Creation and Internal Validation of a Clinical Predictive Model for Fluconazole Resistance in Patients With Candida Bloodstream Infection.

Background: Fluconazole is recommended as first-line therapy for candidemia when risk of fluconazole resistance (fluc-R) is low. Lack of methods to estimate resistance risk results in extended use of echinocandins and prolonged hospitalization. This study aimed to develop a clinical predictive model to identify patients at low risk for fluc-R where initial or early step-down fluconazole would be appropriate. Methods: Retrospective analysis of hospitalized adult patients with positive blood culture for Candida spp from 2013 to 2019. Multivariable logistic regression model was performed to identify factors associated with fluc-R. Stepwise regression was performed on bootstrapped samples to test individual variable stability and estimate confidence intervals (CIs). We used receiver operating characteristic curves to assess performance across the probability spectrum. Results: We identified 539 adults with candidemia and 72 Candida isolates (13.4%) were fluc-R. Increased risk of fluc-R was associated with older age, prior bacterial bloodstream infection (odds ratio [OR], 2.02 [95% CI, 1.13-3.63]), myelodysplastic syndrome (OR, 3.09 [95% CI, 1.13-8.44]), receipt of azole therapy (OR, 5.42 [95% CI, 2.90-10.1]) within 1 year of index blood culture, and history of bone marrow or stem cell transplant (OR, 2.81 [95% CI, 1.41-5.63]). The model had good discrimination (optimism-corrected c-statistic 0.771), and all of the selected variables were stable. The prediction model had a negative predictive value of 95.7% for the selected sensitivity cutoff of 90.3%. Conclusions: This model is a potential tool for identifying patients at low risk for fluc-R candidemia to receive first-line or early step-down fluconazole.

Metabolic syndrome in people with HIV from Guatemala: analysis of components and risk factors.

BACKGROUND: People with HIV (PWH) in Latin America are at a greater risk of developing comorbidities due to the increasing burden of obesity and metabolic syndrome in the region. We explored the associations between social, cardiovascular and HIV-related risk factors with metabolic syndrome in PWH from Guatemala. METHODS: Cross-sectional study analyzing demographic, clinical and laboratory data from PWH. Metabolic syndrome diagnosis and components are defined by the harmonized Joint Scientific Statement criteria. Data were collected from July 2019 to March 2020 and analyzed using correlations and logistic regression. RESULTS: Median age was 39 years [IQR 31-48], 56.8% of participants were male and 31.5% (n = 266, 95% CI 0.28-0.34) had metabolic syndrome. Age (adjusted odds ratio (aOR): 1.03, 95% CI 1.02-1.05, p <0.001), urban dweller (aOR: 1.48, 95% CI 1.00-2.18, p = 0.049), low physical activity (aOR: 1.45, 95% CI 1.01-2.08, p = 0.046), hyperuricemia (aOR: 3.31, 95% CI 1.93-5.67, p <0.001), current CD4+ T cell count < 200 cells/mm3 (aOR: 1.96, 95% CI 1.19-3.23, p = 0.009), 6 months of efavirenz (aOR: 1.89, 95% CI 1.29-2.77, p = 0.001), and obesity (aOR: 37.0, 95% CI 7.70-178.2, p < 0.001) were independently associated with metabolic syndrome. CONCLUSIONS: Prevalence of metabolic syndrome in this study was high and driven mainly by social and cardiovascular risk factors such as age, urban dwelling, obesity, hyperuricemia and low physical activity. Efavirenz use and CD4 count were the only HIV-related factors associated with metabolic syndrome.

Factors associated with viremia in people living with HIV on antiretroviral therapy in Guatemala.

