[Skin lesions associated with invasive candidiasis in a neutropenic patient with acute myeloid leukemia] / Lesiones cutáneas asociadas a candidiasis invasiva en un paciente neutropénico con leucemia mieloide aguda.

A 51-year-old male with profound and prolonged neutropenia 12 days after receiving chemotherapy for an acute myeloid leukemia developed a nodular, erythematous lesion with a necrotic center on the base of the neck, associated with fever, chills, and myalgia. An invasive fungal infection was diagnosed after growth of Candia tropicalis in blood cultures. He evolved with multiple reddish papular lesions concentrated mainly on the trunk, although they also spread to the extremities. The most common skin lesions of disseminated candidiasis are erythematous-violaceous papules with vesicular centers, which, in some cases, can progress to necrosis. Other forms of cutaneous presentation of invasive candidiasis are ecthyma gangrenosum-like lesions, hemorrhagic plaques or bullae, rash resembling folliculitis, and subcutaneous nodules.

Un varón de 51 años que se encontraba con neutropenia profunda y prolongada luego de 12 días del inicio de su quimioterapia por una leucemia mieloide aguda desarrolló una lesión nodular, eritematosa y con centro necrótico en la base del cuello, asociada a fiebre, escalofríos y mialgias. Se diagnosticó infección fúngica invasiva luego del desarrollo de Candia tropicalis en los hemocultivos. Evolucionó con múltiples lesiones papulares rojizas concentradas principalmente en el tronco, aunque también extendidas a las extremidades. Las lesiones cutáneas más frecuentes de la candidiasis diseminada son pápulas eritematosas-violáceas con centros vesiculares, que, en algunos casos, pueden evolucionar a necrosis. Otras formas de presentación cutánea de la candidiasis invasiva son lesiones similares a ectima gangrenoso, placas o bullas hemorrágicas, erupción que resembla foliculitis, y nódulos subcutáneos.

Antibody ligation of CEACAM1, CEACAM3, and CEACAM6, differentially enhance the cytokine release of human neutrophils in responses to Candida albicans.

Invasive candidiasis is a healthcare-associated fungal infection with a high mortality rate. Neutrophils, the first line of defense during fungal infections, express the immunoregulatory Candida albicans receptors CEACAM1, CEACAM3, and CEACAM6. We analyzed the effects of specific antibodies on C. albicans-induced neutrophil responses. CEACAM6 ligation by 1H7-4B and to some extent CEACAM1 ligation by B3-17, but not CEACAM3 ligation by 308/3-3, resulted in the immediate release of stored CXCL8 and altered transcriptional responses of the C. albicans-stimulated neutrophils. Integrated network analyses and dynamic simulations of signaling cascades predicted alterations in apoptosis and cytokine secretion. We verified that CEACAM6 ligation enhanced Candida-induced neutrophil apoptosis and increased long-term IL-1ß/IL-6 release in responses to C. albicans. CEACAM3 ligation, but not CEACAM1 ligation, increased the long-term release of pro-inflammatory IL-1ß/IL-6. Taken together, we demonstrated for the first time that ligation of CEACAM receptors differentially affects the regulation of C. albicans-induced immune functions in human neutrophils.

Factors determining the mortality in cirrhosis patients with invasive candidiasis: A systematic review and meta-analysis.

