The role of age and mode of delivery in the STEPS intervention: a longitudinal pilot-study in treatment of posttraumatic stress symptoms in Danish survivors of sexual assault

Background: The STEPS programme has been succesfully implemented as a group-based treatment of trauma symptoms after rape for adolescents. The STEPS intervention was translated from Dutch to Danish and offered to adults in addition to adolescents as well as an individual intervention in addition to a group-based intervention at a Danish Centre for Rape Victims through 2011 to 2014. The programme was translated from Dutch to Danish and expanded to adults in addition to adolescents as well as to an individual intervention in addition to a group-based intervention at a Danish Centre for Rape Victims through 2011 to 2014. Objective: The present study observes  development in trauma symptoms and ICD-11 diagnostic status during an adapted version of the intervention programme ‘STEPS’ for survivors of sexual assault. Methods: A prospective uncontrolled study was conducted, monitoring symptoms of posttraumatic stress and other trauma-related symptomatology before treatment, after treatment and at 6 and 12 months' follow up for 103 referrals receiving individual or group-based STEPS. Tentative diagnoses of posttraumatic stress disorder (PTSD) and complex PTSD were assigned to participants according to the ICD-11 to observe the development in diagnostic status across time, and multilevel modelling was used to assess the development of symptom severity and to assess the moderating effect of age-group and mode of delivery. Results: A loglinear function representing large and statistically significant decline in symptomatology over time provided the best fit for all measures of trauma-related symptomatology. The decline was not moderated by age-group or mode of intervention. Dropout rates were independent of mode of intervention and age. Conclusion: The adaption of the STEPS programme to adults and as an individual intervention is feasible and maintains effect sizes comparable to those observed in the original intervention. Further research using randomized controlled trials is needed to ascribe the observed effect to the STEPS programme

Treatment of HIV-associated cryptococcal meningitis in South Africa: The case for amphotericin B over conventional dose fluconazole for initial therapy

Cryptococcal meningitis is a major cause of morbidity and mortality in African AIDS patients, accounting for between 13% and 17% of deaths in Ugandan HIV-infected individuals(1,2) and 44% of deaths in a cohort of HIV-seropositive South African miners.(3) This burden of disease is a result of high incidence, especially in southern and East Africa, and high acute mortality.(4,6) In much of Africa, fluconazole rather than amphotericin B was, and still is, widely used as initial therapy, for a variety of reasons. These include the availability of fluconazole through free access programmes and in generic form, and the attractiveness of an easy to. use, safe oral regimen over a difficult to administer intravenous drug with significant side-effects, requiring inpatient admission and close laboratory monitoring. In addition, in the absence of antiretroviral therapy, treatment of cryptococcal meningitis has in the recent past been palliative rather than curative, reducing the rationale for more aggressive therapy, if this is associated with increased side-effects. However, what data there are suggest that outcomes with fluconazole at conventional dosage (up to 400 mg/d) as initial therapy are poor. In addition, the cost of amphotericin B, previously considerable in South Africa, has been reduced! More importantly, increasing access to antiretroviral therapy (ART) now means that the long-term prognosis of patients with cryptococcal meningitis is good, provided they survive the acute infection.(8) We summarise the evidence that a factor contributing to high acute mortality in cryptococcal meningitis is the inadequacy of fluconazole at up to 400 mg/d as an induction regimen, and present the case for initial treatment with amphotericin B in South Africa, where feasible

Treatment of HIV-associated cryptococcal meningitis in South Africa: The case for amphotericin B over conventional dose fluconazole for initial therapy

Cryptococcal meningitis is a major cause of morbidity and mortality in African AIDS patients, accounting for between 13% and 17% of deaths in Ugandan HIV-infected individuals1,2 and 44% of deaths in a cohort of HIV-seropositive South African miners.3 This burden of disease is a result of high incidence, especially in southern and East Africa, and high acute mortality.4-6 In much of Africa, fluconazole rather than amphotericin B was, and still is, widely used as initial therapy, for a variety of reasons. These include the availability of fluconazole through free access programmes and in generic form, and the attractiveness of an easy to use, safe oral regimen over a difficult to administer intravenous drug with significant side-effects, requiring inpatient admission and close laboratory monitoring. In addition, in the absence of antiretroviral therapy, treatment of cryptococcal meningitis has in the recent past been palliative rather than curative, reducing the rationale for more aggressive therapy, if this is associated with increased side-effects. However, what data there are suggest that outcomes with fluconazole at conventional dosage (up to 400 mg/d) as initial therapy are poor. In addition, the cost of amphotericin B, previously considerable in South Africa, has been reduced.7 More importantly, increasing access to antiretroviral therapy (ART) now means that the long-term prognosis of patients with cryptococcal meningitis is good, provided they survive the acute infection.8 We summarise the evidence that a factor contributing to high acute mortality in cryptococcal meningitis is the inadequacy of fluconazole at up to 400 mg/d as an induction regimen, and present the case for initial treatment with amphotericin B in South Africa, where feasible. Southern African Journal of HIV Medicine Vol. 8 (3) 2007: pp. 36-3

Early versus delayed antiretroviral treatment in HIV-positive people with cryptococcal meningitis.

