DeCure's autonomous AMR AI scientist is researching a drug-repurposing hypothesis for infectious meningitis — screening already-approved drugs against its 32-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleInfectious meningitis maps to a 32-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
approvedFlucytosineThymidylate synthase inhibitorapprovedMeropenemBacterial penicillin-binding protein inhibitor
Structures already discussed alongside infectious meningitis in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
OXA-23 mutant F110A/M221A low pH form meropenem complex — Meropenem has a real, experimentally solved structure in complex with this target (PDB 6N6V, 1.55 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet ke1drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6N6V · 1.55 Å · ligand Meropenem (KE1). Experimental structure, not a prediction.
What the evidence adds up to
In a 2018 trial of 721 HIV-positive adults with cryptococcal meningitis in Africa, an entirely oral regimen of fluconazole plus flucytosine for two weeks produced 2-week mortality of 18.2% and 10-week mortality of 35.1%. One week of amphotericin B plus flucytosine gave the lowest 10-week mortality at 24.2%. Two weeks of amphotericin B plus flucytosine produced 10-week mortality of 39.7%. Both shorter regimens met a predefined noninferiority margin compared with the standard two-week amphotericin B regimen. When amphotericin B was used, flucytosine as the partner drug was superior to fluconazole: hazard ratio for death at 10 weeks 0.62, 95% CI 0.45 to 0.84. Severe anaemia was more common with two weeks of amphotericin B than with one week or with the oral regimen.
A 2016 cost-effectiveness analysis using US prices found that a two-week course of flucytosine cost approximately $28,000, compared with about $22 per day in the United Kingdom. Despite that price, the combination of amphotericin B plus flucytosine remained cost-effective in the US model, with an incremental cost-effectiveness ratio of $23,842 per quality-adjusted life-year. The authors noted that the rising price may create access problems.
For coccidioidal meningitis, an uncontrolled 1993 trial of 47 evaluable patients given oral fluconazole 400 mg once daily for a median of 37 months reported a response rate of 79% (95% CI 61% to 90%). Response rates were similar regardless of prior treatment, HIV coinfection, or pre-existing hydrocephalus. Residual low-level cerebrospinal fluid abnormalities persisted in 15 of 20 responding patients followed for 20 months or more. No patient stopped therapy because of side effects, though confusion in two patients resolved after dose reduction.
For bacterial meningitis in children, a 1999 randomised trial of 258 children compared meropenem with cefotaxime. Among 154 fully evaluable patients, clinical cure with or without sequelae was achieved in 97% of the meropenem group and 96% of the cefotaxime group. At 5 to 7 weeks, 54% of meropenem patients and 58% of cefotaxime patients were cured with no sequelae. Seizures occurred in 12% of the meropenem group and 17% of the cefotaxime group; none were considered drug-related. A 2000 trial of 100 children with rapid initial recovery from bacterial meningitis compared four days of ceftriaxone with seven days. On day 7 there were no significant differences in fever, clinical signs, or C-reactive protein. At follow-up 1 to 3 months after discharge, neurologic sequelae were 0% in the four-day group versus 5% in the seven-day group; hearing loss was 3% versus 9%. One child in the four-day group was readmitted 53 days later with recurrent Haemophilus influenzae meningitis. A 1986 study of 50 patients with meningococcal meningitis treated with intravenous penicillin G for four days reported two deaths from fulminant infection within 36 hours and one case of aspiration pneumonia that required longer therapy; the remaining 47 patients recovered without relapse.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
New England Journal of Medicine · 2018 · 410 citations · open access
Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa
AbstractBACKGROUND: Cryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)-related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy. METHODS: We randomly assigned HIV-infected adults with cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per kilogram per day). Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. After induction treatment, all the patients received fluconazole consolidation therapy and were followed to 10 weeks. RESULTS: A total of 721 patients underwent randomization. Mortality in the oral-regimen, 1-week amphotericin B, and 2-week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one-sided 97.5% confidence interval for the difference in 2-week mortality was 4.2 percentage points for the oral-regimen group versus the 2-week amphotericin B groups and 8.1 percentage points for the 1-week amphotericin B groups versus the 2-week amphotericin B groups, both of which were below the predefined 10-percentage-point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P=0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen. CONCLUSIONS: One week of amphotericin B plus flucytosine and 2 weeks of fluconazole plus flucytosine were effective as induction therapy for cryptococcal meningitis in resource-limited settings. (ACTA Current Controlled Trials number, ISRCTN45035509 .).