INTRODUCTION: Viral suppression prevents HIV transmission and disease progression, but socio-economic and clinical factors can hinder the goal of suppression. We evaluated factors associated with viral non suppression (VNS) and persistent viremia (PV) in people living with HIV (PLHIV) receiving antiretroviral therapy (ART) in Guatemala. METHODS: We conducted a cross sectional analysis using data from an ongoing cohort of PLHIV attending the largest HIV clinic in Guatemala. Univariable and multivariable analyses were conducted between PLHIV with viral suppression and detectable viremia. VNS was defined as most recent HIV RNA ≥ 200 copies/ml and PV as two consecutive HIV RNA ≥ 200 copies/ml. RESULTS: Of 664 participants, 13.3% had VNS and 7.1% had PV. In univariable analysis disaggregated by gender, low income, poor education, perceived difficulty attending healthcare, and alcohol use were associated with VNS in men while low CD4 at diagnosis, multiple prior ART regimens and treatment interruptions were significant in both genders. Multiple prior ART regimens (adjusted Odds Ratio (aOR) 2.82, [95% confidence interval (CI) 1.59, 4.99], p < 0.01), treatment interruptions (aOR 4.51, [95% CI 2.13, 9.58], p < 0.01), excessive alcohol consumption (aOR 2.56, [95% CI 1.18, 5.54], p < 0.05) perceived difficulty attending healthcare (aOR 2.07, [ 95% CI 1.25, 3.42], p < 0.01) and low CD4 at diagnosis (aOR 2.34, 95% [CI 1.30, 4.20], p < 0.01) were independently associated with VNS on multivariable regression. CONCLUSIONS: We conclude that socio-economic and clinical factors influence viral suppression in our cohort and vary between men and women. Gender specific approaches are necessary to achieve the 90% suppression goal.

Clinical predictive models of invasive Candida infection: A systematic literature review.

Clinical predictive models (CPM) serve to identify and categorize patients into risk categories to assist in treatment and intervention recommendations. Predictive accuracy and practicality of models varies depending on methods used for their development, and should be evaluated. The aim of this study was to summarize currently available CPM for invasive candidiasis, analyze their performance, and assess their suitability for use in clinical decision making. We identified studies that described the construction of a CPM for invasive candidiasis from PubMed/MEDLINE, EMBASE, SCOPUS, Web of Science, Cochrane Library databases, and Clinicaltrials.gov. Data extracted included: author, data source, study design, recruitment period, characteristics of study population, outcome types, predictor types, number of study participants and outcome events, modelling method, and list of predictors used in the final model. Calibration and discrimination in the derivative datasets were used to assess the performance of each model. Ten articles were identified in our search and included for full text review. Five models were developed using data from ICUs, and five models included all hospitalized patients. The findings of this review highlight the limitations of currently available models to predict invasive candidiasis, including lack of generalizability, difficulty in everyday clinical use, and overly optimistic performance. There are significant concerns regarding predictive performance and usability in every day practice of existing CPM to predict invasive candidiasis.

Clinical predictive models may assist in early identification of patients at risk for invasive candidiasis to initiate appropriate treatment. The findings of this systematic review highlight the limitations of currently available models to predict invasive candidiasis.

Long-Term Mortality after Histoplasma Infection in People with HIV.

Histoplasmosis is a common opportunistic infection in people with HIV (PWH); however, no study has looked at factors associated with the long-term mortality of histoplasmosis in PWH. We conducted a single-center retrospective study on the long-term mortality of PWH diagnosed with histoplasmosis between 2002 and 2017. Patients were categorized into three groups based on length of survival after diagnosis: early mortality (death < 90 days), late mortality (death ≥ 90 days), and long-term survivors. Patients diagnosed during or after 2008 were considered part of the modern antiretroviral therapy (ART) era. Insurance type (private vs. public) was a surrogate indicator of socioeconomic status. Out of 54 PWH infected with histoplasmosis, overall mortality was 37%; 14.8% early mortality and 22.2% late mortality. There was no statistically significant difference in survival based on the availability of modern ART (p = 0.60). Insurance status reached statistical significance with 38% of survivors having private insurance versus only 8% having private insurance in the late mortality group (p = 0.05). High mortality persists despite the advent of modern ART, implicating a contribution from social determinants of health, such as private insurance. Larger studies are needed to elucidate the role of these factors in the mortality of PWH.

A comparison of presentations and outcomes of histoplasmosis across patients with varying immune status.

Few large cohorts have examined histoplasmosis in both immunocompromised and immunocompetent patients. We describe the differences in presentations and outcomes of histoplasmosis by immune and dissemination status. We assembled a retrospective cohort of adult patients diagnosed with histoplasmosis from 2002 to 2017. Patients were grouped by immune status: people living with HIV (PLWH), patients who were HIV negative but had other-immunocompromise (OIC), and immunocompetent patients. Patients were further classified into asymptomatic lung nodule (ALN), localized and disseminated disease groups, and outcomes were compared across patients by these immune status categories We identified 261 patients with histoplasmosis: 54 (21%) PLWH, 98 (38%) OIC, and 109 (42%) immunocompetent. Disseminated disease was more common among PLWH than among other groups (P < .001). In localized disease, median time from symptom onset to diagnosis was longer in immunocompetent patients than in other groups (P = .012), and was not significant in disseminated disease. The 90-day mortality was higher in PLWH (25%) and OIC (26%) with localized disease compared to the immunocompetent group (4%) (P = .009), but this difference was not seen in disseminated disease. Patients with localized disease had lower 90-day mortality (14%) compared to those with disseminated disease (21%) (P = .034). We conclude that immunocompetent individuals present with fewer typical symptoms, laboratory findings, and radiographic features of Histoplasma infection, leading to potential delays in diagnosis in this group. Despite this, immunocompetent patients have lower 90-day mortality in localized disease, and do not experience increased 90-day mortality in disseminated disease. LAY SUMMARY: This article examines how the signs and symptoms of histoplasmosis vary by immune status and dissemination status. Immunocompetent patients with localized disease present with fewer typical signs and symptoms, are diagnosed later, but despite this have lower 90-day mortality.

