UNASSIGNED: Persons with HIV and cryptococcal antigenemia are at high risk of progression to cryptococcal meningitis or death. Baseline cryptococcal antigen (CrAg) plasma titer ≥1:160 is a known risk factor for poor outcomes, but other risk factors are unknown. In HIV-associated cryptococcal meningitis, baseline serum C-reactive protein (CRP) concentrations are positively associated with increased mortality. We hypothesized that CRP might also be associated with meningitis or death in persons with cryptococcal antigenemia.
UNASSIGNED: We measured plasma CrAg titers and CRP concentrations on cryopreserved serum from prospectively enrolled persons with HIV and cryptococcal antigenemia. Using time-to-event analyses, we compared 24-week meningitis-free survival in persons with normal CRP (<8 mg/L) and elevated CRP (≥8 mg/L). Logistic regression was used to assess how CRP concentration and CrAg titer might interact as covariates.
UNASSIGNED: Of the 94 persons with elevated CRP, 19 (20.2%) developed meningitis or death, whereas of the 88 persons with normal CRP, 8 (9.1%) developed meningitis or death (P = .035). Persons with CrAg titer <1:160 and normal CRP had an ∼5% (3/61) event rate, whereas those with CrAg titer <1:160 but elevated CRP had an ∼20% (12/59) event rate. Importantly, we identified a statistically significant interaction effect between CrAg titer and CRP groups, in which elevated CRP increased risk in the low CrAg titer group (odds ratio, 1.54; 95% confidence interval, 1.16-2.04), but this effect was not present in high CrAg titer group (odds ratio, 0.78; 95% confidence interval, .53-1.15).
UNASSIGNED: Our findings demonstrate that CrAg titer may modify the direction of effect of CRP with meningitis-free survival; future studies should account for this interaction.

UNASSIGNED: Mortality among adults diagnosed with HIV-associated cryptococcal meningitis remains high (24%-40%). We hypothesized that nutritional state, as measured by mid-upper arm circumference (MUAC), is a potentially modifiable risk factor for mortality.
UNASSIGNED: Ugandan adults hospitalized with HIV-associated cryptococcal meningitis had MUAC measurements performed at baseline. We compared MUAC measurements with baseline clinical and demographic variables and investigated associations with survival using Cox regression.
UNASSIGNED: Of 433 participants enrolled, 41% were female, the median CD4 T-cell count (interquartile range [IQR]) was 15 (6-41) cells/μL, and 37% were antiretroviral therapy naïve. The median MUAC (IQR) was 24 (22-26) cm, the median weight (IQR) was 53 (50-60) kg, and MUAC correlated with weight (Pearson r = 0.6; P < .001). Overall, 46% (200/433) died during the 18-week follow-up. Participants in the lowest MUAC quartile (≤22 cm) had the highest mortality: 39% (46/118) at 2 weeks and 62% (73/118) at 18 weeks. A baseline MUAC ≤22 cm was associated with an 82% increased risk of 18-week mortality as compared with participants with an MUAC >22 cm (unadjusted hazard ratio, 1.82; 95% CI, 1.36-2.42; P < .001). Following adjustment for antiretroviral therapy status, CD4 count, hemoglobin, amphotericin dose, and tuberculosis status, the adjusted hazard ratio was 1.84 (95% CI, 1.27-2.65; P < .001). As a continuous variable, 18-week mortality was reduced by 10% for every 1-cm increase in MUAC. CSF Th17 immune responses were positively associated with MUAC quartile.
UNASSIGNED: MUAC measurement is a simple bedside tool that can identify adults with HIV-associated cryptococcal meningitis at high risk for mortality for whom an enhanced bundle of care, including nutritional supplementation, should be further investigated.

Cryptococcal meningitis (CM), a common and serious opportunistic infection mostly caused by Cryptococcus neoformans, is primarily treated with fluconazole. Nevertheless, Cryptococcus neoformans strains that undergo repeated exposure to azoles can gradually acquire heteroresistance to fluconazole. The management of this specific CM infection poses a substantial challenge. Determining a globally accepted definition for fluconazole heteroresistance and developing effective and prompt methods for identifying heteroresistance is of utmost importance. We collected data on the clinical and epidemiological characteristics of patients diagnosed with CM. All the available Cryptococcus neoformans strains isolated from these patients were collected and subjected to antifungal susceptibility testing and evaluation of fluconazole heteroresistance. AIDS was present in 40.5% of the patients, whereas 24.1% did not have any underlying diseases. Patients with chronic diseases or impaired immune systems are susceptible to infection by Cryptococcus neoformans, a fungus that frequently (39.6%, 19/48) shows heteroresistance to fluconazole, as confirmed by population analysis profile (PAP).IMPORTANCEFluconazole heteroresistance poses a significant threat to the efficacy of fluconazole in treating cryptococcal meningitis (CM). Unfortunately, the standard broth microdilution method often misses the subtle percentages of subpopulations exhibiting heteroresistance. While the population analysis profile (PAP) method is esteemed as the gold standard, its time-consuming and labor-intensive nature makes it impractical for routine clinical use. In contrast, the Kirby-Bauer (KB) disk diffusion method offers a simple and effective screening solution. Our study highlights the value of KB over PAP and minimum inhibitory concentration (MIC) by demonstrating that when adjusting the inoculum concentration to 1.0 McFarland and subjecting samples to a 72-hour incubation period at 35°C, the KB method closely mirrors the outcomes of the PAP approach in detecting fluconazole heteroresistance. This optimization of the KB method not only enhances assay efficiency but also provides a blueprint for developing a timely and effective strategy for identifying heteroresistance.