The impact of invasive candidiasis (IC) on the outcomes in the non-conventional high-risk cirrhosis population is poorly characterized. Therefore, we reviewed the outcomes and their influencing factors in cirrhosis patients with IC. PubMed, Embase, Ovid, CINHAL, and Web of Science were searched for full-text observational studies describing mortality due to IC in cirrhosis. We did a systematic review and random-effects meta-analysis to pool the point-estimate and comparative-odds of mortality. The estimate's heterogeneity was explored on sub-groups, outliers-test, and meta-regression. We evaluated the asymmetry in estimates on funnel plot and Eggers regression. Quality of studies was assessed on the New-Castle Ottawa scale. Of 3143 articles, 13 studies (611 patients) were included (good/fair quality: 6/7). IC patients were sick with a high model for end-stage liver disease (MELD: 27.0) and long hospital stay (33.2 days). The pooled-mortality was 54.7% (95% CI: 41.3--67.5), I2: 80%, P < 0.01. Intensive care unit (ICU) admission (P < 0.001), site of infection; viz. peritonitis and candidemia (P = 0.014) and high MELD of cases (P = 0.029) were predictors of high mortality. The odds of mortality due to IC was 4.4 times higher than controls and was 8.5 and 3.3 times higher than non-infected, and bacterially-infected controls. Studies in ICU-admitted (OR: 5.0) or acute-on-chronic liver failure (ACLF, OR: 6.3) patients had numerically higher odds of mortality than all-hospitalized cirrhosis patients (OR: 4.0). In conclusion, substantially high mortality is reported in cirrhosis patients with IC. ICU admission, ACLF, high MELD, peritonitis, and candidemia are key factors determining high mortality in cirrhosis patients with IC. LAY SUMMARY: We report a high mortality rate of 55% in patients with liver cirrhosis and invasive candidiasis. Higher odds (4.4 times) of death, especially in patients with ACLF (6.3 times) or ICU admission (5.0 times) were seen. Candida peritonitis and candidemia are associated with high mortality in cirrhosis.

Clinical characteristics and treatment outcome of Candida tracheobronchitis.

ABSTRACT: Although Candida species can cause invasive fungal diseases, such as disseminated infection and pneumonia, they rarely cause tracheobronchitis, which is often fatal.To identify the clinical characteristics of Candida tracheobronchitis, we retrospectively evaluated 8 patients who had pathologically proven Candida tracheobronchitis.Their median age was 64 (range: 51-70) years and 5 were females. Three patients had solid cancers and 5 had hematological malignancies. We classified tracheobronchitis into localized and diffuse types. Of the 8 patients, 5 had localized and 3 had diffuse tracheobronchitis. While all patients with diffuse tracheobronchitis had predisposing risk factors for invasive fungal disease, such as prolonged corticosteroid use, recent use of nucleoside analogues, or recent neutropenia (<500/m3), only 2 of the 5 with localized tracheobronchitis had predisposing risk factors. Four of the 5 patients with localized tracheobronchitis had loco-regional bronchial mucosal damage (e.g., radiation or photodynamic therapy). Although all 8 patients ultimately died, some improved with or without antifungal treatment. Two of the 5 patients (1 with localized and the other with diffuse tracheobronchitis) who received antifungal agents improved after treatment, and 1 patient with localized tracheobronchitis who did not receive antifungal treatment improved spontaneously. Two of the 3 patients with diffuse tracheobronchitis did not respond to antifungal treatment.Candida tracheobronchitis can present as both localized and diffuse types. While the former was influenced more by loco-regional mucosal damage, the latter was influenced more by the patient's immune status. The treatment outcomes were especially poor in patients with diffuse tracheobronchitis.

Potency of gastrointestinal colonization and virulence of Candida auris in a murine endogenous candidiasis.

BACKGROUND: Candida auris infections have recently emerged worldwide, and this species is highly capable of colonization and is associated with high levels of mortality. However, strain-dependent differences in colonization capabilities and virulence have not yet been reported. OBJECTIVES: In the present study, we aimed to clarify the differences between clinically isolated invasive and non-invasive strains of C. auris. METHODS: We evaluated colonization, dissemination, and survival rates in wild C57BL/6J mice inoculated with invasive or non-invasive strains of C. auris under cortisone acetate immunosuppression, comparing with those of Candida albicans and Candida glabrata infections. We also evaluated the potency of biofilm formation. RESULTS: Stool fungal burdens were significantly higher in mice inoculated with the invasive strains than in those infected with the non-invasive strain. Along with intestinal colonization, liver and kidney fungal burdens were also significantly higher in mice inoculated with the invasive strains. In addition, histopathological findings revealed greater dissemination and colonization of the invasive strains. Regarding biofilm-forming capability, the invasive strain of C. auris exhibited a significantly higher capacity of producing biofilms. Moreover, inoculation with the invasive strains resulted in significantly greater loss of body weight than that noted following infection with the non-invasive strain. CONCLUSIONS: Invasive strains showed higher colonization capability and rates of dissemination from gastrointestinal tracts under cortisone acetate immunosuppression than non-invasive strains, although the mortality rates caused by C. auris were lower than those caused by C. albicans.

