Orbital apex syndrome caused by Alternaria species: A novel invasive fungus and new treatment paradigm.

Orbital apex syndrome as a result of invasive fungal sinusitis is a disease entity most commonly found in immunocompromised patients. Infectious invasion affecting the orbital apex can have devastating visual and life-threatening consequences. Mucormycosis and Aspergillus species are the most common causes of such infections. Alternaria fungal sinusitis is a known entity, but its ability to cause an orbital apex syndrome has not yet been reported. Here, we present a case of orbital apex syndrome in an immunocompromised patient with invasive fungal sinusitis caused by Alternaria species. The patient underwent sinus washout and placement of an intraorbital catheter for local instillation of amphotericin B for 10 days, in addition to systemic antifungal treatment, with clinical resolution of infection. The use of an intraorbital catheter for local treatment of fungal infection may offer an exenteration-sparing treatment option in these patients.

Incidence, risk factors, and outcome of blood stream infections during the first 100 days post-pediatric allogeneic and autologous hematopoietic stem cell transplantations.

Bloodstream infections (BSI) are a frequently observed complication after hematopoietic stem cell transplant (HSCT). Retrospective analysis of clinical and microbiological data during the first 100 days from 302 consecutive pediatric patients who underwent HSCT for a malignant disease at our institute between January 2013 and June 2017. A total of 164 patients underwent autologous and 138 allogeneic HSCT. The overall incidence of BSI was 37% with 92% of infectious episodes occurring during the pre-engraftment phase. Gram-positive bacteria (GPB) accounted for 54.6% of the isolated pathogens, gram-negative bacteria (GNB) for 43.9%, and fungi for 1.4%. Coagulase-negative staphylococci and Escherichia coli were the most commonly isolated GPB and GNB, respectively. Forty-five percent of GNB were extended-spectrum beta-lactamase producers and 21% were multidrug-resistant organisms. Fluoroquinolone resistance was 92% and 68%, among GPB and GNB, respectively. Risk factors for BSI in univariate analysis were allogeneic HSCT, delayed time to engraftment more than 12 days, previous BSI before HSCT, and alternative donor. In multivariate analysis, only HSCT type (allogeneic vs autologous P = .03) and previous BSI within 6 months before HSCT (P = .016) were significant. Overall survival at day 100 was 98% and did not differ significantly between patients with and without BSI (P = .76). BSI is common in children undergoing HSCT for malignant diseases. Allogeneic HSCT recipients and previous BSI within 6 months before HSCT are associated with increased risk of post-transplant BSI. With current supportive measures, BSI does not seem to confer an increased risk for 100-day mortality.

Essentials in Candida bloodstream infection.

AIMS: Due to the increase of severely immunocompromised patients, of invasive procedures including central intravascular catheters, and of the use of broad-spectrum antibiotics, the incidence of Candida bloodstream infections has risen intensely in the last decades. Candida bloodstream infection is a serious disease with high mortality. Optimized diagnostic and therapeutic management can improve outcome. Thus, the aim of our mini-review is to highlight important and often missed opportunities in the management of Candida bloodstream infection. METHODS: We searched the published literature and describe the essentials in the management of Candida bloodstream infection. RESULTS: Four essentials were identified: (1) isolation of Candida spp. from a blood culture should always be considered relevant and requires treatment. Daily blood cultures should be drawn to determine cessation of candidemia. (2) Central venous catheter (CVC) and/or other indwelling devices should be removed. (3) Echinocandins are the first choice. Antifungal treatment should be continued for at least 14 days after cessation of fungemia. Susceptibility testing should be performed to identify resistance and to facilitate transition to oral treatment. (4) In persistent candidemia, echocardiography is an important investigation; ophthalmoscopy should be considered. CONCLUSION: Further efforts should be undertaken to increase the adherence to the essentials in the management of Candia bloodstream infection.

