrug-resistant (MDR) TBM and one was culture negative. Xpert MTB/RIF is a rapid and specific test for the diagnosis of tuberculous meningitis. The addition of a vortexing step to sample processing increased sensitivity for confirmed TBM by 20% (P = 0.04). Meticulous examination of a smear from a large volume of cerebrospinal fluid (CSF) remains the most sensitive technique but is not practical in most laboratories. The Xpert MTB/RIF represents a significant advance in the early diagnosis of this devastating condition.

Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Cerebrospinal Fluid; False Positive Reactions; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis, Meningeal; Vietnam; Young Adult

Topics: Adult; Antitubercular Agents; Cerebrospinal Fluid; Delayed Diagnosis; Fatal Outcome; Glucocorticoids; Humans; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Reproducibility of Results; Rifampin; Sensitivity and Specificity; Tuberculosis, Meningeal

Phenytoin, a commonly used antiepileptic, is difficult to dose optimally due to its narrow therapeutic window, nonlinear pharmacokinetics, extensive protein binding, and participation in clinically significant drug interactions. Although clinicians are aware of the interaction with two widely used antituberculosis agents, rifampin and isoniazid, few reports have described the implications for managing phenytoin dosing in this situation. To our knowledge, only two reports of the clinical experience with this interaction have been published, and only one of these reports involved the addition of isoniazid. We present a case of a 60-year-old man treated with triple antiepileptic therapy, including phenytoin, who experienced seizures shortly after hospital admission. Dosing of phenytoin proved difficult in this patient due to an acute kidney injury and severe hypoalbuminemia requiring hemodialysis. A further complexity was the addition of antituberculosis therapy (rifampin, isoniazid, pyrazinamide, and ethambutol [RIPE]) for suspected tuberculosis meningitis after the patient experienced persistent encephalopathy. Phenytoin concentrations decreased steadily after rifampin and isoniazid initiation despite dose increases, and the free concentration of phenytoin reached a low of less than 0.5 µg/ml on day 8 of RIPE therapy. The patient continued on a stable dose of phenytoin and RIPE therapy for unconfirmed tuberculosis meningitis until discharge. This report is the first description of this drug interaction in 20 years and highlights the need for appropriate management of phenytoin in a patient with complicated needs for pharmacotherapy.

Topics: Acute Kidney Injury; Anticonvulsants; Antitubercular Agents; Dose-Response Relationship, Drug; Drug Interactions; Humans; Hypoalbuminemia; Male; Middle Aged; Phenytoin; Renal Dialysis; Rifampin; Seizures; Severity of Illness Index; Tuberculosis, Meningeal

Topics: Antitubercular Agents; Aza Compounds; Humans; Indonesia; Quinolines; Rifampin; Tuberculosis, Meningeal

A 21-year-old woman presented to the hospital with 3 days of headache, fever, mood disturbance and nausea. She had recently emigrated from India, and was noted to have a positive screening purified protein derivative tuberculosis skin test with normal chest x-ray. Meningeal signs were noted prompting lumbar puncture and initiation of presumptive treatment for bacterial meningitis. While tuberculous meningitis (TM) was entertained at admission, diagnosis was clouded by the rapid onset of symptoms and recent major psychosocial stressors. She developed severe hyponatremia. Brain MRI revealed tuberculomas, and she was started on treatment for TM, a diagnosis confirmed by culture. On review, several lessons were learned: (1) globalisation of society makes uncommon diagnoses present in unlikely locations, (2) hyponatremia is a common complication of TM, (3) MRI can aid in diagnosis of TM and (4) cognitive and mood changes can be prodromal symptoms of TM.

Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Female; Humans; Hyponatremia; Isoniazid; Magnetic Resonance Imaging; Pyrazinamide; Rifampin; Southwestern United States; Tuberculosis, Meningeal; Young Adult

Topics: Antitubercular Agents; Aza Compounds; Female; Humans; Male; Quinolines; Rifampin; Tuberculosis, Meningeal

Topics: Antitubercular Agents; Aza Compounds; Female; Humans; Male; Quinolines; Rifampin; Tuberculosis, Meningeal

Topics: Antitubercular Agents; Aza Compounds; Female; Humans; Male; Quinolines; Rifampin; Tuberculosis, Meningeal

The case is presented of a 29-year-old woman who complained of headache over a period of several days, with loss of visual acuity and pain in her left eye. She had a 3-year history of type 1 diabetes mellitus, and was an immigrant from Ecuador. The funduscopic examination revealed a papilledema. The polymerase chain reaction (PCR) study of the cerebrospinal fluid was positive for Mycobacterium tuberculosis (MTB). She showed a marked improvement after treatment with anti-TB drugs.. About a third of the world's population has a latent infection of MTB, comorbidity between diabetes mellitus and tuberculosis has been reported, particularly in undeveloped countries.

Topics: Adult; Antitubercular Agents; Atrophy; Cerebrospinal Fluid; Developing Countries; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Ecuador; False Negative Reactions; Female; Humans; Immunocompromised Host; Isoniazid; Latent Tuberculosis; Mycobacterium tuberculosis; Ophthalmoscopy; Optic Nerve; Papilledema; Rifampin; Spinal Puncture; Tuberculin Test; Tuberculosis, Meningeal

In this paper we present a case of a 58 years old male with a rare form of extrapulmonary tuberculosis--tuberculous meningitis (TBM). Tuberculous meningitis is usually caused by hematogenous spread of Mycobacterium from lungs. The TBM is a severe disease with high mortality. The symptoms usually increase gradually and in the course of the disease 3 clinical stages (prodromal phase, phase of neurological symptoms and phase of paresis) may be differentiated. Cerebrospinal fluid examination, chest x-ray and sputum culture are crucial for diagnosis of TBM. The proper diagnosis and early causative treatment significantly improve the outcome of the disease.

Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Poland; Rifampin; Tuberculosis, Meningeal; Tuberculosis, Miliary

Topics: Antitubercular Agents; Aza Compounds; Female; Fluoroquinolones; Humans; Male; Moxifloxacin; Quinolines; Rifampin; Tuberculosis, Meningeal

Tuberculous meningitis is the most severe form of tuberculosis and causes substantial morbidity and mortality in adults and children. The prevalence of multidrug-resistant (rifampin-isoniazid) strains requires the use of more toxic second-line drugs. We report a case of tuberculous meningitis in a 3-year-old Italian child.

Topics: Antitubercular Agents; Child, Preschool; Drug Resistance, Multiple, Bacterial; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Meningeal; Tuberculosis, Multidrug-Resistant

Tuberculous meningitis (TbM) is a neurological emergency condition that requires prompt initiation of treatment. The standard initial treatment for TbM is often insufficient for producing remission because the anti-tuberculosis agent may cause severe side effects, or vasculitis and hydrocephalus may induce an intractable state. Moreover, it is difficult to distinguish paradoxical expansion from its own deterioration. We treated 2 cases of adult TbM by using multidisciplinary therapy, including methyl prednisolone pulse and intrathecal isoniazid administration. Both cases had not been diagnosed as pulmonary or other tuberculosis, and cerebrospinal fluid (CSF) culture and polymerase chain reaction at approximately 1 week after hospitalization identified the cases as TbM. We administered the standard initial treatment recommended by the British Infection Society guidelines for adults, but both cases deteriorated and showed elevation of intracranial pressure. We indwelled a lumbar drainage for Case 1 and an Ommaya reservoir for Case 2. We removed CSF and administrated isoniazid regularly using each of the drainage devices, added streptomycin, and increased the steroid dose including addition of steroid pulse therapy. Both cases improved, and their neurological dysfunction did not persist. After the induction of an intractable state occurs due to TbM, we are likely to assume poor prognosis and neurological sequelae. However, our experience in these cases showed amelioration of the symptoms leading to the rehabilitation of these patients in society.

Topics: Adult; Antitubercular Agents; Dexamethasone; Drug Therapy, Combination; Ethambutol; Female; Humans; Injections, Spinal; Isoniazid; Male; Methylprednisolone; Middle Aged; Pulse Therapy, Drug; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Meningeal

To compare the effectiveness and safety of short term 6 month-treatment and long term 12 month-treatment schedules for meningoencephalitis due to tuberculosis in two hospitals from Lima-Peru.. Comparative, retrospective and observational study. The patients were divided in two groups: Group 1: long term 12 month-treatment with isoniazid, rifampin, pyrazinamide, and ethambutol for the first 2 months; then isoniazid and rifampin for 10 months. Group 2: short term 6 month-treatment with isoniazid and rifampin, pyrazinamide and ethambutol for the first 2 months; then isoniazid and rifampin for 4 months. Clinical records, effectiveness, treatment failure, treatment side effects, mortality and late consequences after treatment were reviewed.. Twenty-six patients with meningoencephalitis level I were included, 10 received the long term schedule and 16 the short term schedule treatment. From 51 patients with meningoencephalitis level II, 27 received the long term schedule and 24 the short term schedule treatment and of 31 patients with meningoencephalitis level III, 18 received the long term schedule treatment and 13 the short term schedule treatment. There was no statistically significant differences among levels I, II and III when effectiveness of short and long term schedule was evaluated. Moreover, there was no statistically significant difference in the frequency of treatment failure, treatment side effects, mortality and late consequences among groups.. Long term 12 month-treatment and short term 6 month-treatment had similar effectiveness and safety in the treatment of meningoenchephalitis due to tuberculosis in HIV negative patients.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Hospitals; Humans; Isoniazid; Male; Meningoencephalitis; Middle Aged; Peru; Pyrazinamide; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis, Meningeal; Young Adult

Topics: Adult; Aged, 80 and over; Antitubercular Agents; Aphasia; Child, Preschool; Drug Therapy, Combination; Dystonia; Ethambutol; Facial Pain; Female; Humans; Isoniazid; Magnetic Resonance Imaging; Male; Nigeria; Prednisone; Pyrazinamide; Reflex, Abnormal; Rifampin; Tremor; Tuberculoma; Tuberculosis, Meningeal; Tuberculosis, Miliary

