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Introduction: Cryptococcus causes 15% of AIDS-related deaths and in South Africa, with its high HIV burden, is the dominant cause of adult meningitis. Cryptococcal meningitis (CM) mortality is high, partly because patients enter care with advanced HIV disease and because of failure of integrated care following CM diagnosis. We evaluated pathways to hospital care, missed opportunities for HIV testing and initiation of care. Methods: We performed a cross-sectional study at five public-sector urban hospitals. We enrolled adults admitted with a first or recurrent episode of cryptococcal meningitis. Study nurses conducted interviews, supplemented by a prospective review of medical charts and laboratory records. Results: From May to October 2015, 102 participants were enrolled; median age was 40 years (interquartile range [IQR] 33.9–46.7) and 56 (55%) were male. In the six weeks prior to admission, 2/102 participants were asymptomatic, 72/100 participants sought care at a public-sector facility, 16/100 paid for private health care. The median time from seeking care to admission was 4 days (IQR, 0–27 days). Of 94 HIV-seropositive participants, only 62 (66%) knew their status and 41/62 (66%) had ever taken antiretroviral treatment. Among 13 participants with a known previous CM episode, none were taking fluconazole maintenance therapy. In-hospital management was mostly amphotericin B; in-hospital mortality was high (28/92, 30%). Sixty-four participants were discharged, 92% (59/64) on maintenance fluconazole, 4% (3/64) not on fluconazole and 3% (2/64) unknown. Twelve weeks post-discharge, 31/64 (48%) participants were lost to follow up. By 12 weeks post discharge 7/33 (21%) had died. Interviewed patients were asked if they were still on fluconazole, 11% (2/18) were not. Conclusions: Among hospitalised participants with CM, there were many missed opportunities for HIV care and linkage to ART prior to admission. Universal reflex CrAg screening may prompt earlier diagnosis of cryptococcal meningitis but there is a wider problem of timely linkage to care for HIV-seropositive people. [ABSTRACT FROM AUTHOR]

Candida auris is an invasive healthcare-associated fungal pathogen. Cases of candidemia, defined as illness in patients with Candida cultured from blood, were detected through national laboratory-based surveillance in South Africa during 2016-2017. We identified viable isolates by using mass spectrometry and sequencing. Among 6,669 cases (5,876 with species identification) from 269 hospitals, 794 (14%) were caused by C. auris. The incidence risk for all candidemia at 133 hospitals was 83.8 (95% CI 81.2-86.4) cases/100,000 admissions. Prior systemic antifungal drug therapy was associated with a 40% increased adjusted odds of C. auris fungemia compared with bloodstream infection caused by other Candida species (adjusted odds ratio 1.4 [95% CI 0.8-2.3]). The crude in-hospital case-fatality ratio did not differ between Candida species and was 45% for C. auris candidemia, compared with 43% for non-C. auris candidemia. C. auris has caused a major epidemiologic shift in candidemia in South Africa. [ABSTRACT FROM AUTHOR]

To the Editor: We noted the report by Chowdhary et al. (1) and report Candida auris as a causative agent of candidemia in South Africa, with an estimated prevalence of [...]

To determine the epidemiology of Candida auris in South Africa, we reviewed data from public- and private-sector diagnostic laboratories that reported confirmed and probable cases of invasive disease and colonization for October 2012-November 2016. We defined a case as a first isolation of C. auris from any specimen from a person of any age admitted to any healthcare facility in South Africa. We defined probable cases as cases where the diagnostic laboratory had used a nonconfirmatory biochemical identification method and C. haemulonii was cultured. We analyzed 1,692 cases; 93% were from private-sector healthcare facilities, and 92% of cases from known locations were from Gauteng Province. Of cases with available data, 29% were invasive infections. The number of cases increased from 18 (October 2012-November 2013) to 861 (October 2015-November 2016). Our results show a large increase in C. auris cases during the study period, centered on private hospitals in Gauteng Province. [ABSTRACT FROM AUTHOR]

The ecological niche of Emergomyces africanus (formerly Emmonsia species), a dimorphic fungus that causes an AIDS-related mycosis in South Africa, is unknown. We hypothesized that natural infection with E. africanus occurs in wild small mammals. Using molecular detection with primers specific for E. africanus, we examined 1402 DNA samples from 26 species of mole-rats, rodents, and insectivores trapped in South Africa that included 1324 lung, 37 kidney, and 41 liver specimens. DNA of E. africanus was not detected in any animals. We conclude that natural infection of wild small mammals in South Africa with E. africanus has not been proven. [ABSTRACT FROM AUTHOR]