Fungaemia caused by obstructive renal candida bezoars leads to bilateral chorioretinitis: a case report.

BACKGROUND: Renal fungal bezoars are remarkably rare and mostly occur in immunodeficient patients. Only a small number of cases with immunocompetent patients have been published so far. The published treatment approaches comprised systemic antimycotic therapy and surgical or minimal invasive removal of the fungal balls. In some cases irrigation of the renal duct system with amphotericin B was performed. By obstruction of the urinary tract bezoars can lead to infected hydronephrosis and severe urosepsis with high lethality. Fungaemia can cause fungal colonization in different distant organs. Fulminant chorioretinitis and irreversible visual impairment can be the consequence of ocular fundus colonization. The following report highlights that a co-operation between urologists and ophthalmologists is absolutely indispensible in case of fungaemia. CASE PRESENTATION: Hereinafter we describe a case of an immunocompetent 56 years old woman, presenting with flank pain and shivering. The diagnosis turned out to be difficult due to initially negative urine culture. The fungaemia caused by obstructive nephropathy led to bilateral candida chorioretinitis. The patient was treated with intravenous amphotericin b and the bezoar was removed by percutaneous "nephrolitholapaxy". After two months, a follow up revealed the patient felt well, chorioretinal lesions regressed and urine culture did not show any fungal growth. CONCLUSION: To the best of our knowledge, this is the first case reporting on obstructive renal bezoars, which lead to haematogenous fungus spread and bilateral chorioretinitis. It points out that extensive ophthalmologic examination should be performed in case of fungaemia even if the patient is not suffering from any visual impairment.

The epidemiology, antibiograms and predictors of mortality among critically-ill patients with central line-associated bloodstream infections.

BACKGROUND/PURPOSE: For high risk of central line-associated bloodstream infections (CLABSIs) in patients of intensive care units (ICUs) and scarcely epidemiology and therapeutic recommendations in Asia, we aimed to evaluate the annual change in epidemiology, antibiogram, and risk factors for 14-day mortality. METHODS: A retrospective study of ICUs patients with CLABSIs at a medical center in Taiwan (2010-2016), where central line care bundle implemented since 2014, by reviewing clinical data, pathogens, and the antibiogram. RESULTS: Gram-negative bacteria (59.3%) were main microorganisms of CLABSIs, and 9.0% of all GNB were MDROs. Acinetobacter spp., Enterobacter spp., and Stenotrophomonas maltophilia were the most frequently isolated. In multivariate analysis, malignancy, inadequate empirical antimicrobial therapy, inadequate definite antimicrobial therapy, and infection by fungi or multidrug-resistant organisms (MDROs) were associated with 14-day mortality (all p < 0.05). The CLABSI incidence rate decreased from 5.54 to 2.18 per 1000 catheter-day (from 2014 to 2015) with improved compliance to care bundle. Carbapenem and aminoglycoside were suitable empirical drugs in the hospital setting when GNB is predominant for CLABSI. Significant decreasing susceptibility of ampicillin/sulbactam in Enterobacter spp. (36.7%-0.0%), and ampicillin/sulbactam (12.5%-0.0%), ceftazidime (100.0%-52.9%), and tigecycline (87.5%-35.3%) in Serratia marcescens. CONCLUSION: We identified Gram-negative bacteria as leading pathogens of CLABSIs in a Taiwan medical center, and good compliance to care bundle is associated with reduced CLABSI incidence rate. Malignancy, infection by MDROs or fungi, inadequate empirical or definite antimicrobial therapy are significant factors for 14-day mortality.

Central line-associated bloodstream infections among critically-ill patients in the era of bundle care.