[Hepatolienal candidosis as a rare differential diagnosis of disseminated small parenchym lesions]. / Hepatolienale Candidose als seltene Differenzialdiagnose disseminierter kleinherdiger Parenchymveränderungen.

HISTORY: We report about a 17-year-old patient with the secondary malignancy of acute myeloid leukemia (AML). He developed fever of unclear origin during the hematopoietic stem cell transplantation.History We report about a 17-year-old patient with the secondary malignancy of acute myeloid leukemia (AML). He developed fever of unclear origin during the hematopoietic stem cell transplantation. EXAMINATIONS: In the focus search, the routine sonography of the abdomen showed disseminated hypoechoic small- parenchymal lesions of the liver. In the complementary MRI, disseminated small lesions of the liver parenchyma and the spleen were demarked after contrast agent administration. DIAGNOSIS: Imaging revealed suspicion of hepatolienal candiasis.Diagnosis Imaging revealed suspicion of hepatolienal candiasis. THERAPY: Empirical therapy with amphotericin B was used. A sonographic punch biopsy of the liver was performed. The pathological examination showed oval particles in the PAS staining in the sense of an opportunistic mycosis of the Candida infection type. CONCLUSION: The case shows that in immunosuppressed patients, candidiasis must always be considered as a differential diagnosis with simultaneous parenchymal changes in the liver and/or spleen. In addition, in the screening situation, a suitable linear transducer should be used when asking about fungal lesions in the liver and spleen. Alternatively, if suspected hepato-lienal candidiasis could be diagnosed by a contrast-enhanced MRI of the upper abdomen/abdomen.

Candidalysin Is Required for Neutrophil Recruitment and Virulence During Systemic Candida albicans Infection.

BACKGROUND: Candidalysin is a cytolytic peptide toxin secreted by Candida albicans hyphae and has significantly advanced our understanding of fungal pathogenesis. Candidalysin is critical for mucosal C albicans infections and is known to activate epithelial cells to induce downstream innate immune responses that are associated with protection or immunopathology during oral or vaginal infections. Furthermore, candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes. However, the role of candidalysin in driving systemic infections is unknown. METHODS: In this study, using candidalysin-producing and candidalysin-deficient C albicans strains, we show that candidalysin activates mitogen-activated protein kinase (MAPK) signaling and chemokine secretion in endothelial cells in vitro. RESULTS: Candidalysin induces immune activation and neutrophil recruitment in vivo, and it promotes mortality in zebrafish and murine models of systemic fungal infection. CONCLUSIONS: The data demonstrate a key role for candidalysin in neutrophil recruitment and fungal virulence during disseminated systemic C albicans infections.

ECMM CandiReg-A ready to use platform for outbreaks and epidemiological studies.

BACKGROUND: Recent outbreaks of Candida auris further exemplify that invasive Candida infections are a substantial threat to patients and healthcare systems. Even short treatment delays are associated with higher mortality rates. Epidemiological shifts towards more resistant Candida spp. require careful surveillance. OBJECTIVES: Triggered by the emergence of C auris and by increasing antifungal resistance rates the European Confederation of Medical Mycology developed an international Candida Registry (FungiScope™ CandiReg) to allow contemporary multinational surveillance. METHODS: CandiReg serves as platform for international cooperation to enhance research regarding invasive Candida infections. CandiReg uses the General Data Protection Regulation compliant data platform ClinicalSurveys.net that holds the electronic case report forms (eCRF). Data entry is supported via an interactive macro created by the software that can be accessed via any Internet browser. RESULTS: CandiReg provides an eCRF for invasive Candida infections that can be used for a variety of studies from cohort studies on attributable mortality to evaluations of guideline adherence, offering to the investigators of the 28 ECMM member countries the opportunity to document their cases of invasive Candida infection. CandiReg allows the monitoring of epidemiology of invasive Candida infections, including monitoring of multinational outbreaks. Here, we describe the structure and management of the CandiReg platform. CONCLUSION: CandiReg supports the collection of clinical information and isolates to improve the knowledge on epidemiology and eventually to improve management of invasive Candida infections. CandiReg promotes international collaboration, improving the availability and quality of evidence on invasive Candida infection and contributes to improved patient management.