Annals of Internal Medicine · 1993 · 207 citations
Fluconazole Therapy for Coccidioidal Meningitis
AbstractOBJECTIVE: To determine the efficacy and safety of fluconazole treatment of coccidioidal meningitis. DESIGN: Uncontrolled clinical trial. SETTING: Four university-based treatment centers in California, Arizona, and Texas. Most therapy was conducted without hospitalization. PATIENTS: Fifty consecutive patients with active coccidioidal meningitis, of which 47 (94%) were evaluable. Twenty-five patients had received no previous treatment for their meningitis, and nine had coinfection with human immunodeficiency virus (HIV). INTERVENTION: Fluconazole was administered in an oral dose of 400 mg once per day for up to 4 years (median, 37 months) in responding patients. Concurrent therapy with another antifungal agent was prohibited. MEASUREMENTS: Predefined assessment of infection-related abnormalities was done at the time of enrollment and was repeated at least every 4 months during treatment. Elimination of 40% or more of baseline abnormalities was considered a response. RESULTS: Thirty-seven of 47 (79%; 95% CI, 61% to 90%) evaluable patients responded to treatment. Response rates were similar for patients with and without previous therapy, for patients with and without concomitant HIV infection, and for patients with and without pre-existing hydrocephalus. Most improvement occurred within 4 to 8 months after starting treatment. Patient symptoms resolved more quickly than did cerebrospinal fluid abnormalities. In 15 of 20 responding patients followed for 20 months or more, residual low-level cerebrospinal fluid abnormalities remained throughout therapy. No patient discontinued therapy because of drug-related side effects, although confusion developed in two patients that resolved when the dose of fluconazole was reduced. CONCLUSION: Fluconazole therapy is often effective in suppressing coccidioidal meningitis.
The Pediatric Infectious Disease Journal · 1999 · 99 citations
Prospective, randomized, investigator-blinded study of the efficacy and safety of meropenem vs. cefotaxime therapy in bacterial meningitis in children
AbstractOBJECTIVES: To compare the efficacy and safety of meropenem with cefotaxime for the treatment of infants and children with bacterial meningitis. METHODS: Infants and children with strongly suspected or documented bacterial meningitis were randomly assigned in a prospective multicenter study to receive either meropenem or cefotaxime. Patients were assessed at the end of therapy and at 5 to 7 weeks and 5 to 7 months after the end of treatment for the presence of neurologic and sensory neural sequelae. RESULTS: A total of 258 children were randomized to either treatment group. A further 8 patients with suspected pneumococcal meningitis were treated with meropenem without randomization. Of the randomized patients 154 were fully evaluable, 79 in the meropenem group and 75 in the cefotaxime group. At the end of treatment there were no significant differences in clinical outcome between the two treatment groups. Clinical cure with or without sequelae was achieved in 97 and 96% of the meropenem- and cefotaxime-treated patients, respectively. At the end of treatment and at 5 to 7 weeks, 46 and 54% of meropenem patients were cured with no sequelae, respectively. Corresponding results for cefotaxime patients were 56 and 58%. All pathogens were eradicated. In total 37 patients had seizures during treatment, 15 (12%) in the meropenem and 22 (17%) in the cefotaxime group. None of the seizures was considered to be drug-related. CONCLUSIONS: This trial shows that meropenem is suitable therapy for bacterial meningitis in infants and children and that it offers an efficacy and safety profile similar to that of cefotaxime.
Archives of Internal Medicine · 1986 · 49 citations
Four Days of Penicillin Therapy for Meningococcal Meningitis
AbstractFifty consecutive patients with meningococcal meningitis aged 7 to 75 years (mean, 29 years) were treated with intravenous penicillin G sodium (2 to 3 X 10(5) U/kg/d) for four days. Two of the patients (both teenagers) died of fulminant infection during the first 36 hours of therapy and one elderly woman developed aspiration pneumonia requiring penicillin therapy to be prolonged beyond four days. The remaining 47 patients recovered from the infection. On the fourth day, fever, mild meningeal signs, and moderate elevations of cerebrospinal fluid cell counts and protein contents persisted in some patients; nevertheless, all patients were cured without relapse. The results of our study suggest that meningococcal meningitis may be successfully treated with a four-day course of intravenous penicillin G.