Neonatal candidaemia is a common, deadly and costly hospital-associated disease. To determine the genetic diversity of Candida parapsilosis causing fungaemia in South African neonatal intensive care units ( NICUs). From February 2009 through to August 2010, cases of candidaemia were reported through laboratory-based surveillance. C. parapsilosis isolates from neonatal cases were submitted for identification by internal transcribed spacer ( ITS) region sequencing, antifungal susceptibility testing and microsatellite genotyping. Cluster analysis was performed using Unweighted Pair Group Method with Arithmetic Mean ( UPGMA). Of 1671 cases with a viable Candida isolate, 393 (24%) occurred among neonates. Isolates from 143 neonatal cases were confirmed as C. parapsilosis sensu stricto. Many isolates were resistant to fluconazole (77/143; 54%) and voriconazole (20/143; 14%). Of 79 closely-related genotypes, 18 were represented by ≥2 isolates; 61 genotypes had a single isolate each. Seven clusters, comprised of 82 isolates, were identified at five hospitals in three provinces. Isolates belonging to certain clusters were significantly more likely to be fluconazole resistant: all cluster 7 isolates and the majority of cluster 4 (78%), 5 (89%) and 6 (67%) isolates ( P<.001). Candida parapsilosis-associated candidaemia in public-sector NICUs was caused by closely related genotypes and there was molecular evidence of undetected outbreaks as well as intra-hospital transmission. [ABSTRACT FROM AUTHOR]

Purpose of Review In this review, we provide an overview of emergomycosis from a clinical perspective and discuss the taxonomy and classification of the pathogens, epidemiology, pathophysiology of infection and mechanisms of pathogenesis, immunology, clinical manifestations, laboratory culture and diagnosis, molecular characterisation, therapy and prognosis. Recent Findings While Emergomyces pasteurianus is the most geographically-widespread species, Emergomyces africanus is endemic to Southern Africa and causes disseminated disease with cutaneous involvement primarily among patients with advanced human immunodeficiency virus (HIV) disease. Summary Emergomycosis, a disseminated clinical disease resulting from infection with dimorphic fungi in the genus Emergomyces , occurs primarily among immunocompromised patients. Further knowledge is needed on the pathophysiology, diagnosis and management of emergomycosis. [ABSTRACT FROM AUTHOR]

Background. Candida auris, a multidrug-resistant yeast that causes invasive infections, was first described in 2009 in Japan and has since been reported from several countries. Methods. To understand the global emergence and epidemiology of C. auris, we obtained isolates from 54 patients with C. auris infection from Pakistan, India, South Africa, and Venezuela during 2012·015 and the type specimen from Japan. Patient information was available for 41 of the isolates. We conducted antifungal susceptibility testing and whole-genome sequencing (WGS). Results. Available clinical information revealed that 41% of patients had diabetes mellitus, 51% had undergone recent surgery, 73% had a central venous catheter, and 41% were receiving systemic antifungal therapy when C. auris was isolated. The median time from admission to infection was 19 days (interquartile range, 9·6 days), 61% of patients had bloodstream infection, and 59% died. Using stringent break points, 93% of isolates were resistant to fluconazole, 35% to amphotericin B, and 7% to echinocandins; 41% were resistant to 2 antifungal classes and 4% were resistant to 3 classes. WGS demonstrated that isolates were grouped into unique clades by geographic region. Clades were separated by thousands of single-nucleotide polymorphisms, but within each clade isolates were clonal. Different mutations in ERG11 were associated with azole resistance in each geographic clade. Conclusions. C. auris is an emerging healthcare-associated pathogen associated with high mortality. Treatment options are limited, due to antifungal resistance. WGS analysis suggests nearly simultaneous, and recent, independent emergence of different clonal populations on 3 continents. Risk factors and transmission mechanisms need to be elucidated to guide control measures. [ABSTRACT FROM AUTHOR]

