Background Cryptococcus is the most common cause of adult meningitis in Africa. We evaluated the activity of adjunctive sertraline, previously demonstrated to have in vitro and in vivo activity against Cryptococcus. Methods We enrolled 172 HIV-infected Ugandans with cryptococcal meningitis from August 2013 through August 2014 into an open-label dose-finding study to assess safety and microbiologic efficacy. Sertraline 100–400mg/day was added to standard therapy of amphotericin + fluconazole 800mg/day. We evaluated early fungicidal activity via Cryptococcus cerebrospinal fluid (CSF) clearance rate, sertraline pharmacokinetics, and in vitro susceptibility. Findings Participants receiving any sertraline dose averaged a CSF clearance rate of −0·37 (95%CI: −0·41, −0·33) colony forming units (CFU)/mL/day. Incidence of paradoxical immune reconstitution inflammatory syndrome (IRIS) was 5% (2/43) and relapse was 0% through 12-weeks. Sertraline reached steady state concentrations in plasma by day 7, with median steady-state concentrations of 201 ng/mL (IQR, 90–300; n=49) with 200mg/day and 399 ng/mL (IQR, 279–560; n=30) with 400mg/day. Plasma concentrations reached 83% of steady state levels by day 3. The median projected steady state brain tissue concentration at 200mg/day was 3·7 (IQR, 2·0–5·7) mcg/mL and 6·8 (IQR, 4·6–9·7) mcg/mL at 400mg/day. Minimum inhibitory concentrations were ≤2 mcg/mL for 27% (35/128), ≤4 mcg/mL for 84% (108/128), ≤6 mcg/mL for 91% (117/128), and ≤8 mcg/mL for 100% of 128 Cryptococcus isolates. Interpretation Sertraline had faster cryptococcal CSF clearance, decreased IRIS, and decreased relapse compared with historical experiences. Sertraline reaches therapeutic levels in a clinical setting. This inexpensive and off-patent oral medication is a promising adjunctive antifungal therapy. Funding National Institutes of Health, Grand Challenges Canada.
Introduction TB meningitis (TBM) diagnosis is difficult and novel diagnostic methods are needed. The World Health Organization recommends Xpert MTB/RIF (Xpert) as the initial TBM diagnostic test, based on two studies reporting suboptimal sensitivity (~50–60%). Objective To study the effect of cerebrospinal fluid (CSF) centrifugation on Xpert performance for TBM detection. Design 107 predominantly HIV-infected adults with suspected meningitis were screened prospectively in Kampala, Uganda. CSF was tested by 1) microscopy for acid-fast bacilli; 2) Mycobacteria growth indicator tube culture; 3) Xpert of 2mL of unprocessed CSF; 4) Xpert of centrifuged CSF. Diagnostic performance was measured against an a priori composite reference standard of any positive CSF tuberculosis test. Results 17% (18/107) of participants had definite TBM. When CSF was centrifuged, Xpert had better sensitivity (72%, 13/18) than when using 2mL of unprocessed CSF (28%, 5/18; P=0.008). The median centrifuged CSF volume was 6mL (IQR 4–10mL). Mycobacterial culture yielded 71% (12/17) sensitivity at a median delay of 27 days. Only 39% were positive both by culture and centrifuged Xpert, with additional cases detected by Xpert and culture. Conclusions Centrifuging of CSF optimizes Xpert diagnostic performance for detection of TBM. A combination of culture and Xpert detected the largest number of cases.
Background Cryptococcal meningitis is a leading cause of HIV-related mortality in sub-Saharan Africa. Based on phase-II data, we performed a phase-III randomized controlled non-inferiority trial to determine the efficacy of a single high-dose liposomal amphotericin B based treatment regimen. Methods HIV-positive adults with cryptococcal meningitis in Botswana, Malawi, South Africa, Uganda and Zimbabwe were randomized 1:1 to induction therapy of either (i) single, high-dose liposomal amphotericin B 10mg/kg given with 14 days of flucytosine 100mg/kg/day and fluconazole 1200mg/day (AmBisome group), or (ii) the current WHO recommended treatment of 7 daily doses of amphotericin B deoxycholate (1mg/kg/day) plus flucytosine (100mg/kg/day), followed by 7 days of fluconazole 1200mg/day (control group). The primary endpoint was all-cause mortality at 10 weeks with the trial powered to show non-inferiority at a 10% margin. Results We randomized 844 participants. None were lost-to-follow-up. In intention-to-treat analysis, 10-week mortality was 24.8% (101 of 407; 95% confidence interval [CI] 20.7-29.3%) in the AmBisome group and 28.7% (117 of 407; 95% CI 24.4-33.4%) in controls. The absolute difference in mortality was -3.9%, with an upper 1-sided 95% confidence interval of 1.2%. Fungal clearance from cerebrospinal fluid was -0.40 log 10 CFU/ml/day in the AmBisome group and -0.42 log 10 CFU/ml/day in the control group. Fewer participants experienced grade 3 or 4 adverse events in the AmBisome group than the control group (50.0% vs. 62.3%). Conclusions Single dose liposomal amphotericin B (10mg/kg) on a backbone of flucytosine and fluconazole was non-inferior to the current WHO recommended standard of care for HIV-associated cryptococcal meningitis and associated with fewer adverse events. (Trial registration number: ISRCTN72509687.)
