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Higher Dose Oral Fluconazole for the Treatment of AIDS-related Cryptococcal Meningitis (HIFLAC)—report of A5225, a multicentre, phase I/II, two-stage, dose-finding, safety, tolerability and efficacy randomised, amphotericin B-controlled trial of the AIDS Clinical Trials Group
The WHO recommended 1200mg/day of fluconazole (FCZ) in the induction phase of cryptococcal meningitis (CM) in HIV prior to 2018 in regions where amphotericin-B (AMB) was unavailable. A 2-stage AMB-controlled, dose-escalation study to determine the maximum tolerated dose and the safety/efficacy of an induction-consolidation strategy of higher doses FCZ (1200mg-2000mg/day), adjusted for weight and renal function (eGFR)in adults with CM was undertaken.
In Stage-1, three induction doses of FCZ (1200mg/day, 1600mg/day and 2000mg/day) were tested in sequential cohortsand compared with AMB in a 3:1 ratio. A particular dose was not tested in Stage 2 if there were significant predetermined safety or efficacy concerns. In Stage-2, the 1200mg dose was excluded per protocol because of increased mortality, and participants were randomised to 1600mg, 2000mg FCZ or AMB in a 1:1:1 ratio.
One hundred and sixty eight participants were enrolled with 48, 50, and 48 in the AMB, 1600mg and 2000mg cohorts. The Kaplan Meier proportion for mortality (90% CI) at 10 and 24 weeks for AMB was 17% (10, 29) and 24% (15, 37), compared to 20% (12, 32) and 30% (20, 43) for 1600mg, and 33% (23, 46) and 38% (27, 51) for 2000mg/day FCZ. With the exception of a higher incidence of gastrointestinal side effects in the 2000mg cohort, both induction doses of FCZ were safe and well tolerated. There were no life-threatening changes in electrocardiogram QTc which were similar across all doses of FCZ and AMB. The median (IQR) change in log10 cryptoccal colony forming units (CFU) from week 0 to week 2 was -8(-4.1,-1.9) for AMB; -2.5(-4.0, -1.4) for 1600mg FCZ and -8 (-3.2, -1.0) for 2000mg FCZ. The proportion (90% CI) CSF CM negative at 10 weeks was 81%(71,90) for AMB; 56%(45,69) for 1600mg FCZ and 60%(49,73) for 2000mg FCZ.
Induction phase weight and renal-adjusted doses of 1600mg and 2000mg/day FCZ for CM were safe and well tolerated except for increased GI side effects in the 2000mg/day dose, and had similar times to achieve CSF sterilization, but took significantly longer than AMB. The WHO recommended 1200mg FCZ was associated with a high mortality. While not statistically significant, mortality was numerically lower in the AMB compared to 1600mg and 2000mg FCZ These data make a case for a phase 3 study of higher doses of FZC.
Journal Article
Cryptococcus gattii VGIII Isolates Causing Infections in HIV/AIDS Patients in Southern California: Identification of the Local Environmental Source as Arboreal
Ongoing Cryptococcus gattii outbreaks in the Western United States and Canada illustrate the impact of environmental reservoirs and both clonal and recombining propagation in driving emergence and expansion of microbial pathogens. C. gattii comprises four distinct molecular types: VGI, VGII, VGIII, and VGIV, with no evidence of nuclear genetic exchange, indicating these represent distinct species. C. gattii VGII isolates are causing the Pacific Northwest outbreak, whereas VGIII isolates frequently infect HIV/AIDS patients in Southern California. VGI, VGII, and VGIII have been isolated from patients and animals in the Western US, suggesting these molecular types occur in the environment. However, only two environmental isolates of C. gattii have ever been reported from California: CBS7750 (VGII) and WM161 (VGIII). The incongruence of frequent clinical presence and uncommon environmental isolation suggests an unknown C. gattii reservoir in California. Here we report frequent isolation of C. gattii VGIII MATα and MATa isolates and infrequent isolation of VGI MATα from environmental sources in Southern California. VGIII isolates were obtained from soil debris associated with tree species not previously reported as hosts from sites near residences of infected patients. These isolates are fertile under laboratory conditions, produce abundant spores, and are part of both locally and more distantly recombining populations. MLST and whole genome sequence analysis provide compelling evidence that these environmental isolates are the source of human infections. Isolates displayed wide-ranging virulence in macrophage and animal models. When clinical and environmental isolates with indistinguishable MLST profiles were compared, environmental isolates were less virulent. Taken together, our studies reveal an environmental source and risk of C. gattii to HIV/AIDS patients with implications for the >1,000,000 cryptococcal infections occurring annually for which the causative isolate is rarely assigned species status. Thus, the C. gattii global health burden could be more substantial than currently appreciated.