Fatal necrotizing Candida esophagitis in a patient with leukocytoclastic cutaneous vasculitis and ankylosing spondylitis

Esophageal infection by Candida spp. is a common opportunistic entity in immunocompromised hosts; however, systemic fungal dissemination due to perforation or transmural necrosis, also known as necrotizing Candida esophagitis (NCE), is rare. We report the case of a 61-year-old male patient with diagnosed ankylosing spondylitis, severe arteriosclerosis, and vasculitis under immunosuppressive therapy who presented NCE with fungal and bacterial septicemia diagnosed at autopsy. Necrotizing esophagitis is a rare manifestation of Candida infection, which may be a final complication in severely ill patients. Unfortunately, it may be underdiagnosed, and we call attention to this devastating complication in patients with leukocytoclastic cutaneous vasculitis and ankylosing spondylitis.

Invasive Candida tropicalis Infection Caused by Catheter Biofilm in a Patient with Tongue Cancer.

Systemic infections due to Candida tropicalis are conditions which can frequently lead to death. The aim of this report is to describe the features of C. tropicalis biofilm in a patient with catheter-associated fungemia.

Pathology of Neonatal Non- albicans Candidiasis: Autopsy Study and Literature Review.

INTRODUCTION/OBJECTIVES: Non- albicans Candida species such as Candida parapsilosis and Candida glabrata have emerged as prevalent pathogens in premature infants. The aim of this study was to systematically delineate the histopathologic findings in neonatal non- albicans candidiasis. METHODS: We performed a retrospective clinicopathologic analysis of extremely premature (23-28 weeks' gestation) infants diagnosed with invasive candidiasis. Archival autopsy tissues were subjected to periodic acid-Schiff, methenamine-silver and anti- Candida (immuno)histochemical stains, as well as dual anti- Candida and anti-cytokeratin or anti-CD31 immunofluorescence assays. In addition, we studied the prevalence of intestinal Candida colonization in a consecutive autopsy series of extremely premature infants. RESULTS: Based on positive postmortem blood and/or lung cultures, invasive candidiasis (3 non- albicans and 11 Candida albicans) was diagnosed in 14 of the 187 extremely premature infants examined between 1995 and 2017. In contrast to the well-known inflammatory and tissue-destructive phenotype of congenital C. albicans infection, invasive non- albicans candidiasis/candidemia caused by C. parapsilosis and C. glabrata was inconspicuous by routine hematoxylin-eosin-based histopathologic analysis despite a heavy fungal presence detected in intestines, lungs, and blood by targeted (immuno)histochemical assays. Intestinal colonization by Candida species was identified in 16 of the 26 (61%) extremely premature neonates who had lived for at least 1 week, as assessed by anti- Candida immunostaining. CONCLUSION: Invasive neonatal non- albicans candidiasis/candidemia appears to have no distinct histopathologic signature. Based on the notoriously low sensitivity of fungal blood cultures and the observed high frequency of Candida intestinal colonization (>50%), it is likely that non- albicans candidiasis/candidemia may be underdiagnosed in (deceased) preterm infants. Routine inclusion of targeted (immuno)histochemical fungal detection strategies in the perinatal autopsy may lead to deeper insight into the prevalence and clinical relevance of neonatal non- albicans candidiasis.

Fungal spinal epidural abscess: a case series of nine patients.