Background: Identifying new antifungals for cryptococcal meningitis remains a priority given the inadequacy of current therapy. Sertraline has previously demonstrated in vitro and in vivo activity against Cryptococcus. We evaluated the efficacy of adjunctive sertraline for cryptococcal meningitis in a double-blind, randomised, placebo-controlled clinical trial. Methods: We assessed 18-week survival among HIV-infected Ugandan adults with cryptococcal meningitis enrolled from 09 March 2015 to 29 May 2017. Participants were randomly assigned to receive standard therapy with 7-14 days of amphotericin (0•7-1•0 mg/kg/day) + fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. Randomisation in a 1:1 ratio was performed with variable block sizes of 2 and 4, with stratification by site (Kampala or Mbarara) and antiretroviral status (experienced or naïve). Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, number .
The epidemiology of infectious causes of meningitis in sub-Saharan Africa is not well understood, and a common cause of meningitis in this region, Mycobacterium tuberculosis (TB), is notoriously hard to diagnose. Here we show that integrating cerebrospinal fluid (CSF) metagenomic next-generation sequencing (mNGS) with a host gene expression-based machine learning classifier (MLC) enhances diagnostic accuracy for TB meningitis (TBM) and its mimics. 368 HIV-infected Ugandan adults with subacute meningitis were prospectively enrolled. Total RNA and DNA CSF mNGS libraries were sequenced to identify meningitis pathogens. In parallel, a CSF host transcriptomic MLC to distinguish between TBM and other infections was trained and then evaluated in a blinded fashion on an independent dataset. mNGS identifies an array of infectious TBM mimics (and co-infections), including emerging, treatable, and vaccine-preventable pathogens including Wesselsbron virus, Toxoplasma gondii, Streptococcus pneumoniae, Nocardia brasiliensis, measles virus and cytomegalovirus. By leveraging the specificity of mNGS and the sensitivity of an MLC created from CSF host transcriptomes, the combined assay has high sensitivity (88.9%) and specificity (86.7%) for the detection of TBM and its many mimics. Furthermore, we achieve comparable combined assay performance at sequencing depths more amenable to performing diagnostic mNGS in low resource settings.
Introduction Tuberculous meningitis accounts for 1-5% of tuberculosis cases. Diagnostic delay contributes to poor outcomes. We evaluated the performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis diagnosis. Methods In this prospective validation study, we tested the cerebrospinal fluid (CSF) of adults presenting with suspected meningitis (ie, headache or altered mental status with clinical signs of meningism) to the Mulago National Referral Hospital and Mbarara Regional Referral Hospital in Uganda. We centrifuged the CSF, resuspended the cell pellet in 2 mL CSF, and tested 0•5 mL aliquots with Xpert Ultra, Xpert MTB/RIF (Xpert), and mycobacterial growth indicator tube (MGIT) culture. We quantified diagnostic performance against the uniform case definition of probable or definite tuberculous meningitis and a composite microbiological reference standard. Findings From Nov 25, 2016, to Jan 24, 2019, we screened 466 adults with suspected meningitis and tested 204 for tuberculous meningitis. Uniform clinical case definition classified 51 participants as having probable or definite tuberculous meningitis. Against this uniform case definition, Xpert Ultra had 76•5% sensitivity (95% CI 62•5-87•2; 39 of 51 patients) and a negative predictive value of 92•7% (87•6-96•2; 153 of 165), compared with 55•6% sensitivity (44•0-70•4; 25 of 45; p=0•0010) and a negative predictive value of 85•8% (78•9-91•1; 121 of 141) for Xpert and 61•4% sensitivity (45•5-75•6; 27 of 44; p=0•020) and negative predictive value of 85•2% (77•4-91•1; 98 of 115) for MGIT culture. Against the composite microbiological reference standard, Xpert Ultra had sensitivity of 92•9% (80•5-98•5; 39 of 42), higher than Xpert at 65•8% (48•6-80•4; 25 of 38; p=0•0063) and MGIT culture at 72•2% (55•9-86•2; 27 of 37; p=0•092). Xpert Ultra detected nine tuberculous meningitis cases missed by Xpert and MGIT culture. Interpretation Xpert Ultra detected tuberculous meningitis with higher sensitivity than Xpert and MGIT culture in this HIV-positive population. However, with a negative predictive value of 93%, Xpert Ultra cannot be used as a ruleout test. Clinical judgment and novel highly sensitive point-of-care tests are still required.