Cryptococcal Meningitis Treatment Strategies Affected by the Explosive Cost of Flucytosine in the United States: A Cost-effectiveness Analysis
AbstractBACKGROUND: In the United States, cryptococcal meningitis causes approximately 3400 hospitalizations and approximately 330 deaths annually. The US guidelines recommend treatment with amphotericin B plus flucytosine for at least 2 weeks, followed by fluconazole for a minimum of 8 weeks. Due to generic drug manufacturer monopolization, flucytosine currently costs approximately $2000 per day in the United States, with a 2-week flucytosine treatment course costing approximately $28 000. The daily flucytosine treatment cost in the United Kingdom is approximately $22. Cost-effectiveness analysis was performed to determine the value of flucytosine relative to alternative regimens. METHODS: We estimated the incremental cost-effectiveness ratio (ICER) of 3 cryptococcal induction regimens: (1) amphotericin B deoxycholate for 4 weeks; (2) amphotericin and flucytosine (100 mg/kg/day) for 2 weeks; and (3) amphotericin and fluconazole (800 mg/day) for 2 weeks. Costs of care were calculated using 2015 US prices and the medication costs. Survival estimates were derived from a randomized trial and scaled relative to published US survival data. RESULTS: Cost estimates were $83 227 for amphotericin monotherapy, $75 121 for amphotericin plus flucytosine, and $44 605 for amphotericin plus fluconazole. The ICER of amphotericin plus flucytosine was $23 842 per quality-adjusted life-year. CONCLUSIONS: Flucytosine is currently cost-effective in the United States despite a dramatic increase in price in recent years. Combination therapy with amphotericin and flucytosine is the most attractive treatment strategy for cryptococcal meningitis, though the rising price may be creating access issues that will exacerbate if the trend of profiteering continues.
Journal of Antimicrobial Chemotherapy · 1984 · 40 citations
Diffusion of ceftriaxone into the cerebrospinal fluid of adults
AbstractFourteen adults, three recovering from bacterial meningitis, were given a single 2 g dose of ceftriaxone or three 2 g doses at 12-hourly intervals. The mean per cent penetration of drug into cerebrospinal fluid (CSF) across uninflamed meninges was 1.5%. These levels, although low, are bactericidal in vitro against most pathogens causing meningitis.
The Pediatric Infectious Disease Journal · 2000 · 39 citations
Randomized trial of four vs. seven days of ceftriaxone treatment for bacterial meningitis in children with rapid initial recovery
AbstractBACKGROUND: Seven days or more of antimicrobial treatment is the standard for bacterial meningitis, although third generation cephalosporins are usually able to sterilize cerebrospinal fluid within 24 h. The limited experience from shorter regimens in children is encouraging, and we hypothesized that in rapidly recovering patients older than 3 months of age it would pose no risk for adverse outcome. METHODS: Strict clinical and laboratory criteria were used to define rapid initial recovery, in which case ceftriaxone therapy was either stopped after 4 days (4 injections) in children born on even dates (N = 53) or continued for 7 days in patients born on odd dates (N = 47). Outcomes were compared on Day 7 of hospitalization and at 1 to 3 months after discharge. RESULTS: On Day 7 no differences (P > 0.05 for each criteria) were observed between the 4-day and the 7-day groups regarding fever, clinical signs or serum C-reactive protein concentration. At the follow-up visit 1 to 3 months after discharge the 4-day group had fewer sequelae than the 7-day group (0% vs. 5% neurologic sequelae, P = 0.39 and 3% vs. 9% hearing loss, P = 0.49, respectively). One child in the 4-day group who had fully recovered was subsequently readmitted 53 days after the first hospitalization with recurrent Haemophilus influenzae meningitis. CONCLUSIONS: Four days of ceftriaxone therapy proved to be a safe alternative in patients with rapid initial recovery from bacterial meningitis. A 4-day course of treatment is particularly beneficial for countries with limited resources.
Journal of Antimicrobial Chemotherapy · 1981 · 23 citations
Vancomycin therapy of experimental pneumococcal meningitis caused by penicillin-sensitive and resistant strains
AbstractModels of experimental pneumococcal meningitis caused by one penicillin-sensitive and two penicillin-resistant strains were developed. Vancomycin, penicillin and chloramphenicol were delivered by continuous intravenous infusion for 8 or 24 h in several dosing schedules. Results in these rabbit models showed that: (1) vancomycin was efficacious against all three strains; (2) vancomycin was superior to penicillin or chloramphenicol therapy for penicillin-resistant strains; (3) CSF and brain concentrations of antibiotics approximating the MIC resulted in bacterial killing. Concentrations approximating the MBC were not required to achieve cure.
Disease module: DeepOracle (Open Targets). Approved indication: ChEMBL drug_indication (max_phase=4). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works, resolved on OpenAlex.
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