The prognosis of tuberculous meningitis (TBM) is linked to early diagnosis and prescription of adequate treatment.. To evaluate the efficacy of the rpoB nested polymerase chain reaction (PCR) and sequencing assay to detect and identify Mycobacterium tuberculosis complex (MTC) strains and strains resistant to rifampicin (RMP) in cerebrospinal fluid specimens (CSF) from patients with highly suspected TBM.. Retrospective blinded hospital-based study.. rpoB nested PCR and sequencing assay detected MTC in 31/36 CSF specimens from 16 patients with clinically suspected TBM. All of the control CSF specimens from 25 patients with non-TBM showed negative results. One of the 16 patients had a mutation at codon C526G as compared to the rpoB sequences in GenBank. This corresponds to a diagnostic sensitivity of 86% (95%CI 71-95) and a specificity of 100% (95%CI 86-100).. Our results suggest that rpoB nested PCR and sequencing assay can detect MTC and simultaneously determine its RMP susceptibility in CSF from patients with highly suspected TBM.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Bacterial Proteins; Cerebrospinal Fluid; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Bacterial; Early Diagnosis; Female; Humans; Male; Middle Aged; Mutation; Mycobacterium tuberculosis; Polymerase Chain Reaction; Retrospective Studies; Rifampin; Sensitivity and Specificity; Single-Blind Method; Tuberculosis, Meningeal; Young Adult

SUMMARY AND KEY RECOMMENDATIONS: The aim of these guidelines is to describe a practical but evidence-based approach to the diagnosis and treatment of central nervous system tuberculosis in children and adults. We have presented guidance on tuberculous meningitis (TBM), intra-cerebral tuberculoma without meningitis, and tuberculosis affecting the spinal cord. Our key recommendations are as follows: 1. TBM is a medical emergency. Treatment delay is strongly associated with death and empirical anti-tuberculosis therapy should be started promptly in all patients in whom the diagnosis of TBM is suspected. Do not wait for microbiological or molecular diagnostic confirmation. 2. The diagnosis of TBM is best made with lumbar puncture and examination of the cerebrospinal fluid (CSF). Suspect TBM if there is a CSF leucocytosis (predominantly lymphocytes), the CSF protein is raised, and the CSF:plasma glucose is <50%. The diagnostic yield of CSF microscopy and culture for Mycobacterium tuberculosis increases with the volume of CSF submitted; repeat the lumbar puncture if the diagnosis remains uncertain. 3. Imaging is essential for the diagnosis of cerebral tuberculoma and tuberculosis involving the spinal cord, although the radiological appearances do not confirm the diagnosis. A tissue diagnosis (by histopathology and mycobacterial culture) should be attempted whenever possible, either by biopsy of the lesion itself, or through diagnostic sampling from extra-neural sites of disease e.g. lung, gastric fluid, lymph nodes, liver, bone marrow. 4. Treatment for all forms of CNS tuberculosis should consist of 4 drugs (isoniazid, rifampicin, pyrazinamide, ethambutol) for 2 months followed by 2 drugs (isoniazid, rifampicin) for at least 10 months. Adjunctive corticosteroids (either dexamethasone or prednisolone) should be given to all patients with TBM, regardless of disease severity. 5. Children with CNS tuberculosis should ideally be managed by a paediatrician with familiarity and expertise in paediatric tuberculosis or otherwise with input from a paediatric infectious diseases unit. The Children's HIV Association of UK and Ireland (CHIVA) provide further guidance on the management of HIV-infected children (www.chiva.org.uk). 6. All patients with suspected or proven tuberculosis should be offered testing for HIV infection. The principles of CNS tuberculosis diagnosis and treatment are the same for HIV infected and uninfected individuals, although HIV infection broadens t

Topics: Adenosine Deaminase; Adult; Antibiotics, Antitubercular; Antitubercular Agents; Cerebrospinal Fluid; Child; Ethambutol; Humans; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Spinal Puncture; Tuberculin Test; Tuberculoma, Intracranial; Tuberculosis, Meningeal; Tuberculosis, Spinal

Tuberculosis is an endemic disease responsible for death and morbidity in developing countries.. A 50-year-old man with no medical history was admitted to the emergency department for meningism associated with fever and confusion. The ophthalmic exam showed a decline in left visual acuity, reduced to light perception, VIth nerve left oculomotor paralysis, ocular fundus demonstrating a yellow tumor located on the posterior segment, measuring 1.5-2mm, papillomatous and prominent in the vitreous cavity. Fluorescein angiography showed a peritumoral choroiditis area, miliary tubercles of the choroid, and sectorial papillomatous edema. Color retinography unmasked inflamed posterior vitreous areas. Echography demonstrated a 4- to 5-mm oval hyperechogeneous and calcified tumor along with hyperechogeneous vitreous areas. Lumbar puncture showed lymphocytic meningitis associated with hyponatremia. The CT scan and MRI demonstrated optic neuritis. The antibiotic therapy was initiated and the outcome was favorable.. This case report shows the importance of systematic ocular fundus in the presence of systemic tuberculosis and outlines the assessment of color retinography to unmask vitreous lesions. It shows the importance of radiological imaging in the semiological study of orbital and cerebral lesions.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Antitubercular Agents; Calcinosis; Confusion; Diplopia; Drug Therapy, Combination; Fever; Humans; Isoniazid; Magnetic Resonance Imaging; Male; Meningoencephalitis; Middle Aged; Optic Neuritis; Papilledema; Pyrazinamide; Rifampin; Spinal Puncture; Streptomycin; Tuberculoma; Tuberculosis, Meningeal; Ultrasonography

Drug-resistant tuberculosis is an increasing problem worldwide. There are few reports of drug susceptibility patterns of Mycobacterium tuberculosis isolated from cases of tuberculous meningitis. A 5-year retrospective study aimed at analysing the drug susceptibility profile of M. tuberculosis isolated from tuberculous meningitis cases was conducted. A total of 366 isolates were analysed. Among these, 301 (82.2%) were sensitive to all the four primary drugs tested, while 65 (17.8%) showed resistance. There were 46 (12.5%) isolates resistant to isoniazid (INH), while 9 (2.4%) demonstrated multidrug resistance. These data suggest that multidrug resistance in tuberculous meningitis is not yet a serious problem. However, a periodic review is required to ascertain the global incidence of drug-resistant tuberculous meningitis.

Topics: Adolescent; Adult; Antitubercular Agents; Child; Child, Preschool; Drug Resistance, Multiple, Bacterial; Ethambutol; Humans; Infant; Isoniazid; Middle Aged; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Streptomycin; Tuberculosis, Meningeal; Tuberculosis, Multidrug-Resistant

Animal studies point to increased virulence of certain mycobacterial strains, notably those of the Beijing genotype. There are limited data on mycobacterial genotypic diversity in children with tuberculous meningitis (TBM). We investigated mycobacterial genotypic diversity in children with TBM and analyzed the relationship among genotype, clinical presentation and outcome.. Data were extracted from an ongoing prospective study on children with confirmed TBM from 1992 through 2003 at a referral hospital in the Western Cape Province, South Africa. Mycobacterial isolates were genotyped by standardized restriction fragment length polymorphism methodology. Clinical data at diagnosis, inflammatory progression during the first month of antituberculosis therapy and neurologic outcomes after 6 months of therapy were analyzed according to the principal genetic group of the strain and the presence of the Beijing strain, respectively.. Fifty-nine children were included (median age at diagnosis, 23 months); 37 presented with stage II and 22 with stage III presented with TBM. At completion of antituberculosis therapy, 6 children were neurologically normal, 22 were moderately neurologically impaired, 23 were severely neurologically impaired and 6 children died; detailed outcomes were not available in 2 children. All 3 principal genetic groups were represented (group 1, 27.1%; group 2, 59.3%; group 3, 13.6%); the most prevalent strains were of the Beijing genotype (family 29; 25.4%), followed by family 28 (10.2%) and family 11 (8.5%). Predictors of poor neurologic outcome included advanced disease at diagnosis and male gender. There was no association between the principal genetic group of the strain or the presence of the Beijing genotype, and clinical presentation or outcome.. We found no association between Mycobacterium tuberculosis genotypes and clinical presentation or outcome.

Topics: Adolescent; Antibiotics, Antitubercular; Antitubercular Agents; Child; Child, Preschool; Ethionamide; Female; Genotype; Humans; Infant; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazinamide; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis, Meningeal

To evaluate the role of the radiometric BACTEC 460TB system and the conventional Lowenstein-Jensen (LJ) medium for isolation of M. tuberculosis from cerebrospinal fluid (CSF) samples of tuberculous meningitis (TBM) patients.. CSF specimens (n=2325) from suspected TBM patients were processed for isolation of mycobacteria by inoculating BACTEC 12B medium and the LJ medium. The isolation of mycobacteria in both media was confirmed by microscopy and biochemical identification. Drug sensitivity testing for the anti-TB drugs was carried out by BACTEC radiometric method.. Among the total 2325 CSF specimens processed by both methods, M. tuberculosis was isolated from 256 specimens. The isolation rates were 93% and 39% for the BACTEC system and LJ medium respectively. Both the media supported growth in 32% of the culture-positive specimens. BACTEC system alone yielded growth in 61% and LJ alone in 7%, of the culture-positive specimens. Among 205 isolates tested for drug susceptibility 81% were sensitive to all the drugs tested and 19% were resistant.. The BACTEC 460TB system provides a highly sensitive and rapid tool for the isolation and drug susceptibility testing of M. tuberculosis, from CSF of TBM patients. Use of a solid medium in conjunction with the BACTEC 12B medium is essential for optimal recovery for M. tuberculosis from CSF specimens.

Topics: Bacteriological Techniques; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis, Meningeal

Neuromeningeal tuberculosis of deleterious, paradoxical, progression despite appropriate antibiotic therapy is rare.. An immunocompetent woman exhibited an immediately disseminated form of tuberculosis with progressive neurological involvement associating expanding intracranial tuberculomas and meningeal-radiculitis despite adapted anti-tuberculosis quadritherapy.. During anti-tuberculosis therapy clinical worsening is rare, particularly when 2 different manifestations are associated and the worsening occurs in an immunocompetent patient. This possibility should be systematically evoked in such cases. The explanation of this phenomenon is still unclear.

