Nosocomial Bloodstream Infections Research Articles

Nosocomial Bloodstream Infections in Children in Intensive Care Unit: Organisms, Sources, Their Sensitivity Pattern and Outcome of Treatment

Background: Nosocomial bloodstream infection in paediatric ICU is a leading, preventable infectious complication in critically ill patients and has a negative impact on patient’s outcome. This study was done to determine the type of pathogens responsible for nosocomial infections and its sensitivity pattern, to evaluate the probable sources (fomites) of nosocomial infections and also to compare the outcome of treatment between children with and without nosocomial bloodstream infections in terms of length of ICU stay and mortalityMaterial and methods: This study was conducted in the intensive care unit of Dhaka Shishu(children) hospital. Children between 0-5 years of age were included in the study. Blood culture positive case at the time of admission and Children discharged or died within 48 hours of admission were excluded. When children clinically suspected to have nosocomial infections, their blood culture and swab culture of probable sources were done.Results: Out 110 patients, 23(20.9%) patients developed nosocomial BSI. Neonates were found to be more susceptible to develop nosocomial BSI. Most of the organisms (86%) were Gram negative bacilli. Klebsiella was the most common pathogens (30.78%) followed by acinatobacter (21.73%), E-coli (13.04%), Pseudomonas (8.7%). Type of micro-organisms and their sensitivity pattern obtained from blood culture and sources culture of corresponding patient were almost similar which indicate the clue for probable source of nosocomial infection. Microorganisms were almost sensitive to Imipenem but there were high resistance to commonly used antibiotics including third generation cephalosporins. ICU acquired infections increase hospital mortality and duration of hospital stay.Conclusion: Nosocomial bloodstream infections in children in ICU are associated with high mortality rate and prolong hospital stay. Neonates are more susceptible to develop nosocomial BSI than children aged above 28 days. Gram negative organisms are predominant isolates and are developing resistance to commonly used antibiotics including third generation cephalosporin. Imipenem is the most effective and reliable antibiotic option. Fomites especially health care device including IV canula, suction catheter, endotracheal tubes, oxygen mask are the important probable sources of nosocomial infections.J Bangladesh Coll Phys Surg 2017; 35(3): 115-122

Antifungal defense of probiotic Lactobacillus rhamnosus GG is mediated by blocking adhesion and nutrient depletion.

Candida albicans is an inhabitant of mucosal surfaces in healthy individuals but also the most common cause of fungal nosocomial blood stream infections, associated with high morbidity and mortality. As such life-threatening infections often disseminate from superficial mucosal infections we aimed to study the use of probiotic Lactobacillus rhamnosus GG (LGG) in prevention of mucosal C. albicans infections. Here, we demonstrate that LGG protects oral epithelial tissue from damage caused by C. albicans in our in vitro model of oral candidiasis. Furthermore, we provide insights into the mechanisms behind this protection and dissect direct and indirect effects of LGG on C. albicans pathogenicity. C. albicans viability was not affected by LGG. Instead, transcriptional profiling using RNA-Seq indicated dramatic metabolic reprogramming of C. albicans. Additionally, LGG had a significant impact on major virulence attributes, including adhesion, invasion, and hyphal extension, whose reduction, consequently, prevented epithelial damage. This was accompanied by glucose depletion and repression of ergosterol synthesis, caused by LGG, but also due to blocked adhesion sites. Therefore, LGG protects oral epithelia against C. albicans infection by preventing fungal adhesion, invasion and damage, driven, at least in parts, by metabolic reprogramming due to nutrient limitation caused by LGG.

Improved Survival of Candida CLABSI by Adherence to Standard of Care and Involvement of Infectious Diseases Consultant: A 5-Year Experience in a Single Academic Center