BACKGROUND: There remains uncertainty about the optimum timing of antiretroviral therapy (ART) initiation in HIV-positive people with cryptococcal meningitis. This uncertainty is the result of conflicting data on the mortality risk and occurrence of immune reconstitution inflammatory syndrome (IRIS) when ART is initiated less than four weeks after cryptococcal meningitis treatment is commenced. OBJECTIVES: To compare the outcomes of early initiation of ART (less than four weeks after starting antifungal treatment) versus delayed initiation of ART (four weeks or more after starting antifungal treatment) in HIV-positive people with concurrent cryptococcal meningitis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for trials published between 1 January 1980 and 7 August 2017. We additionally searched international trial registries, including ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP), and conference abstracts from the International AIDS Society (IAS) and the Conference on Retroviruses and Opportunistic Infections (CROI) for ongoing or unpublished studies between 2015 and 2017. We reviewed reference lists of included studies to identify additional studies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared early versus delayed ART initiation in HIV-positive people with cryptococcal meningitis. Children, adults, and adolescents from any setting were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the inclusion criteria and extracted data. We presented dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CIs). We presented time-to-death data as hazard ratios with 95% CIs. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Four trials including 294 adult participants met the inclusion criteria of this review. Participants were predominantly from low- and middle-income countries. Two trials treated cryptococcal meningitis with amphotericin B and fluconazole; a third trial used fluconazole monotherapy; and the fourth trial did not specify the antifungal used.Early ART initiation may increase all-cause mortality compared to delayed ART initiation (RR 1.42, 95% CI 1.02 to 1.97; 294 participants, 4 trials; low-certainty evidence). Early ART initiation may reduce relapse of cryptococcal meningitis compared to delayed ART initiation (RR 0.27, 95% CI 0.07 to 1.04; 205 participants, 2 trials, low-certainty evidence). We are uncertain whether early ART initiation increases or reduces cryptococcal IRIS events compared to delayed ART initiation (RR 3.56, 95% CI 0.51 to 25.02; 205 participants, 2 trials; I2 = 54%; very low-certainty evidence). We are uncertain if early ART initiation increases or reduces virological suppression at six months compared to delayed ART initiation (RR 0.93, 95% CI 0.72 to 1.22; 205 participants, 2 trials; I2 statistic = 0%; very low-certainty evidence).We were unable to pool results related to rate of fungal clearance for the two trials that reported this outcome; individual trial results indicated that there was no difference in cerebrospinal fluid fungal clearance between trial arms. Similarly, we were unable to pool results on adverse events for the trials reporting on this outcome; individual trial results indicated no difference in the occurrence of grade 3 to 5 adverse events between trial arms.Three of the four included trials had an overall low or unclear risk of bias related to the primary outcome of all-cause mortality. However, we assessed one trial as at high risk of bias due to selective outcome reporting and other bias. This, in addition to the few clinical events and imprecision of effect estimates, led to downgrading of the evidence to low or very low certainty. AUTHORS' CONCLUSIONS: The results of this review are relevant to HIV-positive adults with cryptococcal meningitis in low- and middle-income countries. These data suggest a higher risk of mortality among people who initiate ART within four weeks of cryptococcal meningitis diagnosis. However, it is unclear if this higher mortality risk is related to cryptococcal meningitis-IRIS

Invasive candidiasis in critical care: challenges and future directions.

Invasive candidiasis is the most common critical care-associated fungal infection with a crude mortality of ~ 40-55%. Important factors contributing to risk of invasive candidiasis in ICU include use of broad-spectrum antimicrobials, immunosuppressive drugs, and total parenteral nutrition alongside iatrogenic interventions which breach natural barriers to infection [vascular catheters, renal replacement therapy, extracorporeal membrane oxygenation (ECMO), surgery]. This review discusses three key challenges in this field. The first is the shift in Candida epidemiology across the globe to more resistant non-albicans species, in particular, the emergence of multi-resistant Candida glabrata and Candida auris, which pose significant treatment and infection control challenges in critical care. The second challenge lies in the timely and appropriate initiation and discontinuation of antifungal therapy. Early antifungal strategies (prophylaxis, empirical and pre-emptive) using tools such as the Candida colonisation index, clinical prediction rules and fungal non-culture-based tests have been developed: we review the evidence on implementation of these tools in critical care to aid clinical decision-making around the prescribing and cessation of antifungal therapy. The third challenge is selection of the most appropriate antifungal to use in critical care patients. While guidelines exist to aid choice, this heterogenous and complex patient group require a more tailored approach, particularly in cases of acute kidney injury, liver impairment and for patients supported by extracorporeal membrane oxygenation. We highlight key research priorities to overcome these challenges in the future

Cryptococcus neoformans ex vivo capsule size is associated with intracranial pressure and host immune response in HIV-associated cryptococcal meningitis