Topics: Aged; Anti-Inflammatory Agents; Antitubercular Agents; Confusion; Disease Progression; Drug Therapy, Combination; Female; Fever; Humans; Immunocompetence; Isoniazid; Magnetic Resonance Imaging; Ofloxacin; Prednisone; Radiculopathy; Rifampin; Spinal Puncture; Tomography, X-Ray Computed; Treatment Outcome; Tuberculoma; Tuberculoma, Intracranial; Tuberculosis, Meningeal

Topics: Adjuvants, Immunologic; Antibiotics, Antitubercular; Dexamethasone; Drug Interactions; Glucocorticoids; Humans; Rifampin; Tuberculosis, Meningeal

Intracranial tuberculoma is a possible complication of meningeal, miliary or pulmonary tuberculosis. In developing countries it represents 30% of space-occupying intracranial lesions, in industrialised countries only 0.1-0.2%. One recently recognised phenomenon is the development ex novo or the enlargement of the tuberculoma during antitubercular chemo-antibiotic therapy. Here we report the clinical case of an immunocompetent Italian baby girl who presented an intracranial tuberculoma during tuberculous meningitis. We underline how such an event is possible, the need for early neuroradiological evaluation and its favourable course, maintaining adequate antitubercular therapy associated with steroid therapy.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Antibiotics, Antitubercular; Antitubercular Agents; Child; Drug Therapy, Combination; Ethambutol; Female; Follow-Up Studies; Humans; Isoniazid; Magnetic Resonance Imaging; Prednisone; Pyrazinamide; Rifampin; Streptomycin; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Tuberculoma, Intracranial; Tuberculosis, Meningeal

A modified clinical presentation of tuberculous meningitis (TBM) in children vaccinated with BCG has been described in the literature. However, most reports are old and not based on actual comparisons and tests of significance. Also, neuroimaging features were not compared. With large scale BCG coverage, it becomes pertinent to describe the "modified" presentation and identify any significant differences between vaccinated and unvaccinated children with TBM.. A total of 150 consecutive hospitalised children (96 unvaccinated, 54 vaccinated) were enrolled. They all satisfied predefined criteria for diagnosis of TBM. Clinical and radiological features of children with/without a BCG scar were compared.. Univariate analysis revealed that the vaccinated children with TBM had significantly lower rates of altered sensorium (68.5% v 85.4% unvaccinated; OR 2.2 (1.1 to 6.2); p = 0.019) and focal neurological deficits (20.3% v 39.5% unvaccinated; OR 2.6 (1.1 to 6.0); p = 0.016), and higher mean (SD) Glasgow Coma Scale score (10.2 (3.4) v 8.76 (2.7) unvaccinated; p = 0.010) and cerebrospinal fluid cell count (210.9 v 140.9 unvaccinated; p = 0.019). No significant radiological differences were seen. Short term outcome was significantly better in the vaccinated group with 70% of the total severe sequelae and 75% of the total deaths occurring in the unvaccinated group (p = 0.018).. Children with TBM who have been vaccinated with BCG appear to maintain better mentation and have a superior outcome. This may in part be explained by the better immune response to infection, as reflected in the higher CSF cell counts in this group in the present study.

Topics: Antitubercular Agents; BCG Vaccine; Child, Preschool; Female; Humans; Injections, Intramuscular; Isoniazid; Male; Pyrazinamide; Rifampin; Tuberculosis, Meningeal; Vaccination

Multidrug-resistant (MDR) pulmonary tuberculosis (TB) is well described in the literature. Reports of MDR TB meningitis (MDR-TBM), however, are limited to case reports and a single case series. During the period of 1999-2002, 350 patients with TBM were identified by cerebrospinal fluid culture for TB. Thirty patients (8.6%) had TB that was resistant to at least isoniazid and rifampicin. All 30 patients were included in this study. We reviewed hospital charts of the patients with MDR-TBM and describe our experience. Seventeen patients with MDR-TBM died, and, of those who were known to be alive, many experienced significant morbidity. Eighteen patients were HIV positive. Twenty-two patients had been treated for TB in the past, 3 patients had received no previous treatment for TB, and the history of TB treatment was unknown for 5 patients. The study highlights the prevalence of MDR-TBM and identifies new challenges in the management of affected patients.

Topics: Adolescent; Adult; Antitubercular Agents; Child; Drug Resistance, Multiple, Bacterial; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Meningeal; Tuberculosis, Multidrug-Resistant

A 36-year-old man was referred to our hospital with complaints of high fever and headache. A diagnosis of miliary tuberculosis with tuberculous meningitis was made. He was treated with isoniazid (400 mg/day), rifampicin (300 mg/day), ethambutol (750 mg/day), pyrazinamide (1.0 g/day) and prednisolone (60 mg/day). However, he lost consciousness because of hydrocephalus on the second day of hospitalization. Emergency cerebrospinal fluid drainage improved his neurological symptoms. After two months, he again complained of headache with nausea and double vision. Numerous tuberculomas were found not only in the cerebrum but also in the liver, the spleen and the retina. Recurrent hydrocephalus was treated with a V-P shunt, and combination therapy with four antituberculous agents was maintained for 18 months. He was discharged in a healthy condition, although a mild left facial palsy remained. In addition, we examined the inflammatory cytokine levels in both the CSF and the serum over the period of the patient's hospitalization. We concluded that the cytokine levels in the CSF may be associated with the progress and the prognosis of tuberculous meningitis.

Topics: Adult; Antitubercular Agents; Cytokines; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Male; Prognosis; Rifampin; Tuberculosis, Meningeal; Tuberculosis, Miliary

The purpose of the present study was to determine the long-term outcome of 76 children (40 females and 36 males) diagnosed and treated with modern antituberculosis drugs. The median age of the children on admission was 29.5 months and on follow-up 9 years. Antituberculosis therapy consisted of daily isoniazid (20 mg/kg), rifampicin (20 mg/kg), ethionamide (20 mg/kg), and pyrazinamide (40 mg/kg) for 6 months. Twenty-three children received daily prednisone (2-4 mg/kg) for the first month of treatment. Raised intracranial pressure was actively monitored and treated. Patients with non-communicating hydrocephalus received ventriculo-peritoneal shunts shortly after admission while communicating hydrocephalus was treated with oral acetazolamide (100 mg/kg/day) and furosemide (1 mg/kg/day) in 3-4 divided doses. Communicating hydrocephalus that did not respond to this regimen within the first month of treatment also underwent ventriculo-peritoneal shunting. Only 20% of children were functionally completely normal at follow-up. Main areas of functional deficit were cognitive impairment (80%), poor scholastic progress (43%), and emotional disturbance (40%). Twenty-five per cent of children had evidence of motor impairment, but all could walk and only 5 of 76 children (6% of total) were unable to run. One child was blind but no child had sensori-neural deafness. It was concluded that these disabilities in children from mainly deprived socioeconomic backgrounds have serious implications for their future social, academic, and career prospects. A high index of suspicion of TBM in high tuberculosis incidence communities will help prevent the morbidity documented in this study.

Topics: Acetazolamide; Anti-Inflammatory Agents; Antitubercular Agents; Brain; Child; Cognition Disorders; Diuretics; Drug Therapy, Combination; Ethionamide; Female; Follow-Up Studies; Furosemide; Humans; Hydrocephalus; Isoniazid; Male; Mycobacterium tuberculosis; Prednisolone; Pyrazinamide; Quality of Life; Rifampin; Tuberculosis, Meningeal; Ventriculoperitoneal Shunt; Wechsler Scales

This study reviewed the clinical manifestations and outcome of tuberculous meningitis in the era of modern antituberculous chemotherapy and applied these data in assessing the role of clinical staging evaluated 30 days after treatment in predicting long-term outcome. A total of 41 adult patients with tuberculous meningitis hospitalized at a university hospital in Taiwan from June 1994 through August 1999 were included in this retrospective study. Their age ranged from 16 to 80 years (median, 41 years), and 17 (41.5%) patients had had a variety of underlying immunocompromising diseases. Fever (90%), headache (75.6%), neck stiffness (68.3%), altered consciousness (26.8%), and nausea and/or vomiting (26.8%) were the leading initial presentations. During the treatment course, 19 patients experienced new neurologic complications. The overall case fatality rate was 9.8% and morbidity rate 56.1%. More advanced clinical stage evaluated at 30 days after initiation of antituberculous chemotherapy and positive cerebrospinal fluid culture for Mycobacterium tuberculosis were the only 2 factors significantly associated with a worse long-term prognosis. Results indicate that tuberculous meningitis is associated with a high morbidity, consisting of minor and major neurologic sequelae, despite modern antituberculous chemotherapy. In addition, more advanced clinical staging evaluated at 30 days after the start of antituberculous chemotherapy and a positive cerebrospinal fluid culture for M. tuberculosis were associated with a poor prognosis.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Female; Humans; Immunocompromised Host; Isoniazid; Leukocyte Count; Male; Mycobacterium tuberculosis; Prognosis; Pyrazinamide; Rifampin; Streptomycin; Treatment Outcome; Tuberculosis, Meningeal

Tuberculous Meningitis is associated with a high morbidity and mortality if there is a delay in diagnosis. The diagnosis is based on clinical evaluation since the bacteriological diagnosis takes time and has a low yield. This study attempts to validate these criteria in children with TBM.. Forty-two children clinically suspected to have TBM were enrolled in the study. History, examination, CT scan and CSF findings were utilized to categorize patients into "definite", "highly probable", "probable" and "possible" TBM based on the criteria laid down by Ahuja et al. The validity of these criteria was tested against bacterial isolation and response to treatment.. Thirty one children, with complete data, were included for analysis. Using "improvement on therapy as a criterion for definite TBM, we analyzed the sensitivity and specificity of the Ahuja criteria in diagnosing TBM. Using the criteria of "highly probable" TBM, the sensitivity was 65% with a specificity of 75%. When the criteria of "probable" TBM were used, the sensitivity increased to 96% while the specificity dropped to 38%. In an attempt to make these criteria more appropriate for children, we modified the criteria by including mantoux reaction, and family history of exposure in the criteria. The modified criteria gave a sensitivity of 83% and a specificity of 63%.. A sensitivity of 65% (highly probable group) implies that 35% of TBM patients will be missed, while the probable criteria gave a 63% false positive rate suggesting that the trade-off for a higher sensitivity makes the criteria very unreliable. Our modification of the criteria gave us a reasonable sensitivity of 83% with a higher specificity of 63%. The false positive rate was also reduced to 38%. Thus the modified Ahuja criteria worked better for children with TBM.. The modified Ahuja criteria are better applicable for use in pediatric patients with TBM . Since the number of patients was small in this study, the study needs to be validated with a larger sample size.