Journal Article
Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America
Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)–infected individuals, (2) organ transplant recipients, and (3) non–HIV-infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource-limited environments, and those with Cryptococcus gattii infection. Recommendations for management also include other sites of infection, including strategies for pulmonary cryptococcosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and cryptococcomas. Three key management principles have been articulated: (1) induction therapy for meningoencephalitis using fungicidal regimens, such as a polyene and flucytosine, followed by suppressive regimens using fluconazole; (2) importance of early recognition and treatment of increased intracranial pressure and/or IRIS; and (3) the use of lipid formulations of amphotericin B regimens in patients with renal impairment. Cryptococcosis remains a challenging management issue, with little new drug development or recent definitive studies. However, if the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, then cryptococcosis can be managed successfully in the vast majority of patients.
Journal Article
A Phase II Randomized Trial of Amphotericin B Alone or Combined with Fluconazole in the Treatment of HIV-Associated Cryptococcal Meningitis
Background. Cryptococcosis is a life-threatening infection among patients with human immunodeficientcy virus (HIV) infection. Therapeutic options for the treatment of central nervous system cryptococcosis are limited, especially in resource-limited settings. Methods. We conducted a randomized, open-label, phase II trial in Thailand and the United States that compared the safety and efficacy of intravenous amphotericin B deoxycholate (AmB) 0.7 mg/kg (the standard therapy) with that of AmB 0.7 mg/kg plus fluconazole 400 mg (the low-dosage combination) or AmB 0.7 mg/kg plus fluconazole 800 mg (the high-dosage combination) administered daily for 14 days, followed by fluconazole alone at the randomized dosage (400 or 800 mg per day) for 56 days. The primary safety end point was the number of severe or life-threatening treatment-related toxicities; the primary efficacy end point was a composite of survival, neurologic stability, and negative cerebrospinal fluid culture results after 14 days of therapy. Results. A total of 143 patients were enrolled. There were no differences in treatment-related toxicities among the 3 arms. Toxicity was predictable and was most often related to AmB, and it included electrolyte abnormalities, anemia, nephrotoxicity, and infusion-related events. At day 14, 41%, 27%, and 54% of patients in the standard therapy, low-dosage combination, and high-dosage combination therapy arms, respectively, demonstrated successful outcomes. A trend towards better outcomes in the combination therapy arms was seen at days 42 and 70. Conclusions. AmB plus fluconazole administered at a dosage of 800 mg for 14 days, followed by fluconazole administered at a dosage of 800 mg daily for 56 days, is well-tolerated and efficacious among HIV-positive patients with central nervous system cryptococcosis. These results have significant treatment implications and should be validated in a randomized phase III trial. Clinical trials registration. This clinical trial is registered in the National Library of Medicine's registry (http://www.clinicaltrials.gov) under the registration number NCT00145249.
Journal Article
A Prospective Observational Study of Candidemia: Epidemiology, Therapy, and Influences on Mortality in Hospitalized Adult and Pediatric Patients
We conducted a prospective, multicenter observational study of adults (n = 1447) and children (n = 144) with candidemia at tertiary care centers in the United States in parallel with a candidemia treatment trial that included nonneutropenic adults. Candida albicans was the most common bloodstream isolate recovered from adults and children (45% vs. 49%) and was associated with high mortality (47% among adults vs. 29% among children). Three-month survival was better among children than among adults (76% vs. 54%; P < .001). Most children received amphotericin B as initial therapy, whereas most adults received fluconazole. In adults, Candida parapsilosis fungemia was associated with lower mortality than was non-parapsilosis candidemia (24% vs. 46%; P < .001). Mortality was similar among subjects with Candida glabrata or non-glabrata candidemia; mortality was also similar among subjects with C. glabrata candidemia who received fluconazole rather than other antifungal therapy. Subjects in the observational cohort had higher Acute Physiology and Chronic Health Evaluation II scores than did participants in the clinical trial (18.6 vs. 16.1), which suggests that the former subjects are more often excluded from therapeutic trials.