Treatment and mortality outcomes in patients with other extrapulmonary cryptococcal disease compared with central nervous system disease.

BACKGROUND: Determining the extent of cryptococcal disease (CD) is key to therapeutic management. Treatment with fluconazole is only recommended for localised pulmonary disease. Induction therapy with amphotericin B (AmB) and flucytosine is recommended for disease at other sites, irrespective of central nervous system (CNS) involvement, but this is not often followed in patients without meningitis. In this study, we compared treatment and mortality between patients with CD of the CNS and other extrapulmonary (OE) sites. METHODS: This is a retrospective, single-centre study of all hospitalised patients with nonpulmonary cryptococcal infection from 2002 to 2015 who underwent lumbar puncture. Demographics, predisposing factors, comorbidities, clinical presentation, laboratory values, antifungal treatment and mortality data were collected to evaluate 90-day mortality and treatment differences between patients with OE and CNS CD. Survival analysis was performed using multivariable Cox regression analysis. RESULTS: Of 193 patients analysed, 143 (74%) had CNS CD and 50 (26%) had OE CD. Ninety-day mortality was 23% and similar between the OE and CNS CD groups (22% vs 23%, p = .9). In the comorbidity-adjusted multivariable Cox regression model, mortality risk was similar in the OE and CNS groups. Fewer patients with OE CD received induction therapy with AmB and flucytosine compared to those with CNS disease (28% vs 71.3%, p < .001). CONCLUSION: Patients with OE CD had similar 90-day mortality compared to those with CNS disease. Despite current guideline recommendations, patients with OE disease were less likely to receive appropriate induction therapy with AmB and flucytosine compared to patients with CNS disease.

Voriconazole Versus Itraconazole for the Initial and Step-down Treatment of Histoplasmosis: A Retrospective Cohort.

BACKGROUND: Itraconazole is the preferred azole for histoplasmosis in the current Infectious Diseases Society of America guidelines. Voriconazole is increasingly used as treatment for histoplasmosis; it has in vitro activity against Histoplasma capsulatum and has shown success in case reports and small case series, but may have a lower barrier to resistance. No comparative studies have been published. METHODS: We constructed a single-center, retrospective cohort of adult patients diagnosed with histoplasmosis from 2002 to 2017. Individual charts were reviewed to gather clinical information, including demographics, clinical features, immune status, treatments, and mortality. Patients were categorized based on the choice of azole and use as an initial treatment or as a step-down therapy from amphotericin B. Initial therapies with other azoles were excluded. Mortality was compared using a multivariable Cox proportional hazards with Heaviside function at 42 days. RESULTS: We identified 261 cases of histoplasmosis from 2002 to 2017. After excluding patients not treated with itraconazole or voriconazole, 194 patients remained. Of these, 175 (90%) patients received itraconazole and 19 (10%) received voriconazole. There were no significant demographic differences between patient populations receiving either azole as their initial azole treatment. Death at 180 days occurred in 41 patients (23.4%) in the itraconazole group and 6 patients (31.6%) in the voriconazole group. Patients on voriconazole had a statistically significant increase in mortality during the first 42 days after initiation of treatment when compared to patients receiving itraconazole (hazard ratio, 4.30; 95% confidence interval, 1.3-13.9; P = .015), when controlled for other risk factors. CONCLUSIONS: Voriconazole in histoplasmosis was associated with increased mortality in the first 42 days when compared to itraconazole.

Potential missed opportunities for diagnosis of cryptococcosis and the association with mortality: A cohort study.