Topics: Antitubercular Agents; Child; Child, Preschool; Humans; Isoniazid; Mycobacterium tuberculosis; Prognosis; Pyrazinamide; Rifampin; Sensitivity and Specificity; Streptomycin; Tuberculin Test; Tuberculosis, Meningeal

Rapidly progressive multidrug-resistant tuberculosis (MDR-TB) is well documented in human immunodeficiency virus (HIV) positive subjects, but it is not fully recognised in HIV-negative subjects in the familial environment. We report three cases of MDR-TB in three young HIV-negative subjects from the same family. All the patients showed signs of meningitis during the course of their disease, and in two cases a resistant strain of Mycobacterium tuberculosis was isolated in cerebrospinal fluid. Two of the three subjects died from neurological complications; the other was successful treated utilising both systemic and intrathecal therapy for tuberculous meningitis. By a retrospective analysis of DNA obtained from Lowenstein-Jensen cultures, the strains were confirmed as M. tuberculosis resistant to rifampicin and isoniazid, and were closely related in the two cases where specimens were available for analysis. The resistance was acquired in two patients initially infected with a susceptible strain; in the other patient, the resistance was present on the first sensitivity test for which results were available. This report demonstrates the high risk of fatality from MDR-TB for HIV-negative subjects in the absence of reliable early diagnostic and preventive tools. It also reinforces the concept that genetic susceptibility to M. tuberculosis may be an important factor in the clinical presentation and outcome of MDR-TB.

Topics: Adolescent; Adult; Antitubercular Agents; Culture Media; Fatal Outcome; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Recurrence; Rifampin; Survival Rate; Tuberculosis, Meningeal; Tuberculosis, Multidrug-Resistant

Tuberculous meningoencephalitis (TBM), an infrequent disease in Western European countries, shows a wide heterogeneity of clinical symptoms.. We present 4 patients (age range 42-72 years) with the definite diagnosis of isolated TBM. All patients were HIV-seronegative, only 1 patient was known to be immunoincompetent on admission due to acute myelocytic leukemia; other reasons for immune suppression were detected in 2 other patients (leukemia and idiopathic CD4+ T-lymphocytopenia, respectively).. The diagnosis of TBM was confirmed in 3 cases by culture from CSF, in 1 case Mycobacterium tuberculosis was proven only in tracheal aspirate. In 1 patient M. bovis was found, which is an extremely rare cause of TBM in Germany. We report the contributions of different diagnostic tools (CSF analysis, neuroimaging) in reaching the presumptive diagnosis and in monitoring the further course. All patients developed neurological complications despite prompt tuberculostatic treatment. Three of the patients presented a chronic severe loss of consciousness of unclear origin.. The possible causative relationships of these complications and their impact on the prognosis are discussed.

Topics: Adult; Aged; Antitubercular Agents; Brain; Drug Therapy, Combination; Ethambutol; Female; HIV Seronegativity; Humans; Isoniazid; Lumbar Vertebrae; Magnetic Resonance Imaging; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Meningeal

The author describes the successful medical management of intramedullary tuberculous lesions in four patients who received treatment between 1994 and 1997. The role of magnetic resonance imaging and the treatment protocol for intramedullary tuberculous lesions are also discussed.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Antitubercular Agents; Clinical Protocols; Female; Follow-Up Studies; Humans; Isoniazid; Magnetic Resonance Imaging; Male; Pyrazinamide; Rifampin; Spinal Cord Diseases; Streptomycin; Tuberculoma; Tuberculosis, Central Nervous System; Tuberculosis, Meningeal; Tuberculosis, Pulmonary

The classical presentation of neurotuberculosis is meningitis. Intracranial tuberculomas are a rare manifestation of neurotuberculosis and are due to hematogenous dissemination of distant focuses of Mycobacterium tuberculosis infection. Around 1% of patients with central nervous system tuberculosis develop intracranial tuberculomas some weeks or months after the beginning of the specific treatment with tuberculostatic chemotherapy. The involution of the lesions is slow and does not mean drug resistance nor lack of adequate treatment. We describe the case, diagnosed and treated at the 25th Infirmary of Santa Casa da Misericórdia do Rio de Janeiro, of an immunocompetent male patient who developed meningitis and multiple intracranial tuberculomas during the specific treatment of miliary tuberculosis. The literature is revised and the diagnosis, treatment and possible immunological mechanisms are discussed.

Topics: Adult; Antitubercular Agents; Humans; Isoniazid; Magnetic Resonance Imaging; Male; Pyrazinamide; Rifampin; Tomography, X-Ray Computed; Tuberculoma, Intracranial; Tuberculosis, Meningeal; Tuberculosis, Miliary; Tuberculosis, Pulmonary

Tuberculosis meningitis is one of the most dangerous forms of tuberculosis (TB). Due to large waves of immigration, the incidence of TB in Israel has increased in recent years, as has that of TB meningitis. Due to its high mortality, rapid diagnosis of TB meningitis is of paramount importance. We present a patient admitted with a acute febrile disease which was subsequently diagnosed as TB meningitis.

Topics: Aged; Antitubercular Agents; Female; Humans; Incidence; Israel; Rifampin; Tuberculosis, Meningeal

We report a case of an HIV-infected child with a second episode of tuberculosis 22 months after completing antituberculosis treatment. DNA fingerprinting of organisms from both episodes showed an identical strain of Mycobacterium tuberculosis. We believe this to be the first case of confirmed relapsed tuberculosis in an HIV-infected child, and suggest that a longer course of antituberculosis treatment be given to such children. ¿ 2000 The British Infection Society.

Topics: AIDS-Related Opportunistic Infections; Amoxicillin-Potassium Clavulanate Combination; Antibiotics, Antitubercular; Antitubercular Agents; Child, Preschool; DNA, Bacterial; Drug Therapy, Combination; Ethionamide; HIV; HIV Infections; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Polymorphism, Restriction Fragment Length; Pyrazinamide; Radiography, Thoracic; Rifampin; Secondary Prevention; South Africa; Tomography, X-Ray Computed; Tuberculin Test; Tuberculosis; Tuberculosis, Meningeal

A 49-year-old male with tuberculous meningitis was reported. When admitted to our hospital with mild right hemiparesis, he was alert but he developed disorientation 7 days later. A diagnosis of tuberculous meningitis was reached because of elevated levels of adenosine-deaminase at 19.6U/liter in the cerebrospinal fluid. MRI showed a marked enhancement in the basal cisterns and an enhanced intraparenchymal lesion in the brainstem. Chronological changes of MRI findings did not closely correlate with the clinical course. Slight meningeal enhancement on MRI seems to remain for a long time without active tuberculous meningitis, and absence of the meningeal enhancement on MRI is not necessarily appropriate as a marker of cure of tuberculous meningitis.

Topics: Adenosine Deaminase; Antitubercular Agents; Biomarkers; Gadolinium DTPA; Humans; Isoniazid; Magnetic Resonance Imaging; Male; Middle Aged; Rifampin; Streptomycin; Tuberculosis, Meningeal

Tuberculous meningitis (TBM) is a devastating form of tuberculosis that occurs predominantly in children and in immunocompromised adults. To study the pathogenesis of TBM, a rabbit model of acute mycobacterial central nervous system infection was set up (8-day study). Inoculation of live Mycobacterium bovis Ravenel intracisternally induced leukocytosis (predominantly mononuclear cells), high protein levels, and release of tumor necrosis factor-alpha (TNF-alpha) into the cerebrospinal fluid within 1 day. Histologically, severe meningitis with thickening of the leptomeninges, prominent vasculitis, and encephalitis was apparent, and mortality was 75% by day 8. In animals treated with antituberculous antibiotics only, the inflammation and lesions of the brain persisted despite a decrease in mycobacteria; 50% of the rabbits died. When thalidomide treatment was combined with antibiotics, there was a marked reduction in TNF-alpha levels, leukocytosis, and brain pathology. With this combination treatment, 100% of the infected rabbits survived, suggesting a potential clinical use for thalidomide in TBM.

Topics: Animals; Antibiotics, Antitubercular; Disease Models, Animal; Drug Therapy, Combination; Immunosuppressive Agents; Isoniazid; Mycobacterium bovis; Rabbits; Rifampin; Thalidomide; Tuberculosis, Meningeal

Topics: Antitubercular Agents; Central Nervous System Infections; Dexamethasone; Drug Therapy, Combination; Ethionamide; Glucocorticoids; Humans; Immunocompetence; Infant; Isoniazid; Male; Prednisolone; Pyrazinamide; Rifampin; Streptomycin; Treatment Failure; Tuberculoma; Tuberculosis, Meningeal; Tuberculosis, Miliary; Tuberculosis, Multidrug-Resistant

Short course chemotherapy for tuberculous meningitis (TBM) is advocated by several groups, but relatively few children have been so treated and followed up.. A prospective, observational study of isoniazid (INH), rifampicin (RMP) and ethionamide (ETH) in a dosage of 20 mg/kg, and pyrazinamide (PZA) 40 mg/kg, all given once daily in hospital for 6 months. Surviving children were followed up for a year after discharge.. Ninety five children, 39 (41%) at stage III, 52 (55%) at stage II and 4 (4%) at stage I TBM were studied. Ten (26%) at stage III and 3 (6%) at stage II died before completion of therapy. Five surviving children (6%) moved on discharge and were untraceable; seven children (9%) were lost during follow up and three were inadvertently restarted on antituberculosis therapy. Two children with severe stage III disease died after discharge. One child experienced a probable disease recrudescence 1 month after discharge. Eighteen children (20%) developed a mildly elevated serum bilirubin concentration during the first month of treatment. In five of these children INH, RMP, ETH and PZA were stopped and streptomycin (SM) and ethambutol substituted. In all cases the original treatment was restarted without incident. One child developed overt jaundice after 5 months of treatment due to hepatitis A infection.. Our experience suggests that young children with TBM can be safely treated for 6 months with high doses of antituberculosis agents without overt hepatotoxicity and with a low risk of relapse.