Cryptococcal meningitis, a severe fungal infection of the central nervous system, is usually found in immunocompromised patients, especially those with human immunodeficiency virus/acquired immunodeficiency syndrome. Its occurrence in immunocompetent individuals is rare and the presentation can be nonspecific. We present a case of cryptococcal meningitis in a young, immunocompetent male with a known history of intravenous drug abuse who was also found to have hepatitis C during admission. Induction therapy with amphotericin B and flucytosine was completed for 14 days. This shorter duration was considered as he had a good clinical response with rapid improvement in mental status and intracranial pressure with an extraventricular drain and negative repeat cerebrospinal fluid (CSF) culture. However, during the consolidation phase with fluconazole, the patient developed new neurologic symptoms and the induction phase had to be re-initiated for a total of 28 days. The patient likewise required the re-placement of an extraventricular drain and the creation of a ventriculoperitoneal shunt due to persistent CSF accumulation and increased intracranial pressure. He was eventually discharged on fluconazole for a planned consolidation phase of eight weeks, followed by a prolonged maintenance phase, but the patient was lost to follow-up.

BACKGROUND: Limited data exist on the antifungal activity of daily liposomal amphotericin B with flucytosine induction regimens for cryptococcal meningitis, which are recommended in high-income countries. Liposomal amphotericin B monotherapy at 3 mg/kg previously failed to meet non-inferiority criteria compared to amphotericin B deoxycholate in its registrational clinical trial. We aimed to compare the quantitative antifungal activity and mortality between daily amphotericin B deoxycholate and daily liposomal amphotericin among persons with HIV-related cryptococcal meningitis receiving adjunctive flucytosine 100 mg/kg/day.
METHODS: We analyzed data from three clinical studies involving participants with HIV-associated cryptococcal meningitis receiving either daily liposomal amphotericin B at 3 mg/kg/day with flucytosine (N = 94) or amphotericin B deoxycholate at 0.7-1.0 mg/kg/day with flucytosine (N = 404) as induction therapy. We compared participant baseline characteristics, CSF early fungicidal activity (EFA), and 10-week mortality.
RESULTS: We included 498 participants in this analysis, of whom 201 had available EFA data (N = 46 liposomal amphotericin; N = 155 amphotericin deoxycholate). Overall, there is no statistical evidence that the antifungal activity of liposomal amphotericin B (mean EFA = 0.495 log10 CFU/mL/day; 95%CI, 0.355-0.634) differ from amphotericin B deoxycholate (mean EFA = 0.402 log10 CFU/mL; 95%CI, 0.360-0.445) (P = 0.13). Mortality at 10 weeks trended lower for liposomal amphotericin (28.2%) vs amphotericin B deoxycholate (34.6%) but was not statistically different when adjusting for baseline characteristics (adjusted Hazard Ratio = 0.74; 95%CI, 0.44-1.25; P = 0.26).
CONCLUSIONS: Daily liposomal amphotericin B induction demonstrated a similar rate of CSF fungal clearance and 10-week mortality as amphotericin B deoxycholate when combined with flucytosine for the treatment of HIV-associated cryptococcal meningitis.

Cryptococcosis causes a high burden of disease worldwide. This systematic review summarizes the literature on Cryptococcus neoformans and C. gattii infections to inform the World Health Organization\'s first Fungal Priority Pathogen List. PubMed and Web of Science were used to identify studies reporting on annual incidence, mortality, morbidity, antifungal resistance, preventability, and distribution/emergence in the past 10 years. Mortality rates due to C. neoformans were 41%-61%. Complications included acute renal impairment, raised intracranial pressure needing shunts, and blindness. There was moderate evidence of reduced susceptibility (MIC range 16-32 mg/l) of C. neoformans to fluconazole, itraconazole, ketoconazole, voriconazole, and amphotericin B. Cryptococcus gattii infections comprised 11%-33% of all cases of invasive cryptococcosis globally. The mortality rates were 10%-23% for central nervous system (CNS) and pulmonary infections, and ∼43% for bloodstream infections. Complications described included neurological sequelae (17%-27% in C. gattii infections) and immune reconstitution inflammatory syndrome. MICs were generally low for amphotericin B (MICs: 0.25-0.5 mg/l), 5-flucytosine (MIC range: 0.5-2 mg/l), itraconazole, posaconazole, and voriconazole (MIC range: 0.06-0.5 mg/l). There is a need for increased surveillance of disease phenotype and outcome, long-term disability, and drug susceptibility to inform robust estimates of disease burden.