From February 2009 through August 2010, we compared species-level identification of bloodstream Candida isolates and susceptibility to fluconazole, voriconazole, and caspofungin between diagnostic and reference South African laboratories during national surveillance for candidemia. Diagnostic laboratories identified isolates to genus/species level and performed antifungal susceptibility testing, as indicated. At a reference laboratory, viable Candida isolates were identified to species-level using automated systems, biochemical tests, or DNA sequencing; broth dilution susceptibility testing was performed. Categorical agreement (CA) was calculated for susceptibility results of isolates with concordant species identification. Overall, 2172 incident cases were detected, 773 (36%) by surveillance audit. The Vitek 2 YST system (bioM' erieux Inc, Marcy l'Etoile, France) was used for identification (360/863, 42%) and susceptibility testing (198/473, 42%) of a large proportion of isolates. For the five most common species (n = 1181), species-level identification was identical in the majority of cases (Candida albicans: 98% (507/517); Candida parapsilosis: 92% (450/488); Candida glabrata: 89% (89/100); Candida tropicalis: 91% (49/54), and Candida krusei: 86% (19/22)). However, diagnostic laboratories were significantly less likely to correctly identify Candida species other than C. albicans versus C. albicans (607/664, 91% vs. 507/517, 98%; P < .001). Susceptibility data were compared for isolates belonging to the five most common species and fluconazole, voriconazole, and caspofungin in 860, 580, and 99 cases, respectively. Diagnostic laboratories significantly under-reported fluconazole resistance in C. parapsilosis (225/393, 57% vs. 239/393, 61%; P < .001) but over-reported fluconazole non-susceptibility in C. albicans (36/362, 10% vs. 3/362, 0.8%; P < .001). Diagnostic laboratories were less likely to correctly identify Candida species other than C. albicans, under-reported fluconazole resistance for C. parapsilosis and over-reported fluconazole resistance for C. albicans. [ABSTRACT FROM AUTHOR]

Background: We aimed to establish the prevalence of amphotericin B deoxycholate (AmBd)-related toxicities among South African patients with cryptococcosis and determine adherence to international recommendations to prevent, monitor and manage AmBd-related toxicities. Methods: Clinical data were collected from cases of laboratory-confirmed cryptococcosis at 25 hospitals, October 2012 –February 2013. Anemia was defined as hemoglobin (Hb) concentration <10 g/dl, hypokalemia as serum potassium (K) <3.4 mEq/L and nephrotoxicity as an increase in serum creatinine (Cr) to >1.1 times the upper limit of normal. To determine adherence to toxicity prevention recommendations, we documented whether baseline Hb, K and Cr tests were performed, whether pre-emptive hydration and IV potassium chloride (KCl) was administered prior to 80% and 60% of AmBd doses and whether daily oral KCl supplementation was given ≥60% of the time. To determine adherence to monitoring recommendations, we ascertained whether a daily fluid chart was completed, Hb was monitored weekly and K or Cr were monitored bi-weekly. Results: Of 846 patients, clinical data were available for 76% (642/846), 82% (524/642) of whom received AmBd. Sixty-four per cent (n = 333) had documented baseline laboratory tests, 40% (n = 211) were given pre-emptive hydration and 14% (n = 72) and 19% (n = 101) received intravenous and oral KCl. While on AmBd, 88% (n = 452) had fluid monitoring; 27% (n = 142), 45% (n = 235) and 44% (n = 232) had Hb, K and Cr levels monitored. Toxicities developed frequently during treatment: anemia, 16% (86/524); hypokalemia, 43% (226/524) and nephrotoxicity, 32% (169/524). Conclusion: AmBd-related toxicities occurred frequently but were potentially preventable with adequate monitoring, supplemental fluid and electrolyte therapies. [ABSTRACT FROM AUTHOR]

Objectives: To compare Candida species distribution and antifungal susceptibility at South African public- and private-sector hospitals.Methods: From February 2009 through to August 2010, laboratory-based surveillance for candidaemia was undertaken at 11 public-sector hospitals and >85 private-sector hospitals across South Africa. A case was defined as a patient of any age admitted to a sentinel hospital with isolation of Candida species from blood culture. Viable isolates were identified and tested for antifungal susceptibility at a reference laboratory. Demographic and limited clinical data were abstracted from laboratory records.Results: In total, 2172 cases of candidaemia were detected. Among patients with available data, almost two-thirds were critically ill (719/1138, 63%). On multivariable analysis, neonates [adjusted OR (aOR), 2.2; 95% CI, 1.5-3.1; P < 0.001] and patients diagnosed in Gauteng province (aOR, 1.9; 95% CI, 1.3-2.7; P < 0.001) or in the private sector (aOR, 1.9; 95% CI, 1.2-3.2; P = 0.008) were significantly more likely to be infected with Candida parapsilosis than any other Candida species. Of 531 C. parapsilosis isolates, only 199 (37%) were susceptible to fluconazole and voriconazole; 44% (123/282) of fluconazole-resistant isolates were voriconazole cross-resistant. Factors associated with fluconazole non-susceptible C. parapsilosis infection on multivariable analysis included diagnosis in Gauteng province (aOR, 4.2; 95% CI, 2.7-6.7; P < 0.001), an ICU (aOR, 2.3; 95% CI, 1.5-3.6; P < 0.001) or the private sector (aOR, 2.2; 95% CI, 1.4-3.5; P < 0.001).Conclusions: The dominance of triazole non-susceptible C. parapsilosis limits the choice of antifungal agents for management of candidaemia among critically ill neonates, children and adults in resource-limited South African hospitals. [ABSTRACT FROM AUTHOR]