Background Candidemia is the fourth most common nosocomial blood stream infection with significant morbidity and mortality. Central lines have been considered a risk factor for invasive fungal infection. We evaluated the epidemiology, management, and outcomes of Candida CLABSI in an academic medical center.Methods We conducted a retrospective cohort study in a single academic center from January 1, 2011 to December 31, 2016 of patients who had positive blood cultures for Candida sp. and met CDC criteria for CLABSI. Outcomes measured were 30-day mortality and relapse or recurrence. Descriptive statistics were used to compare the outcomes of patients who had infectious diseases consult and managed per standard of care (SOC) as defined by IDSA guidelines and those without.ResultsOf 722 CLABSI cases, 82 (11%) were due to Candida sp. Candida species isolated were as follows: C. glabrata (40%), C. albicans (32%), C. parapsilosis (9%), and others (19%). Median age of pediatric patients was 2.25 years (range 0.5–6) and median age of adults was 59 years (19–92). Most common comorbidities were malignancy (35%) and end-stage renal disease (21%). Non-tunneled catheters were present in 58% of cases. Median time from line placement to candidemia was 15 days (IQR 8–29). Sepsis was present in 34 (42%) cases. Seventy-four (90%) cases were initiated on antifungal therapy (AFT) when culture turned positive. After Candida speciation, AFT was adjusted appropriately for 82 (100%) cases. IDC was present in 56 (68%), of which 41 (73%) followed SOC, whereas 15 (27%) did not. Two of 26 patients (8%) without IDC received SOC. Complications occurred in 11/82 (13%) (three endocarditis, two osteomyelitis, three endophthalmitis, and four septic thrombophlebitis). Cure was achieved in 26/82 (32%). Relapse or recurrence occurred in 15/82 (18%). The 30-day mortality for the cohort was 50%. Patients with IDC who received SOC had lower mortality compared with those who did not (35% vs. 67%, respectively; P = 0.03).Conclusion Candida CLABSI was infrequent but had significant mortality in our cohort. Our results suggest that adherence to SOC per IDSA guidelines and involvement of IDC may improve survival of patients with Candida CLABSI. Future studies are needed to validate these findings.Disclosures All authors: No reported disclosures.

In vitro inhibitory activities of magnolol against Candida spp.

Candida spp. cause various infections involving the skin, mucosa, deep tissues, and even life-threatening candidemia. They are regarded as an important pathogen of nosocomial bloodstream infection, with a high mortality rate. As a result of prolonged exposure to azoles, the therapeutic failure associated with azoles resistance has become a serious challenge in clinical situations. Therefore, novel, alternative antifungals are required urgently. In the present study, the CLSI M-27A broth microdilution method and the 2,3-Bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assay were used to evaluate the antifungal effects of magnolol against various standard Candida strains in planktonic mode and biofilm formation, respectively. The antifungal activity of magnolol was demonstrated in planktonic C. albicans and non-albicans Candida species, especially fluconazole-resistant Candida krusei, with the minimum inhibitory concentrations ranging from 10 to 40 μg/mL. The BMIC90 (minimum concentration with 90% Candida biofilm inhibited) values of magnolol ranged from 20 to 160 μg/mL, whereas the BMIC90 values of fluconazole were more than 128 μg/mL. As an alternative and broad-spectrum antifungal agent, magnolol might be of benefit to the treatment of refractory Candida infection.

Loss of C-5 Sterol Desaturase Activity Results in Increased Resistance to Azole and Echinocandin Antifungals in a Clinical Isolate of Candida parapsilosis.

Among emerging non-albicans Candida species, Candida parapsilosis is of particular concern as a cause of nosocomial bloodstream infections in neonatal and intensive care unit patients. While fluconazole and echinocandins are considered effective treatments for such infections, recent reports of fluconazole and echinocandin resistance in C. parapsilosis indicate a growing problem. The present study describes a novel mechanism of antifungal resistance in this organism affecting susceptibility to azole and echinocandin antifungals in a clinical isolate obtained from a patient with prosthetic valve endocarditis. Transcriptome analysis indicated differential expression of several genes in the resistant isolate, including upregulation of ergosterol biosynthesis pathway genes ERG2, ERG5, ERG6, ERG11, ERG24, ERG25, and UPC2 Whole-genome sequencing revealed that the resistant isolate possessed an ERG3 mutation resulting in a G111R amino acid substitution. Sterol profiles indicated a reduction in sterol desaturase activity as a result of this mutation. Replacement of both mutant alleles in the resistant isolate with the susceptible isolate's allele restored wild-type susceptibility to all azoles and echinocandins tested. Disruption of ERG3 in the susceptible and resistant isolates resulted in a loss of sterol desaturase activity, high-level azole resistance, and an echinocandin-intermediate to -resistant phenotype. While disruption of ERG3 in C. albicans resulted in azole resistance, echinocandin MICs, while elevated, remained within the susceptible range. This work demonstrates that the G111R substitution in Erg3 is wholly responsible for the altered azole and echinocandin susceptibilities observed in this C. parapsilosis isolate and is the first report of an ERG3 mutation influencing susceptibility to the echinocandins.