BACKGROUND CONTEXT: Fungal spinal epidural abscess (FSEA) is a rare entity with high morbidity and mortality. Reports describing the clinical features, diagnosis, treatment, and outcomes of FSEA are scarce in the literature. PURPOSE: This study aimed to describe the clinical features, diagnosis, treatment, and outcomes of FSEA. STUDY DESIGN: This study is designed as a retrospective clinical case series. PATIENT SAMPLE: A continuous series of patients with the diagnosis of FSEA who presented at our institution from 1993 to 2016. METHODS: We reviewed the electronic medical records of patients with SEA who were treated within our hospital system from 1993 to 2016. We only included SEA cases that were due to fungi. We also reviewed FSEA cases in the English language literature from 1952 to 2017 to analyze the features of FSEA. RESULTS: From a database of 1,053 SEA patients, we identified 9 patients with FSEA. Aspergillus fumigatus was isolated from 2 (22%) patients, and Candida species were isolated from 7 (78%). Focal spine pain, neurologic deficit, and fever were demonstrated in 89%, 50%, and 44% of FSEA cases, respectively. Five of nine cases involved the thoracic spine, and eight were located anterior to the thecal sac. Three cases had fungemia, six had long symptom duration (>2 weeks) prior to presentation, seven had concurrent immunosuppression, and eight had vertebral osteomyelitis. Additionally, one case had residual motor deficit at last follow-up, one had S1 sensory radicular symptoms, two suffered recurrent FSEA, two died within hospitalization, and two died within 90 days after discharge. CONCLUSIONS: In summary, the classic diagnostic triad (focal spine pain, neurologic deficit, and fever) is not of great clinical utility for FSEA. Biopsy, intraoperative tissue culture, and blood culture can be used to diagnose FSEA. The most common pathogens of FSEA are Aspergillus and Candida species. Therefore, empiric treatment for FSEA should cover these species while definitive identification is pending. FSEA is found in patients with poor baseline health status, which is the essential reason for its high mortality.

Are the Statins promising antifungal agents against invasive candidiasis?

The medical importance of intra-abdominal candidiasis (IAC) contrasts with the limited number of pharmacological treatment options available and the increasing rate of resistance to antifungal drugs. Thus, the repositioning of compounds in clinical use can contribute to the broadening of treatment possibilities for this infection. Statins, a class of drugs used to reduce cardiovascular event risk, have shown antiparasitic, antibacterial, and antiviral activities; however, their antifungal effects remain poorly studied. In this context, the present study aimed to elucidate the antifungal potential of six statins in vitro, as well as to evaluate the therapeutic use of fluvastatin in a mouse model of IAC. The biological effects of statins were evaluated against Candida spp., through the determination of the minimum inhibitory concentration (MIC). For the statins that showed activity, the fungicidal concentration, toxicity/selectivity, synergism with azoles and polyenes, phenotypic effects, and activity against virulence factors were also determined. Atorvastatin, rosuvastatin and fluvastatin were highly active, especially against C. albicans (MIC < 1-128 µg.mL-1) and C. glabrata (MIC 32-64 µg.mL-1). Fluvastatin and atorvastatin were selective for C. albicans in baby hamster kidney (BHK) cells. Moreover, all active statins in the antifungal assay showed high selectivity for fungal cells over bacteria. The combination of atorvastatin, rosuvastatin, and fluvastatin with azoles was associated with a synergistic effect. Active statins do not act on the fungal membrane or wall, but instead stimulate farnesol-dependent pathogenicity factors such as yeast-to-hyphal transition and biofilm generation. Fluvastatin treatment was evaluated in a mouse model of IAC, showing stimulation of the extra-hepatic dissemination of C. albicans but improvements in renal, splenic, and hepatic histological aspects. In conclusion, statins have potent antifungal activity in vitro, but the therapeutic effect in vivo is restricted to their anti-inflammatory activity.

Pathogenic Effects of IFIT2 and Interferon-ß during Fatal Systemic Candida albicans Infection.