BACKGROUND/PURPOSE: Patients admitted to intensive care units (ICUs) are at high risk for central line-associated bloodstream infections (CLABSIs). Bundle care has been documented to reduce CLABSI rates in Western countries, however, few reports were from Asian countries and the differences in the epidemiology or outcomes of critically-ill patients with CLABSIs after implementation of bundle care remain unknown. We aimed to evaluate the incidence, microbiological characteristics, and factors associated with mortality in critically-ill patients after implementation of bundle care. METHODS: Prospective surveillance was performed on patients admitted to ICUs at the National Taiwan University Hospital, Taipei, Taiwan from January 2012 to June 2013. The demographic, microbiological, and clinical data of patients who developed CLABSI according to the National Healthcare Safety Network definition were reviewed. A total of 181 episodes of CLABSI were assessed in 156 patients over 46,020 central-catheter days. RESULTS: The incidence of CLABSI was 3.93 per 1000 central-catheter days. The predominant causative microorganisms isolated from CLABSI episodes were Gram-negative bacteria (39.2%), followed by Gram-positive bacteria (33.2%) and Candida spp. (27.6%). Median time from insertion of a central catheter to occurrence of CLABSI was 8 days. In multivariate analysis, the independent factors associated with mortality were higher Pitt bacteremia score [odds ratio (OR) 1.41; 95% confidence interval (CI) 1.18-1.68] and longer interval between onset of CLABSIs and catheter removal (OR 1.10; 95% CI 1.02-1.20), respectively. CONCLUSION: In institutions with a high proportion of CLABSI caused by Gram-negative bacteria, severity of bacteremia and delay in catheter removal were significant factors associated with mortality.

Fungal Endocarditis: Update on Diagnosis and Management.

Fungal endocarditis is an extremely debilitating disease associated with high morbidity and mortality. Candida spp. are the most common isolated organisms in fungal endocarditis. It is most prevalent in patients who are immunosuppressed and intravenous drug users. Most patients present with constitutional symptoms, which are indistinguishable from bacterial endocarditis, hence a high index of suspicion is required for pursuing diagnosis. Diagnosis of fungal endocarditis can be very challenging: most of the time, blood cultures are negative or take a long time to yield growth. Fungal endocarditis mandates an aggressive treatment strategy. A medical and surgical combined approach is the cornerstone of therapy.

Fungemia por Trichosporon asahii en un paciente con neoplasia hematológica / Fungemia due to Trichosporon asahii in a patient with hematological malignancy

Antecedentes. La tricosporonosis es una infección oportunista debida a hongos levaduriformes del género Trichosporon. La mayoría de los casos de tricosporonosis invasiva acontecen en individuos inmunodeficientes. Caso clínico. Describimos un caso de infección diseminada por Trichosporon asahii en un paciente hematológico. Se trata de un varón de 52 años diagnosticado de leucemia linfoblástica aguda que desarrolla un cuadro febril durante el tercer ciclo de quimioterapia de inducción. A las 24 h de incubación se observó positividad en los hemocultivos extraídos, visualizándose en la tinción de Gram estructuras alargadas compatibles con elementos fúngicos. La identificación del hongo como Trichosporon asahii se llevó a cabo mediante la asimilación de compuestos de carbono y la amplificación y secuenciación de los dominios D1/D2 y la región espaciadora interna transcrita del ADN ribosómico. El hongo se aisló además de unas lesiones pustulosas que presentaba el paciente en la región pectoral. Tras tratamiento con anfotericina B, el paciente evolucionó favorablemente de las lesiones y del proceso febril. Conclusiones. Trichosporon asahii es un patógeno emergente en pacientes inmunodeprimidos y su presencia no debe ser considerada como colonización, pues existe riesgo de infección invasiva (AU)