Topics: Antibiotics, Antitubercular; Antitubercular Agents; Child; Child, Preschool; Drug Therapy, Combination; Ethionamide; Humans; Infant; Isoniazid; Prospective Studies; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Meningeal

The clinical, laboratory and radiological features of 30 children with clinically diagnosed tuberculous meningitis (TBM) who were HIV-seronegative were compared with those of ten HIV-infected children with TBM. Such comparative data are not currently available in the literature and so are an important addition to our knowledge of the HIV-TB co-infection epidemic. In comparison with the HIV-negative children, those infected with HIV were younger, had a shorter duration of symptoms and were more often Mantoux-negative (HIV-positive 23% vs HIV-negative 70%; p = 0.01). On presentation, all children in both groups were in MRC TBM stages II or III. Clinical features were similar in both groups but computed tomography of the brain showed more ventricular enlargement (HIV-positive 80% vs HIV-negative 63%), gyral enhancement (HIV-positive 60% vs HIV-negative 17%; p = 0.01) and cerebral atrophy (HIV-positive 40% vs HIV-negative 17%). Outcome was considerably worse in the HIV-positive children, of whom 30% died (vs HIV-negative 0/30; p = 0.01) and the remainder were moderately (HIV-positive 30% vs HIV-negative 24%) or severely (HIV-positive 30% vs HIV-negative 19%) handicapped at the end of treatment. While clinical features were not markedly different in HIV-infected and uninfected children with TBM, abnormal radiological findings were more common in the HIV-infected group and outcome was considerably worse. Co-existing HIV encephalopathy and diminished immune competence undoubtedly contributed to the more severe clinical and neuro-radiological features.

Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Child; Child, Preschool; HIV Seronegativity; HIV Seropositivity; Humans; Infant; Isoniazid; Mycobacterium tuberculosis; Radiography; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis, Meningeal

Topics: Antibiotics, Antitubercular; Child; Child, Preschool; Humans; Infant; Rifampin; Serum Bactericidal Test; Spectrophotometry; Tuberculosis, Meningeal

Topics: Antitubercular Agents; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Meningeal

Twenty patients of tuberculous meningitis (TBM) in age group of 6 months to 10 years included in the study were divided into two groups of 10 patients each. Rifampicin was administered in dosage of 10 mg and 7.5 mg/kg bw to each patient of groups I and II respectively. Drug concentrations in serum and CSF of these patients were measured by a microbiological tube dilution method using a strain of Sarcina lutea. In group I mean serum and CSF concentration was 3.84 micrograms/ml and 0.178 microgram/ml respectively, while in group II it was 2.16 micrograms/ml and 0.206 microgram/ml respectively. These concentrations were many times higher than the MIC against Mycobacterium tuberculosis. Mean percentage penetration of rifampicin in CSF was 5 and 10% in group I and II respectively. We recommend similar studies in large number of children before advocating the therapy with low dose of rifampicin in TBM.

Topics: Antibiotics, Antitubercular; Child; Child, Preschool; Female; Humans; Infant; Male; Rifampin; Tuberculosis, Meningeal

To elucidate a case of tuberculous choroiditis in a patient with the acquired immunodeficiency syndrome (AIDS).. We treated a 35-year-old woman who had AIDS with neurologic involvement caused by Mycobacterium tuberculosis. She developed a yellow-white chorioretinal infiltrate with indistinct borders and mild vitreitis in the right eye, probably caused by this pathogen.. The patient's visual acuity improved in the right eye with healing of the ocular lesion and her neurologic condition improved after specific therapy with isoniazid, rifampin, and ethambutol.. Tuberculosis must be considered in the differential diagnosis of posterior uveitis and choroiditis in AIDS patients.

Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Chorioretinitis; Drug Therapy, Combination; Ethambutol; Female; Fundus Oculi; HIV-1; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Sputum; Tuberculosis, Meningeal; Tuberculosis, Ocular; Visual Acuity

Topics: Adrenal Cortex Hormones; Amikacin; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antitubercular; Antitubercular Agents; Ciprofloxacin; Clarithromycin; Clofazimine; Drug Therapy, Combination; Ethambutol; HIV Infections; Humans; Isoniazid; Mycobacterium avium-intracellulare Infection; Mycobacterium Infections; Nontuberculous Mycobacteria; Practice Guidelines as Topic; Pyrazinamide; Pyridoxine; Radiography; Rifabutin; Rifampin; Tuberculosis, Meningeal; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Antineoplastic Combined Chemotherapy Protocols; Antitubercular Agents; Child, Preschool; Drug Contamination; Ethionamide; Female; Humans; Iatrogenic Disease; Immunocompromised Host; Isoniazid; Male; Meningitis, Bacterial; Mycobacterium bovis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Meningeal

Topics: Child, Preschool; Humans; Male; Peritonitis, Tuberculous; Rifampin; Tomography, X-Ray Computed; Tuberculosis, Meningeal; Tuberculosis, Miliary; Tuberculosis, Pulmonary

Tuberculosis in HIV infected patients does not carry a worse therapeutic response rate. Treatment failure is usually due to incomplete schedule, with development of acquired resistance. Two patients with HIV infection and disseminated tuberculosis who developed fatal meningitis are presented.. In vitro studies of sensitivity to anti-tuberculous drugs were carried out, using the proportions method.. Following a good initial evolution, both patients were readmitted with tuberculous meningitis resistant to isoniazide in both and to rifampicin in one of the patients. In one patient, the original strain (which was sensitive) was available. In this patient, changes in the treatment were performed in the initial phase.. The importance of anti-tuberculous multiple therapy, particularly in the initial phases, for HIV positive patients is crucial. The lengthen of admission when good patient's compliance is in question, but also to avoid, whenever possible, changes in treatment are important measures in this stage. Meningitis may occur as a form of therapeutic failure and its cure may be difficult if the strains are resistant.

Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Resistance, Microbial; Drug Therapy, Combination; Fatal Outcome; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Meningeal; Zidovudine

Topics: Adult; AIDS-Related Opportunistic Infections; Ethambutol; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Streptomycin; Superinfection; Tuberculosis, Meningeal; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Ninety-four patients, 1-13 years of age suffering from different types of tuberculosis were investigated for serum rifampicin (RIF) and isoniazid (INH) concentrations using microbiological and fluorimetric methods, respectively. Of these, 64 (68.1%) had pulmonary primary complex (PPC); 20 (21.3%) progressive primary disease (PPD) and 10 (10.6%) tuberculous meningitis (TBM). Patients with PPC, PPD and TBM were given two-drug (6HR), three drug (2HRZ, 4HR) and four drug (2SHRZ, 4HRE, 3HE) regimens, respectively. RIF and INH were administered in a dose of 12 and 10 mg/kg/day, respectively. After 10-12 days of continuous therapy, their serum concentrations were estimated at 0, 2, 4, 6, 8 hours for RIF and 0, 1, 3, 5, 7 hours for INH. For RIF, the time to achieve maximum concentrations (Tmax) was 2 hours, range of mean of maximum concentration (Cmax) 3.38 to 3.88 micrograms/ml, terminal half life elimination (T1/2) 3.03 to 3.81 hours and area under serum concentration curve (AUC) 0-8 hours 24.7 to 28.3 micrograms/ml hours in different forms of tuberculosis. INH had a Tmax of 1 h, Cmax 4.38 to 8.17 micrograms/ml, T1/2 4.0 to 4.98 hours and AUC 0-7 hours 34.1 to 57.5 micrograms/ml hours. The concentrations achieved at 7-8 hours with these dosages were much above those required for therapeutic efficacy (minimum inhibitory concentration), being 50 to 250 times for RIF and 35-60 times for INH. We recommend pharmacokinetic studies with lower doses of RIF and INH for less toxic, equally effective and cheaper antitubercular chemotherapy.

Topics: Adolescent; Child; Child, Preschool; Drug Therapy, Combination; Female; Half-Life; Humans; Infant; Isoniazid; Male; Pyrazinamide; Rifampin; Time Factors; Tuberculosis, Meningeal; Tuberculosis, Pulmonary

Topics: Child; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Prednisolone; Rifampin; Tuberculosis, Meningeal

Topics: Adolescent; Choroid Diseases; Drug Combinations; Female; Humans; Infant; Isoniazid; Male; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Meningeal; Tuberculosis, Ocular

Tuberculous meningitis is a very serious form of tuberculosis. In the absence of randomized controlled trials of alternative treatment regimens, its management depends on employing potent drugs that penetrate well into the cerebrospinal fluid (CSF). The penetration of isoniazid, rifampin, and streptomycin into the CSF of 27 Chinese patients was studied using fluorimetric and microbiologic procedures. Isoniazid rapidly diffused into the CSF, peak concentrations in excess of 3 mg/L, or over 30 times its minimal inhibitory concentration (MIC) against Mycobacterium tuberculosis being attained within 4 hr. In contrast, rifampin and streptomycin penetrated very slowly across the meninges, and CSF levels only slightly in excess of their MICs against M. tuberculosis were achieved. The penetration of the drugs into the CSF correlated poorly with differences in their partitioning between octanol/water and cyclohexane/water but could be predicted using a simple model based on their renal clearance rates and plasma protein binding. It is recommended that patients with tuberculous meningitis should be treated for at least 9 months with a combination of isoniazid, rifampin, and pyrazinamide, which may be supplemented in the first 2 mo with streptomycin.