Short-term Peripheral Venous Catheter-Related Bloodstream Infections: A Systematic Review.

Short-term peripheral venous catheters (PVCs) are commonly used in healthcare settings. To determine the magnitude of bloodstream infections (BSIs) related to their use, PubMed, article bibliographies, and the authors' library were searched for pertinent articles. The incidence of PVC-related BSIs was 0.18% among 85063 PVCs. Short-term PVCs accounted for a mean of 6.3% and 23% of nosocomial BSIs and nosocomial catheter-related BSIs, respectively. Prolonged dwell time and catheter insertion under emergent conditions increased risk of PVC-related bloodstream infection (PVCR-BSI). If approximately 200 million PVCs are successfully inserted into adult patients each year in the United States, there may be many PVCR-BSIs occurring yearly. Clinicians should obtain blood cultures in patients with evidence of PVC infection and systemic symptomatology such as fever, carefully inspect the PVC insertion site in bacteremic or fungemic patients, and remove PVCs associated with localized infection with or without associated BSI.

Clinical Characteristics of Nosocomial Bloodstream Infections in Neonates in Two Hospitals, China.

The improvement of medical condition requires prolonged hospital stays, which increase the risk of nosocomial bloodstream infections (BSIs). All nosocomial BSI newborns in two hospitals were included, and the demographic and clinical characteristics of bacteremia patients were obtained from the information systems. Isolates were identified by biochemical assays. Antimicrobial susceptibility was determined using disk diffusion method. Except for three same risk factors, intubation with mechanical ventilation was a risk factor in Chongqing, while low birth weight was a risk factor in Henan. Klebsiella pneumoniae was the predominant strain in Chongqing, and Escherichia coli was the most prevalent strain in Henan. The resistance rate of gram-negative bacteria in Henan was higher than that of strains in Chongqing. The risk factors and resistance rate of pathogens were different in different areas. Therefore, treatment protocols should be established based on the trends of drug resistance and bacterial spectrum.

Secular Trends in Nosocomial Vancomycin-Resistant Enterococcal Bloodstream Infections Among United States Veterans Affairs Hospitals, Fiscal Years 2004 through 2014.

Secular Trends in Nosocomial Vancomycin-Resistant Enterococcal Bloodstream Infections Among United States Veterans Affairs Hospitals, Fiscal Years 2004 through 2014.

Incidence, clinical characteristics, and outcomes of nosocomial Enterococcus spp. bloodstream infections in a tertiary-care hospital in Beijing, China: a four-year retrospective study

BackgroundEnterococcus spp. are the common cause of nosocomial bloodstream infections (BSIs) with high morbidity and mortality. The purpose of this study was to characterize the incidence, clinical and microbiological features, and mortality of nosocomial enterococcal BSIs at a large Chinese tertiary-care hospital in Beijing, China.MethodsA retrospective cohort study on adult patients with nosocomial BSIs due to Enterococcus spp. was performed between January 1, 2012, and December 31, 2015 at the Chinese People’s Liberation Army General Hospital. Patients’ data were gathered by reviewing electronic medical records.ResultsA total of 233 episodes of BSI due to Enterococcus spp. occurred among 224 patients during these 4 years. The overall incidence was 3.9 episodes per 10,000 admissions. Enterococcus faecium (E. faecium) was the major pathogen (74%, 95% CI 68–80%), followed by Enterococcus faecalis (E. faecalis) (20%, 95% CI 15–25%). E. faecium showed higher antimicrobial resistance than E. faecalis. The 30-day mortality of nosocomial enterococcal BSI was 24% (95% CI 18–29%). Predictors for mortality included the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, Charlson comorbidity index (CCI), impaired renal function, prior use of immunosuppressive agents, and appropriate empirical antimicrobial treatment.ConclusionsThis study emphasizes that Enterococcus spp. were major pathogens for nosocomial BSIs and associated with high mortality. Appropriate empirical antimicrobial treatment can improve outcomes. Vancomycin is the best choice for patients with E. faecium BSIs. Penicillins, aminoglycosides, fluoroquinolones, and vancomycin can be considered for patients with E. faecalis BSIs.