Animal models are frequently used as surrogates to understand human disease. In the fungal pathogen Cryptococcus species complex, several variations of a mouse model of disease were developed that recapitulate different aspects of human disease. These mouse models have been implemented using various inbred and outbred mouse backgrounds, many of which have genetic differences that can influence host response and disease outcome. In this review, we will discuss the most commonly used inbred mouse backgrounds in C. neoformans infection models.

UNASSIGNED: Several recent randomized trials have been conducted in resource-limited settings for cryptococcal meningitis that have rapidly innovated international guidelines. The 2010 Infectious Diseases Society of America (IDSA) cryptococcal meningitis guideline has not been updated with recent trials. The 2022 AMBITION-cm trial found that a single 10-mg/kg dose of liposomal amphotericin B plus daily flucytosine and fluconazole for 2 weeks was noninferior to 1 week of amphotericin B deoxycholate with flucytosine. It is unknown whether physicians in high-resource settings are using this regimen or more traditional regimens.
UNASSIGNED: We developed an electronic survey in June 2023 to better understand whether physician members of the IDSA Emerging Infections Network (EIN) and Mycoses Study Group Education and Research Consortium (MSG-ERC) had used the AMBITION-cm induction regimen, would use the regimen in hypothetical clinical scenarios, and what perceived barriers to use existed.
UNASSIGNED: A total of 242 of 561 (43%) physicians responded to the survey, of whom 205 provided care for persons with cryptococcal meningitis in the last year. Overall, 29 (14%) had used the AMBITION-cm regimen, and 176 (86%) had not. In various hypothetical clinical scenarios, only ∼10% of 209 respondents selected the AMBITION-cm regimen as preferred. Perceived barriers to uptake included the applicability of trials performed in low-resource settings to high-resource settings, that the regimen is not recommended in the 2010 IDSA guidelines, and the applicability to persons without HIV.
UNASSIGNED: Most respondents had not used the single-dose liposomal amphotericin B regimen, but the regimen is being used. Further study of this regimen in other patient populations and settings is necessary.

Tuberculous meningitis (TBM) is a prevalent global intracranial infection and the most lethal and disabling form of tuberculosis. TBM with mixed intracranial infections is clinically rare but has a higher mortality rate. To investigate the clinical characteristics of TBM with mixed intracranial infections, demographic and clinical data of TBM and pulmonary tuberculosis (PTB) patients admitted to Shenzhen Third People\'s Hospital between January 2015 and October 2022 were collected anonymously. A total of 207 cases of TBM were diagnosed, of which 16 cases (7.73%) were TBM with mixed intracranial infections. The overall mortality rate of TBM cases was 16.4%, while the mortality rate of TBM cases with mixed intracranial infections was as high as 35.7%. Compared to simple TBM cases, TBM cases with mixed intracranial infections had severer clinical symptoms. The percentage of human immune deficiency virus (HIV)-positive TBM cases with mixed intracranial infections reached up to 68.8%. HIV co-infection, CD4+/CD8+ T-cell counts less than 1, cranial nerve impairment, paralysis, cerebral infarction, PRO less than 450 mg/L, WBC less than 10 × 106 /L, and CL more than 120 mmol/L were risk factors for TBM cases with mixed intracranial infections. Compared to PTB, HIV co-infection, CD4+ T cell less than 550 /uL, and age less than 45 years were risk factors for TBM, and TBM was associated with higher mortality rates. Our study provides additional data to better understand single TBM and TBM with mixed intracranial infections. More than two-thirds of TBM cases with mixed intracranial infections were HIV-positive. Clinicians should consider the possibility of multiple infections in people with TBM/HIV co-infection.
OBJECTIVE: TBM can cause severe neurological damage and death, and TBM with mixed intracranial infections can exacerbate the damage and poor prognosis of the disease. TBM with mixed intracranial infections is a rare disease, which has led to an incomplete understanding of its clinical features. This study investigated the clinical features of TBM and its associated factors by comparing the characteristics of TBM with mixed intracranial infections, single TBM and pulmonary tuberculosis. This information will help to improve the understanding of TBM, diagnostic accuracy and treatment outcomes.

Cryptococcus infection is an invasive fungal infection common in immunocompromised hosts, especially in organ transplant recipients and in patients with HIV. Its presentation varies from localized skin lesions to systemic disseminated infection involving the lungs and the central nervous system (CNS). We present the case of a 50-year-old woman with diabetes mellitus type 2 (DM-2), end-stage renal disease (ESRD) status post deceased donor kidney transplantation seven and a half years ago who presented with a low-grade fever, cough, nausea, vomiting, and a large cystic mass on the right foot. A CT scan of the chest showed a 14 mm cavitary lesion in the middle lobe of the right lung. Serum and cerebrospinal fluid cryptococcal antigens were detected. MRI of the right foot showed a large multilocular lobulated septated cystic mass. Histopathology showed cryptococcus; the diagnosis was made as disseminated cryptococcus infection. She was treated with antifungal therapy successfully. A large cutaneous cystic mass is a rare cutaneous presentation of cryptococcus infection; clinicians should keep it in the differential diagnosis, especially in transplant recipient patients.