Topics: Administration, Oral; Adult; Aged; Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Middle Aged; Models, Biological; Prognosis; Rifampin; Spinal Puncture; Streptomycin; Time Factors; Tuberculosis, Meningeal

Through analysis of the treatment in 205 patients of adult tuberculous meningitis, we considered: 1. effective and vigorous alleviation of high intracranial pressure in early stage, 2. appropriate dosage of corticosteroids and, 3. correct selection of antituberculous drugs was the mainstay for chemotherapy of tuberculous meningitis. The results were 82 patients (40.0%) were cured, 101 cases (49.3%) improved, 15 cases (7.3%) died and 7 cases (3.4%) had complications. 175 cases have been followed-up from two to five years, all of them are alive.

Topics: Adolescent; Adult; Antitubercular Agents; Drug Therapy, Combination; Female; Humans; Intracranial Pressure; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Survival Rate; Tuberculosis, Meningeal

We present a patient acutely ill from severe tuberculous meningo-encephalitis, in whom acute hepatic and renal failure, due to intercurrent septic shock, precluded the administration of full systemic dosage of antituberculous drugs. Daily direct intraventricular administration of 5 mg rifampicin, via a subcutaneous Ommaya reservoir connected to a catheter placed in the right lateral cerebral ventricle, resulted in rapid improvement without neurological sequelae. Intraventricular rifampicin administration for 50 consecutive days was well-tolerated without local or systemic side-effects. In well-selected patients with severe tuberculous meningo-encephalitis, intraventricular rifampicin may safely and highly effectively be added to systemic antituberculous therapy.

Topics: Acute Kidney Injury; Catheters, Indwelling; Cerebral Ventricles; Humans; Infusion Pumps, Implantable; Liver Diseases; Male; Meningoencephalitis; Middle Aged; Rifampin; Shock, Septic; Tuberculosis, Meningeal

This nonrandomized, open clinical investigation of tuberculous meningitis evaluated 53 children with Stage I (n = 8), Stage II (n = 29) and Stage III (n = 16) disease. The overall mortality was 20.8% (11 of 53) with a rate of sequelae of 35.7% (15 of 42) in survivors reflecting the advanced stages of children at diagnosis. Various combinations of standard antituberculous drugs including isoniazid, rifampin, pyrazinamide, streptomycin and ethambutol were given. Three treatment durations used during various time periods were evaluated: 12, 9 and 6 months with only the 6-month regimen receiving pyrazinamide (PZA). This prospective evaluation demonstrated that: (1) severe disease at presentation is highly associated with early mortality (P less than 0.05), regardless of drug regimen; and (2) intensive short course chemotherapy (6 months) with PZA, regardless of stage of disease at presentation, is more efficacious than longer course therapy (9 or 12 months) without PZA in preventing total negative outcomes and sequelae (P less than 0.05). This study demonstrates that a 6-month regimen containing PZA can be used in treating children with tuberculous meningitis.

Topics: Antitubercular Agents; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Humans; Infant; Isoniazid; Male; Prospective Studies; Pyrazinamide; Rifampin; Streptomycin; Treatment Outcome; Tuberculosis, Meningeal

Sixteen patients with oral isoniazid, pyrazinamide, rifampin, and intramuscular streptomycin for tuberculous meningitis were studied. The concentrations of isoniazid, pyrazinamide, rifampin, and streptomycin in cerebrospinal fluid (CSF) obtained 3 hours after administration were 2.40, 34.78, 0.29, and 3.78 micrograms/ml, respectively. The CSF concentrations of isoniazid and pyrazinamide were well above the minimum inhibitory concentration for Mycobacterium tuberculosis. Concentrations of rifampin and streptomycin were above the minimal inhibitory concentration initially but declined below the minimal inhibitory concentration at later times. The CSF penetration of isoniazid, pyrazinamide, rifampin, and streptomycin was about 89%, 91%, 5%, and 20%, respectively. In eight patients who received antituberculous drugs in combination with steroids, the mean CSF and serum concentrations, as well as CSF/serum ratios at various intervals of treatment, were not statistically different (p greater than 0.05) from those of the eight patients who did not receive steroids.

Topics: Adult; Aged; Antitubercular Agents; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Steroids; Streptomycin; Tuberculosis, Meningeal

In March 1986, we began a 6-month short course trial of therapy for tuberculous meningitis, in which 28 patients were analyzed. The diagnosis was based on the following cerebrospinal fluid test results: in 53.5% of the cases, Mycobacterium tuberculosis was identified by direct smear; in 57%, culture in Löwenstein-Jensen medium was positive; in 83.3%, the detection of anti-bacille Calmette-Guérin (BCG) antibodies by enzyme-linked immunosorbent assay was positive; and in 74%, the dosification of adenosine deaminase activity was positive. In addition, in 21.4% of the cases, the diagnosis was established by means of autopsy findings. Moreover, the diagnosis was supported by bacteriological analyses from another tissue or body fluids. Despite the administration of an antituberculous therapy, 32.4% of the patients died: all of the decreased had reached the last stage of the disease by the beginning of treatment. Sixteen percent of the patients who survived after more than 18 months of follow-up after therapy had ended suffered neurological sequelae. With the 6-month therapeutic regimen, the morbidity/mortality is similar to that found in the longer-course therapies. The latter regimen is therefore thought to be a good and acceptable therapeutic option for the treatment of tuberculous meningitis.

Topics: Adolescent; Adult; Aged; Child; Drug Combinations; Female; Humans; Infant; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Meningeal

Twenty-three patients with tuberculous meningitis were reviewed to see whether clinical features or initial laboratory findings could discriminate between these patients and other patients with bacterial meningitis. Nineteen patients were Danes and four immigrants. Preexisting diseases were found in eight cases. Duration of symptoms could be related to neurological sequelae, but not to death. The initial clinical picture was indistinguishable from meningitis of other causes. Microscopy of the cerebrospinal fluid (CSF) was negative in all but two cases, where acid fast bacilli were found. CSF cytology and biochemistry could not discriminate from other causes bacteria of meningitis although CSF/blood glucose ratio in 56% was below 0.3. One of the most important pieces of information in establishing an early diagnosis in tuberculous meningitis is the anamnestic information, and therapy often has to be started without knowing the microbiological data.

Topics: Adolescent; Adult; Blood Cell Count; Child; Child, Preschool; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Prednisone; Pyridoxine; Retrospective Studies; Rifampin; Tuberculosis, Meningeal

A case of tuberculous brain infection following tuberculous meningitis in a 67-year-old man is presented. It was located in an old cerebral infarct associated with left internal carotid artery occlusion. CT demonstrated capsule enhancement in the left temporal area after iodinated contrast medium. Chemotherapy with INH, RFP and SM diminished the lesion and the capsule disappeared thirteen months later. It is suggested that a relatively long clinical history together with the appearance of a thick-walled abscess-like lesion on the CT scan is consistent with the diagnosis of tuberculous brain infection, perhaps an abscess.

Topics: Aged; Brain Abscess; Cerebral Infarction; Humans; Isonicotinic Acids; Male; Rifampin; Streptomycin; Tomography, X-Ray Computed; Tuberculosis; Tuberculosis, Meningeal

A 54-year-old Chinese woman with miliary choroidal tuberculosis was followed for more than three years. She had had tuberculous meningitis for about one month before an ophthalmologic examination for blurred vision OU. There were 50 to 60 choroidal tubercles OU which were located mostly at the posterior poles including the macular areas. The meningitis and tubercular lesions resolved with antituberculous medications. In a series of fundus photographs and fluorescein angiograms, a macular subretinal neovascularization was noted in association with the tubercular lesions which resulted in disciform maculopathy. To the best of our knowledge, this case had the largest number of tubercles reported in this century, and the association of macular subretinal neovascularization with choroidal tuberculosis has never been reported.

Topics: Choroid; Ethambutol; Female; Fluorescein Angiography; Fundus Oculi; Humans; Isoniazid; Macula Lutea; Middle Aged; Neovascularization, Pathologic; Photography; Retina; Retinal Diseases; Rifampin; Tuberculosis, Meningeal; Tuberculosis, Ocular; Visual Acuity

Patients with tuberculous meningitis were treated with isoniazid and rifampicin for 12 months. To evaluate the result of treatment, we studied the outcome of patients treated from January 1979 to December 1985. Of the 51 patients, 27 were female, and 5, 25, and 21 patients were in the first, second, and third stages of the disease, respectively. Increased intracranial pressure of greater than 200 mm H2O was observed in 42 patients. Three patients required ventriculostomy, and one of them needed ventriculoperitoneal shunting. Three patients died within the first week of admission, and four patients were lost to follow-up. Forty-four patients were followed for 1 1/2 to 7 years; 31 of them recovered completely. Thirteen patients recovered with neurologic sequelae, which included mental retardation, motor weakness, seizures, and hydrocephalus. No serious side effect of the drugs were observed except for transient elevation of liver enzyme activities in four patients. The combination of isoniazid and rifampicin for 1 year, with appropriate management of increased intracranial pressure, seemed to be safe and effective enough to be used as a routine treatment of tuberculous meningitis in areas where resistance to these drugs is uncommon.

Topics: Adolescent; Child; Child, Preschool; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hydrocephalus; Infant; Intellectual Disability; Isoniazid; Male; Rifampin; Tuberculosis, Meningeal

15 patients with tuberculous meningitis were treated with isoniazid, streptomycin and rifampicin and 14 with isoniazid, streptomycin and ethambutol for 12 months. Both groups received prednisolone at the beginning of treatment. The two groups were compared with regard to clinical improvement, presence of neurological sequelae and mortality. No difference in recovery rate between the groups was observed. 6 patients (21%) died (5 in group I and 1 in group II). Residual sequelae developed in 9 cases (5 in group I and 4 in group II; 31%). The difference between the groups was not significant. The regimen including rifampicin for tuberculous meningitis did not result in any superiority compared to standard therapy.