Extensively Drug-Resistant Klebsiella pneumoniae Causing Nosocomial Bloodstream Infections in China: Molecular Investigation of Antibiotic Resistance Determinants, Informing Therapy, and Clinical Outcomes.

The rise in diversity of antimicrobial resistance phenotypes seen in Klebsiella pneumoniae is becoming a serious antibiotic management problem. We sought to investigate the molecular characteristics and clinical implications of extensively drug-resistant (XDR) K. pneumoniae isolated from different nosocomial bloodstream infections (BSIs) patients from July 2013 to November 2015. Even in combination treatment, meropenem did not protect against mortality of BSIs patients (P = 0.015). In contrast, tigecycline in combination with other antimicrobial agents significantly protected against mortality (P = 0.016). Antimicrobial susceptibility tests, molecular detection of antibiotic resistance determinants, conjugation experiments, multilocus sequence typing (MLST), S1-PFGE, Southern blot, SDS-PAGE, immunoblot analysis, and pulsed-field gel electrophoresis (PFGE) were used to characterize these isolates. These XDR K. pneumoniae strains were resistant to conventional antimicrobials except tigecycline and polymyxin B and co-harbored diverse resistance determinants. rmtB, blaKPC−2 as well as blaCTX−M−9 were located on a transferable plasmid of ~54.2 kb and the most predominant replicon type was IncF. 23 of the 35 isolates belonging the predominant clone were found to incorporate the globally-disseminated sequence type ST11, but others including a unique, previously undiscovered lineage ST2281 (allelic profile: 4-1-1-22-7-4-35) were also found and characterized. The porins OmpK35 and OmpK36 were deficient in two carbapenemase-negative carbapenem-resistant strains, suggesting decreased drug uptake as a mechanism for carbapenem resistance. This study highlights the importance of tracking hospital acquired infections, monitoring modes of antibiotic resistance to improve health outcomes of BSIs patients and to highlight the problems of XDR K. pneumoniae dissemination in healthcare settings.

Factors associated with candidemia by non-albicans Candida group in midwest region of Brazil: Eight-year cross-sectional study

The alarming increase in the non-albicans Candida group (NAC) as the etiologic agent of bloodstream infections has made it necessary for the factors associated with candidemia caused by NAC to be elucidated. A cross-sectional retrospective study was conducted which included analysis of microbiological reports, medical records and hospital infection notifications in two tertiary hospitals (Mato Grosso, Brazil) over 8 years (2006 to 2014). Of 144 observed episodes of candidemia, the NAC group represented 64.6%. The prevalence of candidemia caused by NAC was equal to 1.10 × 1,000 admissions, which was statistically different (p<0.001) from and greater than the prevalence of Candida albicans (CA). Hospitalization in the intensive care unit (PR = 1.83; p = 0.05), length of stay ≥42 days (PR = 0.62; p = 0.01) and the use of H2 blockers (PR = 1.75; p = 0.03) were significantly associated with death in patients with candidemia caused by NAC, regardless of gender, use of central venous catheter, treatment with amphotericin B and mechanical ventilation. The incidence of candidemia caused by NAC was 34% higher in men and 40% higher in patients who remained hospitalized for ≥42 days, regardless of prematurity, neutropenia, catheter, mechanical ventilation and age. After 42 days of hospitalization, the chances of survival were 67.3% among patients with candidemia caused by NAC and 56.4% among patients with candidemia caused by CA. This study suggests a different behavior between CA and NAC groups, which should be especially considered for choice of treatment regimen with antifungals. Key words: Candidemia, nosocomial bloodstream infection, epidemiology, tertiary care centers.

Peptidoglycan Association of Murein Lipoprotein Is Required for KpsD-Dependent Group 2 Capsular Polysaccharide Expression and Serum Resistance in a Uropathogenic Escherichia coli Isolate.

