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We investigated the value of susceptibility testing in predicting response in AIDS-associated cryptococcal meningitis using clinical isolates from a randomized controlled trial of antifungal treatment (amphotericin monotherapy, amphotericin with flucytosine, or amphotericin with fluconazole). We found no correlation between antifungal susceptibility and either early or late survival, or fungal clearance., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Talaromycosis is an invasive mycosis endemic in Southeast Asia and causes substantial morbidity and mortality in individuals with advanced human immunodeficiency virus (HIV) disease. Current diagnosis relies on isolating Talaromyces marneffei in cultures, which takes up to 14 days and is detectable only during late-stage infection, leading to high mortality., Methods: In this retrospective case-control study, we assessed the accuracy of a novel Mp1p antigen-detecting enzyme immunoassay (EIA) in stored plasma samples of 372 patients who had culture-proven talaromycosis from blood or sterile body fluids (reference standard) and 517 individuals without talaromycosis (338 healthy volunteers; 179 with other infections). All participants were recruited between 2011 and 2017 in Vietnam., Results: Of cases and controls, 66.1% and 75.4%, respectively, were male; the median age was 33 and 37, respectively. All cases were HIV infected; median CD4 count was 10 cells/μL. At an optical density cutoff of 0.5, the specificity was 98.1% (95% CI, 96.3%-99.0%); the sensitivity was superior to blood culture (86.3% [95% CI, 82.3%-89.5%] vs 72.8% [95% CI, 68.0%-77.2%]) (P < .001, McNemar test). The time to diagnosis was 6 hours vs 6.6 ± 3.0 days for blood culture. Paired plasma and urine testing in the same patients (n = 269) significantly increased sensitivity compared to testing plasma alone or testing urine alone (P < .001 and P = .02, respectively, McNemar test)., Conclusions: The Mp1p EIA is highly specific and is superior in sensitivity and time to diagnosis compared to blood culture for the diagnosis of talaromycosis. Paired plasma and urine testing further increases sensitivity, introducing a new tool for rapid diagnosis, enabling early treatment and potentially reducing mortality., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: The CryptoDex trial showed that dexamethasone caused poorer clinical outcomes and slowed fungal clearance in human immunodeficiency virus-associated cryptococcal meningitis. We analyzed cerebrospinal fluid (CSF) cytokine concentrations from participants over the first week of treatment to investigate mechanisms of harm and test 2 hypotheses: (1) dexamethasone reduced proinflammatory cytokine concentrations, leading to poorer outcomes and (2) leukotriene A4 hydrolase (LTA4H) genotype influenced the clinical impact of dexamethasone, as observed in tuberculous meningitis., Methods: We included participants from Vietnam, Thailand, and Uganda. Using the Luminex system, we measured CSF concentrations of the following: interferon γ, tumor necrosis factor (TNF) α, granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant 1, macrophage inflammatory protein 1α, and interleukin 6, 12p70, 8, 4, 10, and 17. We determined the LTA4H genotype based on the promoter region single-nucleotide polymorphism rs17525495. We assessed the impact of dexamethasone on cytokine concentration dynamics and the association between cytokine concentration dynamics and fungal clearance with mixed effect models. We measured the influence of LTA4H genotype on outcomes with Cox regression models., Results: Dexamethasone increased the rate TNF-α concentration's decline in (-0.13 log2pg/mL/d (95% confidence interval, -.22 to -.06 log2pg/mL/d; P = .03), which was associated with slower fungal clearance (correlation, -0.62; 95% confidence interval, -.83 to -.26). LTA4H genotype had no statistically significant impact on outcome or response to dexamethasone therapy. Better clinical outcomes were associated with higher baseline concentrations of interferon γ., Conclusions: Dexamethasone may slow fungal clearance and worsen outcomes by increasing TNF-α concentration's rate of decline., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Penicillium marneffei is an important human immunodeficiency virus (HIV)-associated opportunistic pathogen in Southeast Asia. The epidemiology and the predictors of penicilliosis outcome are poorly understood., Methods: We performed a retrospective study of culture-confirmed incident penicilliosis admissions during 1996-2009 at the Hospital for Tropical Diseases in Ho Chi Minh City, Viet Nam. Seasonality of penicilliosis was assessed using cosinor models. Logistic regression was used to assess predictors of death or worsening disease based on 10 predefined covariates, and Cox regression was performed to model time-to-antifungal initiation., Results: A total of 795 patients were identified; hospital charts were obtainable for 513 patients (65%). Cases increased exponentially and peaked in 2007 (156 cases), mirroring the trends in AIDS admissions during the study period. A highly significant seasonality for penicilliosis (P<.001) but not for cryptococcosis (P=.63) or AIDS admissions (P=.83) was observed, with a 27% (95% confidence interval, 14%-41%) increase in incidence during rainy months. All patients were HIV infected; the median CD4 cell count (62 patients) was 7 cells/μL (interquartile range, 4-24 cells/μL). Hospital outcome was an improvement in 347 (68%), death in 101 (20%), worsening in 42 (8%), and nonassessable in 23 (5%) cases. Injection drug use, shorter history, absence of fever or skin lesions, elevated respiratory rates, higher lymphocyte count, and lower platelet count independently predicted poor outcome in both complete-case and multiple-imputation analyses. Time-to-treatment initiation was shorter for patients with skin lesions (hazard ratio, 3.78; 95% confidence interval, 2.96-4.84; P<.001)., Conclusions: Penicilliosis incidence correlates with the HIV/AIDS epidemic in Viet nam. The number of cases increases during rainy months. Injection drug use, shorter history, absence of fever or skin lesions, respiratory difficulty, higher lymphocyte count, and lower platelet count predict poor in-hospital outcome., (© The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.)