<p>Background. The Cryptococcus neoformans polysaccharide capsule is a well-characterised virulence factor with immunomodulatory properties. The organism and/or shed capsule is postulated to raise intracranial pressure(ICP) in cryptococcal meningitis(CM) by mechanical obstruction of cerebrospinal fluid(CSF) outflow. Little is known regarding capsule phenotype in human cryptococcosis. We investigated the relationship of ex vivo CSF capsular phenotype with ICP and CSF immune response, as well as in vitro phenotype.</p> <p>Methods. 134 HIV-infected Ugandan adults with CM had serial lumbar punctures with measurement of CSF opening pressures, quantitative cultures, ex vivo capsule size and shedding, viscosity, and CSF cytokines. 108 had complete data. Induced capsular size and shedding were measured in vitro for 48 C. neoformans isolates.</p> <p>Results. Cryptococcal strains producing larger ex vivo capsules in the baseline(pre-treatment) CSF correlated with higher ICP(P=.02), slower rate of fungal clearance(P=.02), and paucity of CSF inflammation, including decreased CSF white blood cell(WBC) count(P<.001), interleukin(IL)-4(P=.02), IL-6(P=.01), IL-7(P=.04), IL-8(P=.03), and interferon-gamma(P=.03). CSF capsule shedding did not correlate with ICP. On multivariable analysis, capsule size remained independently associated with ICP. Ex vivo capsular size and shedding did not correlate with that of the same isolates grown in vitro.</p> <P>Conclusions. Cryptococcal capsule size ex vivo is an important contributor to virulence in human cryptococcal meningitis.</P&gt

Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CM) causes an estimated 180,000 deaths annually, predominantly in sub-Saharan Africa, where most patients receive fluconazole (FLC) monotherapy. While relapse after FLC monotherapy with resistant strains is frequently observed, the mechanisms and impact of emergence of FLC resistance in human CM are poorly understood. Heteroresistance (HetR) - a resistant subpopulation within a susceptible strain - is a recently described phenomenon in Cryptococcus neoformans (Cn) and Cryptococcus gattii (Cg), the significance of which has not previously been studied in humans. METHODS: A cohort of 20 patients with HIV-associated CM in Tanzania was prospectively observed during therapy with either FLC monotherapy or in combination with flucytosine (5FC). Total and resistant subpopulations of Cryptococcus spp. were quantified directly from patient cerebrospinal fluid (CSF). Stored isolates underwent whole genome sequencing and phenotypic characterization. RESULTS: Heteroresistance was detectable in Cryptococcus spp. in the CSF of all patients at baseline (i.e., prior to initiation of therapy). During FLC monotherapy, the proportion of resistant colonies in the CSF increased during the first 2 weeks of treatment. In contrast, no resistant subpopulation was detectable in CSF by day 14 in those receiving a combination of FLC and 5FC. Genomic analysis revealed high rates of aneuploidy in heteroresistant colonies as well as in relapse isolates, with chromosome 1 (Chr1) disomy predominating. This is apparently due to the presence on Chr1 of ERG11, which is the FLC drug target, and AFR1, which encodes a drug efflux pump. In vitro efflux levels positively correlated with the level of heteroresistance. CONCLUSION: Our findings demonstrate for what we believe is the first time the presence and emergence of aneuploidy-driven FLC heteroresistance in human CM, association of efflux levels with heteroresistance, and the successful suppression of heteroresistance with 5FC/FLC combination therapy. FUNDING: This work was supported by the Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377/Z/11/Z and the Daniel Turnberg Travel Fellowship

A Prospective Longitudinal Study of the Clinical Outcomes from Cryptococcal Meningitis following Treatment Induction with 800 mg Oral Fluconazole in Blantyre, Malawi

Introduction: Cryptococcal meningitis is the most common neurological infection in HIV infected patients in Sub Saharan Africa, where gold standard treatment with intravenous amphotericin B and 5 flucytosine is often unavailable or difficult to administer. Fluconazole monotherapy is frequently recommended in national guidelines but is a fungistatic drug compromised by uncertainty over optimal dosing and a paucity of clinical end-point outcome data. Methods: From July 2010 until March 2011, HIV infected adults with a first episode of cryptococcal meningitis were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Patients were treated with oral fluconazole monotherapy 800 mg daily, as per national guidelines. ART was started at 4 weeks. Outcomes and factors associated with treatment failure were assessed 4, 10 and 52 weeks after fluconazole initiation. Results: Sixty patients were recruited. 26/60 (43%) died by 4 weeks. 35/60 (58.0%) and 43/56 (77%) died or failed treatment by 10 or 52 weeks respectively. Reduced consciousness (Glasgow Coma Score ,14 of 15), moderate/severe neurological disability (modified Rankin Score .3 of 5) and confusion (Abbreviated Mental Test Score ,8 of 10) were all common at baseline and associated with death or treatment failure. ART prior to recruitment was not associated with better outcomes. Conclusions: Mortality and treatment failure from cryptococcal meningitis following initiation of treatment with 800 mg oral fluconazole is unacceptably high. To improve outcomes, there is an urgent need for better therapeutic strategies and point-of-care diagnostics, allowing earlier diagnosis before development of neurological deficit