Background. Trichosporonosis is an opportunistic infection caused by the genus Trichosporon. The majority of cases of invasive trichosporonosis occurs in immunocompromised individuals. Case report. We describe a case of disseminated infection by Trichosporon asahii in a hematology patient. A 52-year-old man diagnosed with acute lymphoblastic leukemia developed a febrile episode during the third cycle of the induction chemotherapy. The blood cultures were positive after 24 h incubation, showing elongated structures compatible with fungal elements in the Gram stain. The identification of the fungus as Trichosporon asahii was carried out by the assimilation of compounds of carbon and the amplification and sequencing of the D1/D2 domain and the internal transcribed spacer of the ribosomal DNA. The fungus was also isolated from the pustular lesions that the patient had in the chest. After treatment with amphotericin B, the patient progressed satisfactorily. Conclusions. Trichosporon asahii is an emergent pathogen in immunosupressed patients and its presence should not be considered as colonization, as there is risk of invasive infection (AU)

Invasive infections due to filamentous fungi other than Aspergillus: epidemiology and determinants of mortality.

The epidemiology of invasive fungal disease (IFD) due to filamentous fungi other than Aspergillus may be changing. We analysed clinical, microbiological and outcome data in Australian patients to determine the predisposing factors and identify determinants of mortality. Proven and probable non-Aspergillus mould infections (defined according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria) from 2004 to 2012 were evaluated in a multicentre study. Variables associated with infection and mortality were determined. Of 162 episodes of non-Aspergillus IFD, 145 (89.5%) were proven infections and 17 (10.5%) were probable infections. The pathogens included 29 fungal species/species complexes; mucormycetes (45.7%) and Scedosporium species (33.3%) were most common. The commonest comorbidities were haematological malignancies (HMs) (46.3%) diabetes mellitus (23.5%), and chronic pulmonary disease (16%); antecedent trauma was present in 21% of cases. Twenty-five (15.4%) patients had no immunocompromised status or comorbidity, and were more likely to have acquired infection following major trauma (p <0.01); 61 (37.7%) of cases affected patients without HMs or transplantation. Antifungal therapy was administered to 93.2% of patients (median 68 days, interquartile range 19-275), and adjunctive surgery was performed in 58.6%. The all-cause 90-day mortality was 44.4%; HMs and intensive-care admission were the strongest predictors of death (both p <0.001). Survival varied by fungal group, with the risk of death being significantly lower in patients with dematiaceous mould infections than in patients with other non-Aspergillus mould infections. Non-Aspergillus IFD affected diverse patient groups, including non-immunocompromised hosts and those outside traditional risk groups; therefore, definitions of IFD in these patients are required. Given the high mortality, increased recognition of infections and accurate identification of the causative agent are required.

[Invasive fungal disease due to Scedosporium, Fusarium and mucorales]. / Enfermedad fúngica invasora por Scedosporium, Fusarium y Mucor.

The number of emerging organisms causing invasive fungal infections has increased in the last decades. These etiological agents include Scedosporium, Fusarium and mucorales. All of them can cause disseminated, virulent, and difficult-to treat infections in immunosuppressed patients, the most affected, due to their resistance to most available antifungal agents. Current trends in transplantation including the use of new immunosuppressive treatments, the common prescription of antifungal agents for prophylaxis, and new ecological niches could explain the emergence of these fungal pathogens. These pathogens can also affect immunocompetent individuals, especially after natural disasters (earthquakes, floods, tsunamis), combat wounds or near drowning. All the invasive infections caused by Scedosporium, Fusarium, and mucorales are potentially lethal and a favourable outcome is associated with rapid diagnosis by direct microscopic examination of the involved tissue, wide debridement of infected material, early use of antifungal agents including combination therapy, and an improvement in host defenses, especially neutropenia.