Background:We aimed to establish the characteristics of patients with confirmedPneumocystis jiroveciipneumonia recruited by passive, sentinel laboratory-based surveillance. Method:The study design was prospective, observational, cross-sectional, laboratory-based sentinel surveillance. Laboratory-based surveillance ofPneumocystis jiroveciipneumonia (PJP), formerly known as Pneumocystis carinii pneumonia (PCP), was conducted in six South African provinces at 61 hospitals, of which 17 were sentinel sites, where surveillance officers collected clinical and demographic data from cases. A case was defined as a patient with a respiratory tract specimen that was confirmed positive forP. jiroveciiby immunofluorescent microscopy or PCR test, either as a first diagnosis or ≥ 30 days after the last confirmed laboratory diagnosis of PJP. The chi-square test or Fisher’s exact test were used to compare the categorical variables. Results:From 2006–2010, 1 537 cases of PJP were recorded. Eighty-nine per cent (460/518) were found to be human immunodeficiency virus (HIV)-infected. This was a first diagnosis of HIV infection in 57% of the cases. The case fatality ratio was 34% (177/525). Recurrent infection was significantly more common in the 26- to 45-year age group, compared to children aged ≤ 5 years (odds ratio 1.7, 95% confidence interval: 1.1–2.8) (p 0.040). Treatment for tuberculosis was common in cases aged ≥ 5 years (37%, 85/229). Conclusion:PJP was the acquired immune deficiency syndrome-defining illness in more than half of the patients detected through laboratory-based surveillance. The high mortality rate and number of recurrent cases is noteworthy. This study may not have reflected the full spectrum of clinical presentation of the disease as case report forms were only completed for hospitalised patients at sentinel surveillance sites. [ABSTRACT FROM AUTHOR]

Background. Retrospective data suggest that cryptococcal antigen (CrAg) screening in patients with late-stage human immunodeficiency virus (HIV) initiating antiretroviral therapy (ART) may reduce cryptococcal disease and deaths. Prospective data are limited. Methods. CrAg was measured using lateral flow assays (LFA) and latex agglutination (LA) tests in 645 HIV-positive, ART-naive patients with CD4 counts ≤100 cells/μL in Cape Town, South Africa. CrAg-positive patients were offered lumbar puncture (LP) and treated with antifungals. Patients were started on ART between 2 and 4 weeks and followed up for 1 year. Results. A total of 4.3% (28/645) of patients were CrAg positive in serum and plasma with LFA. These included 16 also positive by urine LFA (2.5% of total screened) and 7 by serum LA (1.1% of total). In 4 of 10 LFA-positive cases agreeing to LP, the cerebrospinal fluid (CSF) CrAg LFA was positive. A positive CSF CrAg was associated with higher screening plasma/serum LFA titers. Among the 28 CrAg-positive patients, mortality was 14.3% at 10 weeks and 25% at 12 months. Only 1 CrAg-positive patient, who defaulted from care, died from cryptococcal meningitis (CM). Mortality in CrAg-negative patients was 11.5% at 1 year. Only 2 possible CM cases were identified in CrAg-negative patients. Conclusions. CrAg screening of individuals initiating ART and preemptive fluconazole treatment of CrAg-positive patients resulted in markedly fewer cases of CM compared with historic unscreened cohorts. Studies are needed to refine management of CrAg-positive patients who have high mortality that does not appear to be wholly attributable to cryptococcal disease. [ABSTRACT FROM AUTHOR]