Penicillium marneffei is an important human immunodeficiency virus-associated opportunistic infection endemic in Southeast Asia. Central nervous system infection has not been described. We report the first case series of 21 human immunodeficiency virus-infected patients who presented with a syndrome consistent with acute central nervous system infection and who had Penicillium marneffei isolated from cerebrospinal fluid.

AIDS&#x2010;associated Cryptococcus neoformans and Penicillium marneffei coinfection has not been adequately studied and poses unique therapeutic challenges in resource&#x2010;limited settings. Itraconazole poorly penetrates the central nervous system, whereas fluconazole has poor activity against P. marneffei. We prospectively report management of 1 patient and retrospectively review 7 coinfection cases from Vietnam.

Background: Enteric fever is a major global problem. Emergence of antibacterial resistance threatens to render current treatments ineffective. There is little research or public health effort directed toward Salmonella enterica serovar Paratyphi A, because it is assumed to cause less severe enteric fever than does S. enterica serovar Typhi. There are few data on which to base this assumption, little is known of the serovar's antibacterial susceptibilities, and there is no readily available tolerable vaccination., Methods: A prospective study was conducted of 609 consecutive cases of enteric fever (confirmed by blood culture) to compare the clinical phenotypes and antibacterial susceptibilities in S. Typhi and S. Paratyphi A infections. Variables independently associated with either infection were identified to develop a diagnostic rule to distinguish the infections. All isolates were tested for susceptibility to antibacterials., Results: Six hundred nine patients (409 with S. Typhi infection and 200 with S. Paratyphi A infection) presented during the study period. The infections were clinically indistinguishable and had equal severity. Nalidixic acid resistance, which predicts a poor response to fluoroquinolone treatment, was extremely common (75.25% of S. Paratyphi A isolates and 50.5% of S. Typhi isolates; P < .001). S. Paratyphi A was more likely to be resistant to ofloxacin (3.6% vs. 0.5%; P = .007) or to have intermediate susceptibility to ofloxacin (28.7% vs. 1.8%; P < .001) or ciprofloxacin (39.4% vs. 8.2%; P < .001). MICs for S. Paratyphi A were higher than for S. Typhi (MIC of ciprofloxacin, 0.75 vs. 0.38 microg/mL [P < .001]; MIC of ofloxacin, 2.0 vs. 0.75 microg/mL [P < .001])., Conclusions: The importance of S. Paratyphi A has been underestimated. Infection is common, the agent causes disease as severe as that caused by S. Typhi and is highly likely to be drug resistant. Drug resistance and lack of effective vaccination suggest that S. Paratyphi A infection may become a major world health problem.