BACKGROUND: Cryptococcosis is one of the most common life-threatening opportunistic mycoses worldwide. Insidious presentation and slow onset of symptoms make it difficult to recognize, complicating the diagnostic process. Delays in diagnosis may lead to increased mortality. We aim to determine the frequency of missed opportunities for diagnosis of cryptococcosis and its effects on mortality. METHODS: To estimate the proportion of individuals with a potentially missed diagnosis for cryptococcosis in hospitalized patients, we conducted a retrospective cohort study using the Healthcare Cost and Utilization Project State Inpatient Databases from 2005 to 2015 from eight states. All hospitalized adult patients diagnosed with cryptococcal infection or cryptococcal meningitis were included. Potentially missed diagnoses were defined as admissions coded for a procedure or diagnosis suggestive of cryptococcosis in the 90-days prior to the initial cryptococcosis admission. Generalized estimating equations models were used to evaluate the association between underlying comorbidities and potential missed diagnosis of cryptococcosis and 90-day all-cause in-hospital mortality. FINDINGS: Of 5,354 patients with cryptococcosis, 2,445 (45·7%) were people living with HIV (PLWH). Among PLWH, 493/2,445 (20·2%) had a potentially missed diagnosis, of which 83/493 (16·8%) died while hospitalized compared with 265/1,952 (13·6%) of those without a potentially missed diagnosis (relative risk [RR] 1·04, 95% CI 0·99-1·09). Among HIV-negative patients, 977/2,909 (33·6%) had a potentially missed diagnosis, of which 236/977 (24·2%) died while hospitalized compared with 298/1,932 (15·4%) of those not missed (RR 1·12, 95% CI 1·07-1·16). INTERPRETATION: Missed opportunities to diagnose cryptococcosis are common despite highly efficacious diagnostic tests and are associated with increased risk of 90-day mortality in HIV-negative patients. A high index of clinical suspicion is paramount to promptly diagnose, treat, and improve cryptococcosis-related mortality. FUNDING: National Center for Advancing Translational Sciences, Washington University Institute of Clinical and Translational Sciences, and the Agency for Healthcare Research and Quality.

Performance of the Lateral Flow Assay and the Latex Agglutination Serum Cryptococcal Antigen Test in Cryptococcal Disease in Patients with and without HIV.

Cryptococcal epidemiology is shifting toward HIV-negative populations who have diverse presentations. Cryptococcal antigen (CrAg) testing is also changing, with development of the lateral flow assay (LFA) having reported increased sensitivity and specificity, but with minimal knowledge in the HIV-negative population. In this study, we evaluate the real-life performance of CrAg testing in patients with cryptococcal disease. We conducted a retrospective review of patients with cryptococcosis from 2002 to 2019 at Barnes-Jewish Hospital. Latex agglutination (LA) was used exclusively until April 2016, at which point LFA was used exclusively. Demographics, presentations, and testing outcomes were evaluated. Serum CrAg testing was completed in 227 patients with cryptococcosis. Of 141 HIV-negative patients, 107 had LA testing and 34 had LFA testing. In patients with disseminated disease, serum CrAg sensitivity by LA was 78.1% compared to 82.6% for LFA. In patients with localized pulmonary disease, serum CrAg sensitivity was 23.5% compared to 90.9% for LFA. Of 86 people living with HIV (PLWH), 76 had LA testing, and 10 had LFA testing. Serum CrAg sensitivity for LA was 94.7% compared to 100% for LFA in patients with disseminated disease. We noted a significant improvement in sensitivity from LA testing to LFA testing, predominantly in those with localized pulmonary disease. However, both LFA and LA appear to be less sensitive in HIV-negative patients than previously described in PLWH.

Hope on the Horizon: Novel Fungal Treatments in Development.

The treatment of invasive fungal infections remains challenging due to limitations in currently available antifungal therapies including toxicity, interactions, restricted routes of administration, and drug resistance. This review focuses on novel therapies in clinical development, including drugs and a device. These drugs have novel mechanisms of action to overcome resistance, and some offer new formulations providing distinct advantages over current therapies to improve safety profiles and reduce interactions. Among agents that target the cell wall, 2 glucan synthesis inhibitors are discussed (rezafungin and ibrexafungerp), as well as fosmanogepix and nikkomycin Z. Agents that target the cell membrane include 3 fourth-generation azoles, oral encochleated amphotericin B, and aureobasidin A. Among agents with intracellular targets, we will review olorofim, VL-2397, T-2307, AR-12, and MGCD290. In addition, we will describe neurapheresis, a device used as adjunctive therapy for cryptococcosis. With a field full of novel treatments for fungal infections, the future looks promising.

Effect of infectious disease consultation on mortality and treatment of patients with candida bloodstream infections: a retrospective, cohort study.