Background: The high burden of cryptococcal meningitis (CM) among people living with HIV persists despite widespread access to antiretroviral therapy. Efforts to prevent CM among people living with HIV could be hindered by a limited understanding of their lived experiences of CM and its diagnosis. Objectives: To explore and describe the experiences of people diagnosed with HIV-associated CM in routine care. Two public healthcare facilities in Johannesburg, South Africa. Method: This was a qualitative-methods exploratory, descriptive, phenomenological study. We conducted semi-structured, individual in-depth interviews with nine purposively sampled participants (comprising 5 men and 4 women). Data were analysed using the Moustakas phenomenological approach. Results: Five themes and several sub-themes emerged from the data. Participants described their experiences of being diagnosed, which were marked by intense headaches. Diagnosis of CM led to reduced quality of life, fear of death, and loss of income. Participants described their CM treatment experience and health-seeking behaviour including self-medication, seeking help from traditional healers and general practitioners and utilising public health facilities as a last resort. Barriers to care included negative healthcare workers' attitudes, unhealthy lifestyles, and poor knowledge of CM. Conclusion: People with HIV-associated CM face negative impacts prior to and after diagnosis. These patients struggled to access timely quality healthcare. Patients starting or restarting antiretroviral therapy, and thus at risk for CM, should receive CM education as part of HIV counselling. [ABSTRACT FROM AUTHOR]

Background: We describe the geographic distribution, clinical characteristics, and management of patients with disease caused by Emmonsia sp., a novel dimorphic fungal pathogen recently described in South Africa. Methods: We performed a multicenter, retrospective chart review of laboratory-confirmed cases of emmonsiosis diagnosed across South Africa from January 2008 through February 2015. Results: Fifty-four patients were diagnosed in 5/9 provinces. Fifty-one patients (94%) were human immunodeficiency virus coinfected (median CD4 count 16 cells/μL [interquartile range, 6-40]). In 12 (24%) of these, antiretroviral therapy had been initiated in the preceding 2 months. All patients had disseminated disease, most commonly involving skin (n = 50/52, 96%) and lung (n = 42/48, 88%). Yeasts were visualized on histopathologic examination of skin (n = 34/37), respiratory tissue (n = 2/4), brain (n = 1/1), liver (n = 1/2), and bone marrow (n = 1/15). Emmonsia sp. was cultured from skin biopsy (n = 20/28), mycobacterial/fungal and aerobic blood culture (n = 15/25 and n = 9/37, respectively), bone marrow (n = 12/14), lung (n = 1/1), lymph node (n = 1/1), and brain (n = 1/1). Twenty-four of 34 patients (71%) treated with amphotericin B deoxycholate, 4/12 (33%) treated with a triazole alone, and none of 8 (0%) who received no antifungals survived. Twenty-six patients (48%) died, half undiagnosed. Conclusions: Disseminated emmonsiosis is more widespread in South Africa and carries a higher case fatality rate than previously appreciated. Cutaneous involvement is near universal, and skin biopsy can be used to diagnose the majority of patients. [ABSTRACT FROM AUTHOR]

Vitamin D deficiency may increase susceptibility to opportunistic infections in HIV-infected individuals. We found no evidence that vitamin D deficiency increases risk of cryptococcal meningitis or leads to impaired immune responses or microbiological clearance in HIV-infected patients with cryptococcal meningitis.Background. Vitamin D deficiency is associated with impaired immune responses and increased susceptibility to a number of intracellular pathogens in individuals infected with human immunodeficiency virus (HIV). It is not known whether such an association exists with Cryptococcus neoformans.Methods. Levels of 25-hydroxyvitamin D (25[OH]D) were measured in 150 patients with cryptococcal meningitis (CM) and 150 HIV-infected controls in Cape Town, South Africa, and associations between vitamin D deficiency and CM were examined. The 25-hydroxyvitamin D levels and cryptococcal notifications were analyzed for evidence of reciprocal seasonality. Associations between 25(OH)D levels and disease severity, immune responses, and microbiological clearance were investigated in the patients with CM.Results. Vitamin D deficiency (plasma 25[OH]D ≤50 nmol/L) was present in 74% of patients. Vitamin D deficiency was not associated with CM (adjusted odds ratio, 0.93 [95% confidence interval, .6–1.6]; P = .796). Levels of 25(OH)D showed marked seasonality, but no reciprocal seasonality was seen in CM notifications. No significant associations were found between 25(OH)D levels and fungal burden or levels of tumor necrosis factor α, interferon γ, interleukin 6, soluble CD14, or neopterin in cerebrospinal fluid. Rates of fungal clearance did not vary according to vitamin D status.Conclusions. Vitamin D deficiency does not predispose to the development of CM, or lead to impaired immune responses or microbiological clearance in HIV-infected patients with CM. [ABSTRACT FROM PUBLISHER]