Topics: Adolescent; Adult; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Nervous System Diseases; Prospective Studies; Rifampin; Streptomycin; Tuberculosis, Meningeal

2 cases of tuberculous meningitis are presented, 1 in a 54-year-old woman who had immigrated to Israel from Turkey 36 years before, and the other in a 10-year-old girl who recently immigrated from Ethiopia. Since diagnosis is difficult and prompt antituberculous treatment is life-saving, treatment may be instituted before the bacteriological diagnosis is established. A short term treatment of 9 months and a combination of rifampicin and isoniazid were successful in our patients.

Topics: Child; Drug Therapy, Combination; Female; Humans; Isoniazid; Middle Aged; Rifampin; Time Factors; Tuberculosis, Meningeal

Two patients with tuberculous meningitis and internuclear ophthalmoplegia are described. Despite treatment with anti-tuberculosis chemotherapy and corticosteroids, both patients died. In one case autopsy showed severe basal meningitis with diffuse brain stem infarction secondary to widespread vasculitis.

Topics: Adult; Brain Stem; Cerebral Infarction; Dexamethasone; Drug Therapy, Combination; Endarteritis; Humans; Isoniazid; Male; Middle Aged; Ophthalmoplegia; Prognosis; Pyrazinamide; Rifampin; Tuberculosis, Meningeal

The possible development of hepatotoxic effects as a result of high dosages of isoniazid, rifampin, pyrazinamide, and ethionamide was assessed in 56 young children (median age, 22 months) treated for severe tuberculous meningitis (TBM). Only one of the 56 children became jaundiced, probably as result of hepatitis A infection. Of 33 children observed for at least eight weeks, only five (15%) had normal serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase levels throughout, but in only three patients were AST or ALT values greater than 200 U/L, and enzyme levels tended to normalize toward the end of the period. In this group of 33 children, those at stage III TBM had higher enzyme levels than did those at stage II. The remaining 23 children were observed for a mean period of only four weeks, and 18 (75%) had at least one abnormal liver function test result.

Topics: Alanine Transaminase; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Child, Preschool; Drug Combinations; Ethionamide; gamma-Glutamyltransferase; Humans; Infant; Isoniazid; Liver Diseases; Pyrazinamide; Rifampin; Tuberculosis, Meningeal

Topics: Adolescent; Adult; Child; Female; Humans; Infusions, Intravenous; Male; Rifampin; Tuberculosis, Meningeal

Twenty-eight adult patients admitted consecutively with tuberculous meningitis were treated with pyrazinamide, isoniazid, rifampicin and streptomycin daily during the first two months, followed by isoniazid and rifampicin daily for seven months with intensive management of the complications during the active stage of the meningitis. Twenty-two patients completed the course of treatment and recovered with minimal morbidity in three patients. Two patients died in a vegetative state from other causes seven and nine months after the start of treatment. No evidence of recurrence of meningitis was observed in the 21 patients who were regularly observed for 12 to 29 months after completing treatment. Four patients dropped out during the early stage of treatment. Intensive chemotherapy of tuberculous meningitis with this regimen before the development of serious neurological damage can shorten the duration of treatment to nine months with a favourable outcome.

Topics: Adolescent; Adult; Aged; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Middle Aged; Prospective Studies; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Meningeal

A simple high-performance liquid chromatographic assay for the simultaneous determination of pyrazinamide and rifampicin in serum from patients with tuberculous meningitis is presented. The drugs and internal standard, p-acetamidobenzoic acid, were extracted from the acidified sample containing 2% ascorbic acid at pH 4.2 into dichloromethane-diethyl ether (2:3). The solvent extract was evaporated to dryness with the aid of nitrogen and the residue redissolved in methanol (75 microliters). The concentrate was analysed by a liquid chromatograph using a reversed-phase 30-microns C8 pre-column linked to a 5-microns C8 analytical column with a gradient solvent programme, which delivered 6% to 48% (v/v) acetonitrile in phosphate buffer (10 mM potassium dihydrogenphosphate, pH 3.5) in 10 min at 1.5 ml/min. The eluate was detected at 215 nm. Twelve patients with tuberculous meningitis were given daily chemotherapy, and their serum samples were assayed for pyrazinamide and rifampicin.

Topics: Calibration; Chromatography, High Pressure Liquid; Humans; Pyrazinamide; Rifampin; Tuberculosis, Meningeal

In an 8-month-old infant with tuberculous meningitis treatment with isoniazid was unsuccessful and was associated with lower than expected plasma concentrations of isoniazid (measured concentration 0.1 microgram/mL). The infant had received isoniazid as a crushed tablet admixed with apple sauce. Oral administration of the parenteral solution of isoniazid (Nydrazid, Squibb) mixed in apple juice produced a higher isoniazid concentration (2.9 micrograms/mL) and the child improved clinically. Pharmacokinetic studies in two subjects were performed following intramuscular injection of isoniazid and oral administration of (1) an isoniazid tablet crushed and mixed with apple sauce, (2) parenteral isoniazid solution mixed with apple juice, and (3) a commercially available syrup containing isoniazid and pyridoxine (P-I-N Forte, Lannett). Of the three oral preparations, the syrup produced the highest peak concentrations (8.3 and 6.9 micrograms/mL). The crushed tablets in apple sauce produced the lowest peak concentrations (1.4 and 2.4 micrograms/mL). Administration of crushed isoniazid tablets with food may be associated with impaired gastrointestinal absorption, lower than expected isoniazid concentrations, and treatment failure.

Topics: Administration, Oral; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Infant; Injections, Intramuscular; Intestinal Absorption; Isoniazid; Kinetics; Mycobacterium tuberculosis; Rifampin; Time Factors; Tuberculosis, Meningeal

Topics: Antibiotics, Antitubercular; Child, Preschool; Humans; Infant; Rifampin; Rifamycins; Tuberculosis, Meningeal

Topics: Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis, Meningeal

Results are presented of the incidence of hepatitis, nearly always with jaundice, among 1686 patients in clinical trials of the treatment of spinal tuberculosis, of tuberculosis meningitis and of pulmonary tuberculosis with short-course regimens containing rifampicin, isoniazid, streptomycin and pyrazinamide. The incidence was high in patients treated with daily regimens of isoniazid and rifampicin: 16-39% in children with tuberculous meningitis, 10% in patients with spinal tuberculosis (non-surgical cases), and 2-8% in those with pulmonary tuberculosis. Hepatitis, in those receiving rifampicin occurred more often in slow than in rapid acetylators of isoniazid, the proportions amongst those whose acetylator phenotype had been determined being 11% of 317 slow acetylators and 1% of 244 rapid acetylators. In children with tuberculous meningitis, the risk of hepatitis with isoniazid 20 mg/kg (39%) was higher than that with 12 mg/kg (16%), and appreciably lower in patients given rifampicin twice-weekly (5%) rather than daily (21%). There was no indication that pyrazinamide contributed to the hepatic toxicity.

Topics: Adolescent; Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Humans; Infant; Isoniazid; Jaundice; Liver; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Meningeal; Tuberculosis, Pulmonary; Tuberculosis, Spinal

There are no published data defining efficacious drug therapy for obese patients with active tuberculosis. Current dosage recommendations are based on total body weight (TBW); drug toxicity might result in obese patients receiving TBW doses. Peak and trough serum levels were measured for rifampin, streptomycin, ethambutol, and pyrazinamide in an obese patient (166 kg TBW, 87 kg ideal body weight (IBW] with miliary and meningeal tuberculosis. The observed drug levels and the calculated serum half-lives of these drugs were compared with the expected serum levels and serum half-lives in lean patients treated with literature-recommended doses. The observed serum levels in our obese patients were within the expected range for lean patients when dosage was based on IBW rather than on TBW. The observed cerebrospinal fluid penetrations of the drugs studied in our obese patient were similar to those reported in lean patients.

Topics: Adult; Antitubercular Agents; Ethambutol; Humans; Male; Obesity; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Meningeal; Tuberculosis, Miliary

Topics: Adolescent; Adult; Aminosalicylic Acid; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Prospective Studies; Pyrazinamide; Random Allocation; Rifampin; Streptomycin; Tuberculosis, Meningeal

To shed some light on the potential value of rifampicin in the treatment of tuberculous meningitis (TBM) in adults, a retrospective analysis has been made of 143 medical records from 4 hospitals for the period 1967-80. Treatment of TBM with rifampicin and other antituberculous drugs in combination (Group B) was compared to other regimes which did not include rifampicin (Group A). There were 64 patients in Group B and 79 in Group A. The two groups of patients did not differ significantly in their prognostic characteristics. The total mortality was 14.7%: it was higher among patients not treated with rifampicin (24%; Group A) than amongst those given rifampicin (3.1%; Group B; chi 2 = 10.74; p less than 0.005). The difference was also statistically significant (chi 2 = 6.88; p less than 0.01) if patients who died during the first 48 h after the institution of treatment were excluded. No significant difference in mortality rate was found when patients treated with rifampicin plus isoniazid (INH) 8-10 mg/kg (1 death out of 41 patients) were compared to patients treated with INH 15 mg/kg (2 deaths out of 20 patients). Neurological sequelae recorded during a 6 month follow-up period were more severe among patients not treated with rifampicin.

Topics: Adolescent; Adult; Child; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Retrospective Studies; Rifampin; Tuberculosis, Meningeal

A patient with tuberculous meningitis is described, who developed brainstem tuberculoma after 7 months of adequate drug therapy and while improving satisfactorily. The possible factors resulting in the development of tuberculoma are discussed. The tuberculoma responded to the medical therapy. Tuberculoma should be looked for if the condition of the patient worsens or if the patient develops new neurological signs during the course of TB meningitis.