ABSTRACTMurein lipoprotein (Lpp) and peptidoglycan-associated lipoprotein (Pal) are major outer membrane lipoproteins in Escherichia coli. Their roles in cell-envelope integrity have been documented in E. coli laboratory strains, and while Lpp has been linked to serum resistance in vitro, the underlying mechanism has not been established. Here, lpp and pal mutants of uropathogenic E. coli strain CFT073 showed reduced survival in a mouse bacteremia model, but only the lpp mutant was sensitive to serum killing in vitro. The peptidoglycan-bound Lpp form was specifically required for preventing complement-mediated bacterial lysis in vitro and complement-mediated clearance in vivo. Compared to the wild-type strain, the lpp mutant had impaired K2 capsular polysaccharide production and was unable to respond to exposure to serum by elevating capsular polysaccharide amounts. These properties correlated with altered cellular distribution of KpsD, the predicted outer membrane translocon for “group 2” capsular polysaccharides. We identified a novel Lpp-dependent association between functional KpsD and peptidoglycan, highlighting important interplay between cell envelope components required for resistance to complement-mediated lysis in uropathogenic E. coli isolates.

Ccr7-dependent amelioration of renal tubular injury protects against infection-induced acute kidney injury

Abstract Systemic candidiasis (SC) is a leading cause of nosocomial bloodstream infections, with mortality of &amp;gt;40% despite therapy. In a mouse model of SC, the most highly infected organ is the kidney, and myeloid cells, including dendritic cells (DCs), are integral for host defense. We hypothesized that Ccr7, which mediates DC trafficking and survival, is critical for host defense during SC. Ccr7 and its ligands, Ccl19 and Ccl21, were highly up-regulated in the Candida-infected kidney. All Ccr7−/− mice rapidly succumbed during SC, whereas WT mice had 80% survival at day 14. Infected Ccr7−/− mice had significantly greater kidney fungal burden, with greater tissue damage, and more severe renal failure. Infection in Ccl19−/− mice and in plt/plt mice (that lack Ccl19 and the CCL21a isoform of Ccl21) did not phenocopy the susceptibility of Ccr7−/− mice, indicating that the CCL21b-Ccr7 axis is critical for protection. Surprisingly, bone marrow chimeras revealed that the protective effects of Ccr7 are solely mediated by non-hematopoietic cells. Studies using FACS, IHC, and mRNA from sorted renal cells showed that Ccr7 is expressed by renal tubular cells (RTCs), not other renal stromal cells. Our preliminary data show the Ccr7 is a survival factor for RTCs; indeed, Ccr7 deficiency resulted in significantly greater tubulitis and tubular necrosis during SC. The renal protective effects of Ccr7 were also evident during bacterial sepsis, indicating that Ccr7 is broadly protective against infection-induced acute kidney injury. In summary, our data are the first to implicate Ccr7 in innate control of any pathogen and to uncover the contribution of Ccr7 on non-hematopoietic cells in protection against acute kidney injury and systemic fungal infection.

Past, Recent Progresses and Future Perspectives of Nanotechnology Applied to Antifungal Agents.

Candida species remain a significant cause of nosocomial bloodstream infections, associated with prolonged hospital stay in the ICU and high healthcare cost. The incidence of Candida is very high in certain risk groups of patients (AIDS, diabetes, cancer, etc.). Recent developments of nanotechnology have strongly contributed to the design of new multifunctional drug carriers that improve drug bioavailability through a controlled and prolonged release profile or even through a more specific targeted delivery of the antifungal agent. Those types of systems have strongly increased with a progressive generation of new structures, permitting the conjunction of new materials, biomolecules, physical and chemical techniques, for better outcomes. Nanotechnology shows expanded possibilities within the medical field and in the case of the yeast infections it may overcome several issues related with the fungal proliferation or higher inhibition of the pathogen causing the infection. This review covers a period of the most representative research of Candidiasis since 1993 to the present.

Changing Epidemiology of Coagulase-Negative Staphylococci in Normal Flora of Skin

Coagulase negative staphylococci (CoNS) have recently emerged as important pathogens causing nosocomial blood stream infections. To evaluate the prevalence of CoNS in cutaneous normal flora, skin swabs were collected from voluntary blood donors and processed for culture and identification using matrix assisted laser desorption ionisation-time of flight (MALDI-TOF). CoNS were isolated from 96% of blood donors, most commonly Staphylococcus hominis (86%), followed by Staphylococcus epidermidis (22%) and Staphylococcus haemolyticus (9%). There has been a shift in the prevalent species of CoNS in the community in India, from the earlier known S. epidermidis towards resistant species such as S. hominis and S. haemolyticus. Routine and rapid speciation of CoNS in clinical isolates with MALDI-TOF should be used effectively to manage these resistant species.