Journal Article
Cryptococcal Immune Reconstitution Inflammatory Syndrome after Antiretroviral Therapy in AIDS Patients with Cryptococcal Meningitis: A Prospective Multicenter Study
A prospective multicenter study of cryptococcal immune reconstitution inflammatory syndrome (IRIS) was conducted as a substudy of the Bacteriology and Mycology Study Group 3-01. Of 101 AIDS patients with cryptococcal meningitis who received highly active antiretroviral therapy (HAART), 13 experienced cryptococcal IRIS. No association between the timing of HAART initiation and the diagnosis of IRIS was identified. Increased baseline serum cryptococcal antigen (CrAg) titer was a risk factor for cryptococcal IRIS.
Journal Article
Higher hospital level does not improve 30-day survival after road traffic accidents
Globally, road traffic accidents (RTAs) remain a major cause of death, particularly among individuals aged 15–30 years. While Sweden has been at the forefront of traffic safety through the
Vision Zero
initiative, in-hospital management remains crucial in determining RTA outcomes. Drawing on North American evidence suggesting improved survival at trauma centres, the Swedish healthcare system has increasingly emphasised trauma centralisation. However, comprehensive national data from Sweden are scarce. Given the country’s unique demographic and geographic characteristics, including vast sparsely populated areas, direct comparisons with other Western systems are challenging. We analysed the epidemiology and risk factors for 30-day mortality among 95,954 RTA-related hospital admissions in Sweden between 2008 and 2021. Predictors included the ICD-based Injury Severity Score (ICISS), age, sex, Charlson Comorbidity Index (CCI), year of event, and hospital level. Mortality risk was modelled using explainable artificial intelligence (XAI) via Extreme Gradient Boosting (XGBoost) with SHapley Additive exPlanations (SHAP), alongside conventional multivariable logistic regression for comparison. The most influential predictors of 30-day mortality, in descending order, were ICISS, age, CCI, event year, hospital level, and sex. A clear trend toward centralisation was observed, with Level 1 hospitals admitting the most severely injured patients. However, after risk adjustment, the hospital level was not independently associated with 30-day mortality. The XAI model outperformed logistic regression in both discrimination and calibration, confirming these findings. This study represents a comprehensive national analysis of in-hospital outcomes following RTAs in Europe. ICISS, age, sex, and comorbidity influenced mortality risk, while overall survival improved over time. The assumption that trauma centralisation confers a universal survival advantage does not appear to hold in the Swedish context. These findings underscore the need to re-evaluate trauma system design under Scandinavian conditions—ensuring that timely access to hospital care is not compromised by centralisation.
Journal Article
Violation of Bell inequality by photon scattering on a two-level emitter
Entanglement, the non-local correlations present in multipartite quantum systems, is a key resource for quantum technologies. It is therefore a major priority to develop simple and energy-efficient methods for generating high-fidelity entangled states. In the case of light, entanglement can be realized by interactions with matter but the required nonlinear interaction is often impractically weak. Here we show how a single two-level emitter deterministically coupled to light in a nanophotonic waveguide can be used to realize photonic quantum entanglement by excitation at the single-photon level. Efficient optical coupling enables mediation of two-photon interactions by the emitter, creating a strong nonlinearity that leads to entanglement. We experimentally verify energy–time entanglement by violating a Bell inequality in an interferometric measurement of the two-photon scattering response. The on-chip two-level emitter acts as a passive scatterer, so that no advanced spin control is required. As such, our method may provide a more efficient approach to synthesizing photonic entangled states for quantum simulators or metrology.
A semiconductor quantum dot can passively mediate interactions between two photons, enabling the creation of entangled photon states.
Journal Article