Topics: Adolescent; Brain Stem; Female; Humans; Isoniazid; Prednisolone; Pyrazinamide; Rifampin; Tomography, X-Ray Computed; Tuberculoma; Tuberculosis, Meningeal

Topics: Aged; Antitubercular Agents; Ethambutol; Female; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculin Test; Tuberculosis; Tuberculosis, Meningeal; Tuberculosis, Miliary; Tuberculosis, Osteoarticular; Tuberculosis, Pulmonary; Tuberculosis, Urogenital

A case of tuberculous meningitis associated with cerebral tuberculomas, and resistant to antituberculous therapy is reported. Repeated injections of rifampin, administered through an intraventricular Ommaya drain, provided an effective control of the meningeal infection.

Topics: Adult; Antitubercular Agents; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Injections, Intraventricular; Male; Recurrence; Rifampin; Tuberculoma; Tuberculosis, Meningeal

Six children with tuberculous infection were given their daily prescribed doses of isoniazid by the oral and the intramuscular route on different days. The plasma concentrations reached after both routes of administration were nearly equivalent. The plasma half-life of isoniazid ranged from 1.6 to 4.8 hours. The observed plasma concentrations in these children were higher than those reported in many adults. This difference is due to the larger doses of isoniazid prescribed for children.

Topics: Administration, Oral; Adolescent; Adult; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Infant; Injections, Intramuscular; Isoniazid; Male; Phenytoin; Rifampin; Tuberculin Test; Tuberculosis, Meningeal; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Female; Humans; Male; Meningoencephalitis; Middle Aged; Retrospective Studies; Rifampin; Tuberculosis, Meningeal

Topics: Chemical and Drug Induced Liver Injury; Child; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Rifampin; Tuberculosis, Meningeal; Tuberculosis, Pleural; Tuberculosis, Pulmonary

Thirty four children with tuberculous meningitis were treated with rifampicin (mean, 17 mg/kg/day) and isoniazid (mean, 18 mg/kg/day). Fifteen (44%) showed rise in transaminase GOT and GPT values and four cases (11.7%) developed jaundice, hepatomegaly and low prothrombin levels. Rifampicin was removed in only nine of these 15 cases with signs of liver disfunction, but complete normalization of liver function and disappearance of symptoms occurred in all cases even when the treatment was not interrupted. Children are more sensitive to hepatic injury during rifampicin and isoniazid combination therapy than adults. Our results indicate very good prognosis for this hepatopathy and suggest that rifampicin need not be withdrawn in the benign situations. Removal of the rifampicin treatment may delay recovery of serious cases of tuberculous meningitis.

Topics: Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Hepatomegaly; Humans; Infant; Isoniazid; Liver Diseases; Rifampin; Transaminases; Tuberculosis, Meningeal

Serum and CSF protein electrophoresis was performed on cellulose acetate in 8 controls and 30 cases of tuberculous meningitis before treatment and during a hospitalization period of 5 months. The analysis of the CSF electrophoretic pattern showed that abnormalities in the prealbumin, beta and gamma fractions may still exist as late as 5 months after initiation of treatment. An increase in alpha 2 and decrease in the albumin fractions in the serum also persisted. Treatment for 20 weeks improved the clinical condition of the patients and resulted in a significant improvement in the CSF prealbumin and alpha 1 fractions. These findings indicate that changes in these fractions may be considered a good prognostic aid.

Topics: Adolescent; Adult; Blood Proteins; Cerebrospinal Fluid Proteins; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Prognosis; Rifampin; Streptomycin; Time Factors; Tuberculosis, Meningeal

Topics: Aminosalicylic Acid; Aminosalicylic Acids; Child; Child, Preschool; Ethambutol; Humans; Infant; Isoniazid; Pilot Projects; Rifampin; Streptomycin; Time Factors; Tuberculosis, Meningeal

Ten patients with confirmed tuberculous meningitis were seen at Meilahti Hospital, University of Helsinki, in 1966--1977. Six of the patients had a positive CSF culture for M. tuberculosis, and a positive CSF smear for acid-fast bacilli was found in one case. On admission, seven patients had an altered state of consciousness, five complained of headache, and nuchal rigidity was noted in two. Five patients recovered completely, three had persistent late sequelae, and two of the patients died. The most important fact influencing the prognosis was an early institution of adequate antituberculous chemotherapy.

Topics: Adolescent; Adult; Drug Therapy, Combination; Female; Finland; Humans; Isoniazid; Male; Middle Aged; Prognosis; Rifampin; Streptomycin; Tuberculosis, Meningeal

Twenty two children with tuberculous meningitis were treated with isoniazid, streptomycin and rifampicin and 19 were treated with isoniazid, PAS and streptomycin for at least 18 months. Both groups received corticosteroids at the beginning of treatment. The 2 groups were compared for clinical and neurological improvement, rate of recovery, the presence of neurological sequelae and for mortality. The drug toxicity of both regimens was also compared. The rate of recovery in the first 2 months of treatment was slightly more rapid in group I than in group II and neurological sequelae were less frequent in group I than in group II, but the differences between the groups were not statistically significant. There was very little difference in the death rate in both groups. A high incidence of jaundice was found amongst the children who received rifampicin.

Topics: Child; Child, Preschool; Female; Humans; Infant; Isoniazid; Male; Rifampin; Streptomycin; Tuberculosis, Meningeal

Topics: Adult; Aphasia; Carotid Artery Diseases; Carotid Artery, Internal; Cerebral Infarction; Cerebral Ventricles; Cerebrospinal Fluid; Encephalitis; Female; Humans; Male; Middle Aged; Rifampin; Streptomycin; Tuberculosis, Meningeal; Tuberculosis, Miliary; Tuberculosis, Renal

Topics: Aminosalicylic Acid; Antitubercular Agents; Drug Evaluation; Drug Therapy, Combination; Ethambutol; Ethionamide; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Meningeal

Topics: Child; Drug Therapy, Combination; Humans; Isoniazid; Rifampin; Tuberculosis, Meningeal

Topics: Age Factors; Chemical and Drug Induced Liver Injury; Female; Humans; Infant; Infant, Newborn; Male; Rifampin; Tuberculosis, Meningeal; Turkey

Topics: Female; Humans; Infant; Isoniazid; Rifampin; Tuberculosis, Meningeal

Topics: Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Meningeal

Topics: Adult; Child; Drug Evaluation; Ethambutol; Female; Humans; Male; Middle Aged; Rifampin; Time Factors; Tuberculosis, Meningeal

Topics: Blood Glucose; Child, Preschool; Drug Resistance, Microbial; Ethambutol; Glucose; Humans; Isoniazid; Lung; Male; Mycobacterium tuberculosis; Radiography; Rifampin; Salicylates; Tuberculin Test; Tuberculosis, Meningeal; Tuberculosis, Pulmonary

Topics: Humans; Rifampin; Tuberculosis, Meningeal

Topics: Child; Child, Preschool; Drug Hypersensitivity; Drug Interactions; Drug Therapy, Combination; Humans; Infant; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Meningeal

Of the 20 patients given rifampicin and isoniazid, 19 survived and one died. Twelve patients recovered from the disease without any significant neurologic defect. Seven patients had moderate to severe handicaps which included hemiparesis in four, hydrocephalus in two,mental retardation in three, and blindness in one. There was no hearing deficit. The average hospital stay in this group was 3-1/2 weeks. Among the 13 patients given streptomycin, PAS, and isoniazid, four are dead. Only three patients recovered with a completely good condition. The remainder had either single or multiple neurologic defects. The moderate degree of nerve deafness was also observed in two patients.

Topics: Adolescent; Aminosalicylic Acids; Blindness; Child; Child, Preschool; Drug Evaluation; Drug Therapy, Combination; Hemiplegia; Humans; Hydrocephalus; Infant; Infant, Newborn; Intellectual Disability; Isoniazid; Rifampin; Tuberculosis, Meningeal

Topics: Aminosalicylic Acids; Cell Migration Inhibition; Drug Hypersensitivity; Drug Therapy, Combination; Humans; Immunity, Cellular; In Vitro Techniques; Isoniazid; Macrophages; Rifampin; Tuberculosis, Lymph Node; Tuberculosis, Meningeal; Tuberculosis, Pulmonary; Tuberculosis, Renal

Topics: Adult; Child, Preschool; Female; Humans; Male; Rifampin; Tuberculosis, Meningeal

Topics: Adult; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Otitis Media; Pyridoxine; Rifampin; Tuberculosis; Tuberculosis, Meningeal

Topics: Adult; Burns; Cell Count; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Drug Therapy, Combination; Ethambutol; Humans; Kanamycin; Lymphocytes; Male; Mycobacterium; Prednisolone; Pyrazinamide; Rifampin; Tuberculosis, Meningeal; Tuberculosis, Pulmonary; Uveitis

Topics: Adult; Blood-Brain Barrier; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Meningeal

Topics: Adolescent; Adult; Alanine Transaminase; Aspartate Aminotransferases; Biopsy; Chemical and Drug Induced Liver Injury; Female; Humans; Liver; Male; Middle Aged; Rifampin; Rifamycins; Staining and Labeling; Tuberculosis, Meningeal

Topics: Adolescent; Adult; Aminosalicylic Acids; Anesthesia, General; Cross Infection; Delivery, Obstetric; Female; Fetus; Humans; Infant, Newborn; Isoniazid; Labor, Obstetric; Pregnancy; Pregnancy Complications, Infectious; Rifampin; Streptomycin; Tuberculin Test; Tuberculosis; Tuberculosis, Meningeal; Tuberculosis, Pulmonary

Topics: Blood-Brain Barrier; Humans; Rifampin; Tuberculosis, Meningeal

Topics: Adult; Ethambutol; Female; Humans; Male; Middle Aged; Rifampin; Tuberculosis, Meningeal

Topics: Adolescent; Adult; Child; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Time Factors; Tuberculosis, Meningeal

Topics: Female; Humans; Male; Rifampin; Tuberculosis, Meningeal

Topics: Ethambutol; Female; Humans; Male; Rifampin; Tuberculosis; Tuberculosis, Meningeal

Topics: Humans; Rifampin; Tuberculosis, Meningeal

Topics: Child; Female; Humans; Male; Rifampin; Tuberculosis, Meningeal