A balanced immune response to infection is essential to prevent the pathology and tissue damage that can occur from an unregulated or hyperactive host defense. Interferons (IFNs) are critical mediators of the innate defense to infection, and in this study we evaluated the contribution of a specific gene coding for IFIT2 induced by type I IFNs in a murine model of disseminated Candida albicans Invasive candidiasis is a frequent challenge during immunosuppression or surgical medical interventions, and C. albicans is a common culprit that leads to high rates of mortality. When IFIT2 knockout mice were infected systemically with C. albicans, they were found to have improved survival and reduced fungal burden compared to wild-type mice. One of the mechanisms by which IFIT2 increases the pathological effects of invasive C. albicans appears to be suppression of NADPH oxidase activation. Loss of IFIT2 increases production of reactive oxygen species by leukocytes, and we demonstrate that IFIT2 is a binding partner of a critical regulatory subunit of NADPH oxidase, p67phox Since the administration of IFN has been used therapeutically to combat viral infections, cancer, and multiple sclerosis, we evaluated administration of IFN-ß to mice prior to C. albicans infection. IFN-ß treatment promoted pathology and death from C. albicans infection. We provide evidence that IFIT2 increases the pathological effects of invasive C. albicans and that administration of IFN-ß has deleterious effects during infection.IMPORTANCE The attributable mortality associated with systemic C. albicans infections in health care settings is significant, with estimates greater than 40%. This life-threatening disease is common in patients with weakened immune systems, either due to disease or as a result of therapies. Type I interferons (IFN) are cytokines of the innate defense response that are used as immune modulators in the treatment of specific cancers, viral infections, and multiple sclerosis. In this study, we show using a murine model that the loss of a specific IFN-stimulated gene coding for IFIT2 improves survival following systemic C. albicans infection. This result infers a harmful effect of IFN during C. albicans infection and is supported by our finding that administration of IFN-ß prior to invasive infection promotes fatal pathology. The findings contribute to our understanding of the innate immune response to C. albicans, and they suggest that IFN therapies present a risk factor for disseminated candidiasis.

Comparative virulence of Candida auris with Candida haemulonii, Candida glabrata and Candida albicans in a murine model.

The incidence of invasive fungal infections (IFIs) caused by uncommon Candida species with diverse virulence and susceptibility profiles has increased in recent years. Due to scarce clinical and experimental data on the pathogenicity of Candida auris, the aim of this study was to evaluate and compare the virulence of two rare clinically relevant species, C. auris and Candida haemulonii with Candida glabrata and Candida albicans in an immunocompetent murine model of disseminated infection. Immunocompetent ICR female mice were infected with three inoculum sizes (1 × 105 , 1 × 106 and 1 × 107 CFU/mouse) of two C. auris strains and one isolate of C. haemulonii, C. glabrata and C. albicans. Tissue burden on days 5 and 10 postchallenge and mortality rate were used as virulence markers. A high virulence was found for C. albicans, followed by C. auris, C. glabrata and C. haemulonii, respectively. Candida albicans showed high virulence with a medium survival time of 9.5 days for mice infected with 1 × 107 CFU/mouse. For inocula at 1 × 106 and 1 × 107 CFU/mouse, there were significant differences in fungal burden at day 10 between C. albicans, C. auris and C. glabrata isolates compared with C. haemulonii (P < .0001). Overall, no significant differences between C. albicans with C. auris and C. glabrata were observed in mice infected with three different inocula (P > .05). In general, the highest fungal load of all isolates was detected in kidney followed by spleen, liver and lung tested with three different inocula on the two different experimental days. Histopathological examination revealed the abundant presence of yeast cells with pseudohyphae for C. albicans and only yeast cells for C. auris, C. glabrata and C. haemulonii, in all the kidney tissue samples. In conclusion, C. albicans is a highly virulent opportunistic fungus, as the clinical and experimental data demonstrate, and also our results demonstrate a low virulence of C. haemulonii in immunocompetent animals. Altogether, this study highlights the pathogenic potential of C. auris.

Acute disseminated candidiasis with skin lesions: a systematic review.