Tuberculous meningitis (TBM) results from dissemination of M. tuberculosis to the cerebrospinal fluid (CSF) and meninges. Ischaemia, hydrocephalus and raised intracranial pressure frequently result, leading to extensive brain injury and neurodisability. The global burden of TBM is unclear and it is likely that many cases are undiagnosed, with many treated cases unreported. Untreated, TBM is uniformly fatal, and even if treated, mortality and morbidity are high. Young age and human immunodeficiency virus (HIV) infection are potent risk factors for TBM, while Bacillus Calmette–Guérin (BCG) vaccination is protective, particularly in young children. Diagnosis of TBM usually relies on characteristic clinical symptoms and signs, together with consistent neuroimaging and CSF parameters. The ability to confirm the TBM diagnosis via CSF isolation of M. tuberculosis depends on the type of diagnostic tests available. In most cases, the diagnosis remains unconfirmed. GeneXpert MTB/RIF and the next generation Xpert Ultra offer improved sensitivity and rapid turnaround times, and while roll-out has scaled up, availability remains limited. Many locations rely only on acid fast bacilli smear, which is insensitive. Treatment regimens for TBM are based on evidence for pulmonary tuberculosis treatment, with little consideration to CSF penetration or mode of drug action required. The World Health Organization recommends a 12-month treatment course, although data on which to base this duration is lacking. New treatment regimens and drug dosages are under evaluation, with much higher dosages of rifampicin and the inclusion of fluoroquinolones and linezolid identified as promising innovations. The inclusion of corticosteroids at the start of treatment has been demonstrated to reduce mortality in HIV-negative individuals but whether they are universally beneficial is unclear. Other host-directed therapies show promise but evidence for widespread use is lacking. Finally, the management of TBM within health systems is sub-optimal, with drop-offs at every stage in the care cascade.
Background There is substantial variation in the reported treatment outcomes for adult tuberculous meningitis (TBM). Data on survival and neurological disability by continent and HIV serostatus are scarce. Methods We performed a systematic review and meta-analysis to characterize treatment outcomes for adult TBM. Following a systematic literature search (MEDLINE and EMBASE), studies underwent duplicate screening by independent reviewers in two stages to assess eligibility for inclusion. Two independent reviewers extracted data from included studies. We employed a random effects model for all meta-analyses. We evaluated heterogeneity by the I2 statistic. Results We assessed 2,197 records for eligibility; 39 primary research articles met our inclusion criteria reporting on treatment outcomes for 5,752 adults with TBM. The commonest reported outcome measure was six-month mortality. Pooled six-month mortality was 24% and showed significant heterogeneity (I2 >95%; p<0·01). Mortality ranged from 2% to 67% in Asian studies and from 23% to 80% in sub-Saharan African studies. Mortality was significantly worse in HIV-positive adults at 57% (95%CI; 48-67%), compared with 16% (95%CI; 10-24%) in HIV-negative adults (p<0·01). Physical disability was reported in 32% (95%CI; 22-43%) of adult TBM survivors. There was considerable heterogeneity between studies in all meta-analyses with I2 statistics consistently >50%. Conclusions Mortality in adult TBM is high and varies considerably by continent and HIV-status. The highest mortality is amongst HIV-positive adults in sub-Saharan Africa. Standardized reporting of treatment outcomes will be essential to improve future data quality and increase potential for data sharing, meta-analyses, and facilitating multi-center tuberculosis research to improve outcomes.
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