Chronic granulomatous disease presenting as hemophagocytic lymphohistiocytosis: a case report.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent infections and a dysregulated inflammatory response. Infection-triggered hemophagocytic lymphohistiocytosis (HLH), which manifests itself as pathologic hyperactive inflammation, has been observed in subjects with CGD. However, there have been no reports of HLH as the initial presentation with subsequent diagnosis of CGD. Furthermore, the primary therapeutic strategy for HLH focuses on immunosuppressive therapies, which limits immune-mediated tissue damage. With immunodeficiency, this therapeutic strategy may worsen the outcome. This article discusses an 8-week-old Hispanic male who presented with fever of unknown origin. The initial diagnostic evaluation demonstrated pathologic hyperactive inflammation, meeting the HLH-2004 diagnostic criteria without an identified infectious etiology. Immunosuppressive therapy was initiated, with subsequent disseminated candida septic shock and sepsis-induced multisystem organ failure. Additional evaluations ultimately established the diagnosis of CGD. We transitioned to an immune-enhancing strategy with granulocyte and immunoglobulin infusions, and intensified antifungal therapies. These interventions ultimately led to the clearance of the fungal infection and the resolution of the hyperactive inflammatory state. This case represents the first reported case of HLH as the presenting finding leading to the subsequent diagnosis of CGD. It serves as a reminder that both immunodeficiency and inflammatory disorders may share features of pathologic hyperactive inflammation and highlights the conundrum that clinicians face when treating HLH in the setting of an unresolved infection. In this case report, we demonstrate that immune-enhancing therapies may aid in the control and the clearance of the infection, thus paradoxically decreasing the pathologic hyperactive inflammatory response.

Clinical and microbiological characteristics of Rhodotorula mucilaginosa infections in a tertiary-care facility.

BACKGROUND: Rhodotorula spp. are an emergent opportunistic pathogen, particularly in immunocompromised individuals. MATERIALS AND METHODS: The aim of the study was to review reported cases of Rhodotorula infection over a period of 9 years to determine epidemiology, risk factors, treatment and outcome. RESULTS: The Rhodotorula spp. were isolated from cerebrospinal fluid (9) and blood (5). The most common pre-disposing factors were prolonged hospital stay (>1 month) and prolonged usage of broad-spectrum antibiotics (>1 month). All the isolates were identified as R. mucilaginosa by conventional methods. Amphotericin B demonstrated lowest minimum inhibitory concentration (MIC) as compared with other anti-fungal agents (fluconazole, itraconazole and voriconazole). CONCLUSIONS: The recognition of unusual yeasts as an agent of life-threatening infection and their intrinsic resistance increases the burden on the mycology laboratory for complete species identification and to determine minimum inhibitory concentration.

Brote de fungemia por Candida parapsilosis en una unidad de cuidados intensivos neonetal: genotipificación molecular basada en el estudio de microsatélites / Outbreak of fungemia caused by Candida parapsilosis in a neonatal intensive care unit: Molecular investigation through microsatellite analysis

Antecedentes. Las infecciones oportunistas son un problema cada vez más frecuente en los hospitales, y Candida parapsilosis se está convirtiendo en un importante patógeno nosocomial, sobre todo en las unidades de cuidados intensivos neonatales (UCIN) donde ha sido responsable de brotes de candidiasis invasoras. En recién nacidos, los factores de riesgo de infección por C. parapsilosis incluyen la prematuridad, bajo peso al nacer, la hospitalización prolongada, los catéteres venosos centrales permanentes, alimentación parenteral, las emulsiones grasas por vía intravenosa y la administración de antibióticos de amplio espectro. Para esclarecer el origen y evolución de estos brotes hospitalarios, pueden utilizarse métodos moleculares, que permiten estudiar las variaciones genéticas entre los aislamientos clínicos. Objetivos. El objetivo del presente estudio fue estudiar un brote de C. parapsilosis en la UCIN del Hospital das Clinicas, Facultad de Medicina de Botucatu, un hospital de asistencia terciaria de São Paulo, Brasil, usando una técnica de genotipificación molecular basada en el estudio de microsatélites. Métodos. Durante un período de 43 días en la UCIN, se diagnosticaron un total de 11 casos de fungemia por C. parapsilosis. Para confirmar el brote, todas las cepas se sometieron a análisis de tipificación molecular utilizando la técnica de microsatélites. Resultados. Se observó el mismo genotipo en 9 de las 11 cepas estudiadas, lo que permitió confirmar la presencia de un brote de C. parapsilosis en la UCIN del hospital. Conclusiones. El presente estudio revela que el análisis de marcadores de microsatélites puede ser de utilidad para los objetivos ya mencionados. Es de destacar la importancia de usar técnicas moleculares para la detección precoz de brotes hospitalarios y la introducción eficaz de medidas preventivas, en especial en las UCIN(AU)