BACKGROUND: Neutropenic patients developing acute disseminated candidiasis may present with skin lesions. AIMS: To evaluate the epidemiology of acute disseminated candidiasis with skin lesions in neutropenic patients, taking into consideration changes caused by different prophylactic strategies. SOURCES: A systematic review of English-language articles found via PubMed (1963-2016) was performed. We asked the following questions: (a) What Candida species are more frequently involved in this syndrome? (b) Has antifungal prophylaxis changed the species causing skin lesions? (c) What are the typical patterns of skin lesions? (d) What is the frequency of skin lesions in neutropenic patients with candidaemia or acute disseminated candidiasis? (e) Has antifungal prophylaxis decreased the incidence of acute disseminated candidiasis with skin lesions? CONTENT: Among 183 studies, 33 were selected, reporting 100 cases of acute disseminated candidiasis with skin lesions in neutropenic patients. It occurred more frequently in the setting of induction therapy for de novo or relapsed acute leukaemia, and the most frequent Candida species were C. tropicalis (68%) and C. krusei (15%). Diffuse maculopapular lesions predominated in cases caused by C. tropicalis and nodular and papular lesions in cases caused by C. krusei. Prophylaxis with fluconazole was reported in six cases, C. krusei in five and C. ciferrii in one. The death rate was 45.4%. IMPLICATIONS: Two patterns were recognized: disseminated maculopapular lesions caused by C. tropicalis in patients not receiving fluconazole prophylaxis, occurring in 39% to 44% of neutropenic patients with acute disseminated candidiasis, and nodular lesions caused by C. krusei in patients receiving fluconazole prophylaxis, occurring less frequently.

Pharmacokinetic Properties of Micafungin in Critically Ill Patients Diagnosed with Invasive Candidiasis.

The estimated attributable mortality rate for invasive candidiasis (IC) in the intensive care unit (ICU) setting varies from 30 to 40%. Physiological changes in critically ill patients may affect the distribution and elimination of micafungin, and therefore, dosing adjustments might be mandatory. The objective of this study was to determine the pharmacokinetic parameters of micafungin in critically ill patients and assess the probability of target attainment. Micafungin plasma concentrations were measured to estimate the pharmacokinetic properties of micafungin. MIC values for Candida isolates were determined to assess the probability of target attainment for patients. Data from 19 patients with suspected or proven invasive candidiasis were available for analysis. The median area under the concentration-time curve from 0 to 24 h at steady state (AUC0-24) was 89.6 mg · h/liter (interquartile range [IQR], 75.4 to 113.6 mg · h/liter); this was significantly lower than the median micafungin AUC0-24 values of 152.0 mg · h/liter (IQR, 136.0 to 162.0 mg · h/liter) and 134.0 mg · h/liter (IQR, 118.0 to 148.6 mg · h/liter) in healthy volunteers (P = <0.0001 and P = <0.001, respectively). All Candida isolates were susceptible to micafungin, with a median MIC of 0.016 mg/liter (IQR, 0.012 to 0.023 mg/liter). The median AUC0-24/MIC ratio was 5,684 (IQR, 4,325 to 7,578), and 3 of the 17 evaluable patients (17.6%) diagnosed with proven invasive candidiasis did not meet the AUC/MIC ratio target of 5,000. Micafungin exposure was lower in critically ill patients than in healthy volunteers. The variability in micafungin exposure in this ICU population could be explained by the patients' body weight. Our findings suggest that healthier patients (sequential organ failure assessment [SOFA] score of <10) weighing more than 100 kg and receiving 100 mg micafungin daily are at risk for inappropriate micafungin exposure and potentially inadequate antifungal treatment. (This study has been registered at ClinicalTrials.gov under identifier NCT01716988.).

Epidemiology, clinical characteristics, and risk factors for mortality of early- and late-onset invasive candidiasis in intensive care units in China.