BACKGROUND: Candida bloodstream infection is associated with high mortality. Infectious disease consultation improves outcomes in several infections, including Staphylococcus aureus and cryptococcosis, as well as multidrug-resistant organisms. We aimed to examine the association between infectious disease consultation and differences in management with mortality in candida bloodstream infections. METHODS: In this retrospective, single-centre cohort study, we reviewed the medical charts of all patients admitted to Barnes-Jewish Hospital (St Louis, MO, USA), a tertiary referral centre, aged 18 years or older with candida bloodstream infection from 2002 to 2015. We collected data for demographics, comorbidities, predisposing factors, all-cause mortality, antifungal use, central-line removal, and ophthalmological and echocardiographic evaluation to assess 90-day all-cause mortality between individuals with and without an infectious disease consultation. For the survival analysis we used Cox proportional hazards model with inverse weighting by propensity score to assess the effects of infectious disease consultation on mortality and differences in management. FINDINGS: Between Jan 1, 2002, and Dec 31, 2015, of 1794 patients assessed for eligibility, we analysed 1691 patients with candida bloodstream infection; 776 (45·9%) who had an infectious disease consultation and 915 (54·1%) who did not have an infectious disease consultation. All 1691 patients were included in the analysis. None were missing data. Most underlying comorbidities were evenly distributed between groups. 90-day mortality was lower in the infectious disease consultation group than in patients who did not receive an infectious disease consultation (29% [222/776] vs 51% [468/915]; p<0·0001). In the model with inverse weighting by the propensity score, infectious disease consultation was associated with a hazard ratio of 0·81 (95% CI 0·73-0·91; p<0·0001) for mortality. In the consultation group, median duration of antifungal therapy was longer (18 [IQR 14-35] vs 14 [6-20] days; p<0·0001) and central-line removal (587 [76%] of 776 vs 538 [59%] of 915; p<0·0001), echocardiography use (442 [57%] of 776 vs 305 [33%] of 915; p<0·0001), and ophthalmological examination (412 [53%] of 776 vs 160 [17%] of 915; p<0·0001) were more frequently done. Fewer patients in the infectious disease consultation group were not treated (13 [2%] of 776 vs 128 [14%] of 915; p<0·0001). INTERPRETATION: Patients with candida bloodstream infection receiving an infectious disease consultation have lower mortality. This finding might be attributable to these individuals receiving a higher number of non-pharmacological, evidence-based interventions and lower amounts of non-treatment. These data suggest that an infectious disease consultation should be an integral part of clinical care of patients with candida bloodstream infection. FUNDING: Astellas Global Development Pharma, Washington University Institute of Clinical and Translational Sciences, and the Agency for Healthcare Research and Quality.

Mortality After Cryptococcal Infection in the Modern Antiretroviral Therapy Era.

BACKGROUND: The prevalence of cryptococcosis in people living with HIV (PLWH) in the developed world has decreased considerably in the modern antiretroviral therapy (ART) era. Although early mortality of PLWH with opportunistic infections is well understood, overall mortality has not been previously evaluated. METHODS: We conducted a retrospective cohort study of cryptococcosis in PLWH from January 1, 2002, to July 1, 2017. Data were also evaluated before and after 2008 to evaluate the possible effect of modern ART on outcomes. Death date was obtained from the hospital's medical informatics database and the Social Security Death Index. Participants were grouped as survivors, early-mortality (death <90 days), and late-mortality (death ≥90 days) individuals. RESULTS: We reviewed 105 PLWH with cryptococcosis, with 55 survivors (52.4%), 17 early-mortality (16.2%), and 33 late-mortality individuals (31.4%). Overall, mortality was 47.6% (n = 50) with a median follow-up of 3.7 years (interquartile range 1.1, 8.1 years). Late-mortality individuals were less likely to be virally suppressed at the last observation compared with survivors (24% vs 62%, P < 0.001). Individuals diagnosed in the modern ART era had significantly lower mortality (hazard ratio 0.5, confidence interval: 0.2 to 0.8) and were more likely to be virally suppressed at the last observation (57% vs 29%, P = 0.003). Individuals with government-provided insurance had a higher mortality compared to those with private insurance (hazard ratio 2.8, confidence interval: 1.1 to 7.2, P = 0.013). CONCLUSIONS: Despite improvements in ART, PLWH have high mortality after cryptococcal infection that persists beyond their initial hospitalization. Lower mortality was associated with increased HIV viral suppression and private insurance in the modern ART era.