Background. Opportunistic infections are an increasingly common problem in hospitals, and the yeast Candida parapsilosis has emerged as an important nosocomial pathogen, especially in neonatal intensive care units (NICUs) where it has been responsible for outbreak cases. Risk factors for C. parapsilosis infection in neonates include prematurity, very low birth weight, prolonged hospitalization, indwelling central venous catheters, hyperalimentation, intravenous fatty emulsions and broad spectrum antibiotic therapy. Molecular methods are widely used to elucidate these hospital outbreaks, establishing genetic variations among strains of yeast. Aims. The aim of this study was to detect an outbreak of C. parapsilosis in an NICU at the “Hospital das Clinicas”, Faculty of Medicine of Botucatu, a tertiary hospital located in São Paulo, Brazil, using the molecular genotyping by the microsatellite markers analysis. Methods. A total of 11 cases of fungemia caused by C. parapsilosis were identified during a period of 43 days in the NICU. To confirm the outbreak all strains were molecularly typed using the technique of microsatellites. Results. Out of the 11 yeast samples studied, nine showed the same genotypic profile using the technique of microsatellites. Conclusions. Our study shows that the technique of microsatellites can be useful for these purposes. In conclusion, we detected the presence of an outbreak of C. parapsilosis in the NICU of the hospital analyzed, emphasizing the importance of using molecular tools, for the early detection of hospital outbreaks, and for the introduction of effective preventive measures, especially in NICUs(AU)

Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis.

INTRODUCTION: Fungal sepsis is an increasingly common problem in intensive care unit patients.Mortality from fungal sepsis remains high despite antimicrobial therapy that is highly active against most fungal pathogens, a finding consistent with defective host immunity that is present in many patients with disseminated fungemia.One recently recognized immunologic defect that occurs in patients with sepsis is T cell "exhaustion" due to increased expression of programmed cell death -1 (PD-1).This study tested the ability of anti-PD-1 and anti-programmed cell death ligand -1 (anti-PD-L1) antagonistic antibodies to improve survival and reverse sepsis-induced immunosuppression in two mouse models of fungal sepsis. METHODS: Fungal sepsis was induced in mice using two different models of infection, that is, primary fungal sepsis and secondary fungal sepsis occurring after sub-lethal cecal ligation and puncture (CLP).Anti-PD-1 and anti-PD-L1 were administered 24 to 48 h after fungal infection and effects on survival, interferon gamma production, and MHC II expression were examined. RESULTS: Anti-PD-1 and anti-PD-L1 antibodies were highly effective at improving survival in primary and secondary fungal sepsis.Both antibodies reversed sepsis-induced suppression of interferon gamma and increased expression of MHC II on antigen presenting cells.Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4), a second negative co-stimulatory molecule that is up-regulated in sepsis and acts like PD-1 to suppress T cell function, also improved survival in fungal sepsis. CONCLUSIONS: Immuno-adjuvant therapy with anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies reverse sepsis-induced immunosuppression and improve survival in fungal sepsis.The present results are consistent with previous studies showing that blockade of PD-1 and CTLA-4 improves survival in bacterial sepsis.Thus, immuno-adjuvant therapy represents a novel approach to sepsis and may have broad applicability in the disorder.Given the relative safety of anti-PD-1 antibody in cancer clinical trials to date, therapy with anti-PD-1 in patients with life-threatening sepsis who have demonstrable immunosuppression should be strongly considered.