To identify the epidemiology, treatments, outcomes, and risk factors for patients with early- or late-onset invasive candidiasis (EOIC or LOIC) in intensive care units in China.Patients were classified as EOIC (≤10 days) or LOIC (>10 days) according to the time from hospital admission to IC onset to identify distinct clinical characteristics.There were 105 EOIC cases and 201 LOIC cases in this study. EOIC was related to more severe clinical conditions at ICU admission or prior to IC. Significantly, more cases of Candida parapsilosis infection were found in patients with LOIC than in those with EOIC. The mortality of EOIC was significantly lower than that for LOIC. Sequential Organ Failure Assessment (SOFA) score at ICI diagnosis in the EOIC group and the interval from ICU admission to ICI occurrence in the LOIC group were identified as risk factors for mortality. Susceptibility to the first-line agent was associated with a lower risk of mortality in the LOIC group.The mortality rate was significantly lower in the EOIC group, and there were more cases of non-albicans infection in the LOIC group. Susceptibility to the first-line agent was an important predictor of mortality in the LOIC group. SOFA score at ICI diagnosis in the EOIC group and interval from ICU admission to ICI occurrence in the LOIC group were identified as risk factors for mortality.

Disseminated Candidiasis in a Young, Previously Healthy, Dog and Review of Literature.

BACKGROUND: The reports on disseminated candidiasis in dogs so far describe at least one predisposing factor. This case report, however, highlights candidiasis in a dog without any known predisposition. PATIENT: A 1.5-year-old intact female Hovawart dog was presented with subcutaneous nodules and polyuria/polydipsia. An excisional biopsy revealed a chronic pyogranulomatous and necrotizing inflammation with mycotic structures. The patient became febrile and lethargic, and developed lameness. METHODS: A physical examination, blood tests, urinalysis, thoracic radiographs, abdominal ultrasonography of the abdomen, fine-needle aspiration biopsies, and a culture of a subcutaneous nodule aspirate were obtained. Selected sections of multiple organs were collected for routine histology postmortem. The isolate and a subcutaneous mass were subjected to molecular identification and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analysis. RESULTS: Clinical, laboratory, and radiological findings were consistent with a granulomatous chronic systemic inflammation. Cytology and histology showed a pyogranulomatous and necrotizing inflammation with myriads of intra- and extra-cellular yeasts and extracellular hyphae. Culture yielded numerous yeast colonies, which appeared Candida albicans-like, but showed a negative serum test and a low identification in API 20 C AUX. Nucleic acid sequences showed homology with the C. albicans-type strain CBS 562. Multilocus sequence typing (MLST) resulted in a new type with designation DST121. The identification of the isolates was confirmed by MALDI-TOF-MS analysis. CONCLUSION AND CLINICAL IMPORTANCE: Future MLST typing and investigation of virulence can provide further evidence whether this MLST-type is associated with clinical cases of disseminated candidiasis without an apparent predisposing condition.

Initiation of phospholipomannan ß-1,2 mannosylation involves Bmts with redundant activity, influences its cell wall location and regulates ß-glucans homeostasis but is dispensable for Candida albicans systemic infection.

Pathogenic and non-pathogenic fungi synthesize glycosphingolipids, which have a crucial role in growth and viability. Glycosphingolipids also contribute to fungal-associated pathogenesis. The opportunistic yeast pathogen Candida albicans synthesizes phospholipomannan (PLM), which is a glycosphingolipid of the mannosylinositol phosphorylceramide family. Through its lipid and glycan moieties, PLM contributes to the initial recognition of the yeast, causing immune system disorder and persistent fungal disease through activation of host signaling pathways. The lipid moiety of PLM activates the deregulation signaling pathway involved in yeast phagocytosis whereas its glycan moiety, composed of ß-1,2 mannosides (ß-Mans), participates to inflammatory processes through a mechanism involving Galectin-3. Biosynthesis of PLM ß-Mans involves two ß-1,2 mannosyltransferases (Bmts) that initiate (Bmt5) and elongate (Bmt6) the glycan chains. After generation of double bmtsΔ mutants, we show that Bmt5 has redundant activity with Bmt2, which can replace Bmt5 in bmt5Δ mutant. We also report that PLM is located in the inner layer of the yeast cell wall. PLM seems to be not essential for systemic infection of the yeast. However, defect of PLM ß-mannosylation increases resistance of C. albicans to inhibitors of ß-glucans and chitin synthesis, highlighting a role of PLM in cell wall homeostasis.