NOSOCOMIAL BLOOD STREAM INFECTIONS IN ADULT PATIENTS ADMITTED TO AL JUMHORIA HOSPITAL -BENGHAZI-LIBYA

As little information of antibiotic resistance in Libya is known.This study included 937 patients admitted to Al Jamhoryia hospital, Benghazi during 20092010.The results showed that rate of nosocomial blood stream infection (BSI) was 28% in 2009 and 27% in 2010 with the highest percentage of ICU (61%) in 2009. This study also showed that in 2009, the most frequently isolated bacteria among staphylococci was methicillin resistance Staphylococcus aureus (MRSA). However methicillin resistant Coagulase negative staphylococci accounted for (27.4%) Klebsiellapneumoniaere presented the highest percentage followed by Escherichia coli, S. hominis, S. aurues, S. epidermides, and Acinetobacterbaumannii. The rate of infection recorded in 2010 was (52.5%). This study showed that MRSA was the most prevalent pathogen. S. aurues isolates represented the highest percentage among all bacteria isolated (24.8%) followed by E. coli % S. hominis and S. epidermides. The occurrence of Extended Spectrum Beta-lactamase (ESBL) producing bacteria was 15.9% and 14.9% in 2009 and 2010 respectively. Antimicrobial sensitivity testing showed that Gram-positive isolates exhibited higher sensitivity patterns toward Rifampin (95.8%) followed by Teicoplanin (91.6%), Ciprofloxacin (90.2%), Vancomycin (87.4%), and Linezolid (84). High rate of resistance was observed against penicillins and 3rd generation cephalosporins. The rate of antibiotic resistant bacteria causing NBSI is increasing among Gram-positive and negative bacteria and creates a serious health problem in hospitals.

Candidemia in a major regional tertiary referral hospital – epidemiology, practice patterns and outcomes

BackgroundCandidemia is a common cause of nosocomial bloodstream infections, resulting in high morbidity and mortality. This study was conducted to describe the epidemiology, species distribution, antifungal susceptibility patterns and outcomes of candidemia in a large regional tertiary referral hospital.MethodsA retrospective surveillance study of patients with candidemia was conducted at Singapore General Hospital between July 2012 and December 2015. In addition, incidence densities and species distribution of candidemia episodes were analysed from 2008 to 2015.ResultsIn the period of 2012 to 2015, 261 candidemia episodes were identified. The overall incidence was 0.14/1000 inpatient-days. C. glabrata (31.4%), C. tropicalis (29.9%), and C. albicans (23.8%) were most commonly isolated. The incidence of C. glabrata significantly increased from 2008 to 2015 (Coefficient 0.004, confidence interval 0–0.007, p = 0.04). Fluconazole resistance was detected primarily in C. tropicalis (16.7%) and C. glabrata (7.2%). fks mutations were identified in one C. albicans and one C. tropicalis. Candidemia episodes caused by C. tropicalis were more commonly encountered in patients with haematological malignancies (p = 0.01), neutropenia (p < 0.001) and higher SAPS II scores (p = 0.02), while prior exposure to echinocandins was associated with isolation of C. parapsilosis (p = 0.001). Echinocandins (73.3%) were most commonly prescribed as initial treatment. The median (range) time to initial treatment was 1 (0–9) days. The 30-day in-hospital mortality rate was 49.8%. High SAPS II score (Odds ratio, OR 1.08; 95% confidence interval, CI 1.05–1.11) and renal replacement therapy (OR 5.54; CI 2.80–10.97) were independent predictors of mortality, while drain placement (OR 0.44; CI 0.19–0.99) was protective.ConclusionsDecreasing azole susceptibilities to C. tropicalis and the emergence of echinocandin resistance suggest that susceptibility patterns may no longer be sufficiently predicted by speciation in our institution. Candidemia is associated with poor outcomes. Strategies optimising antifungal therapy, especially in the critically-ill population, should be explored.

Pharmacological Blockade of the Chemokine Receptor CCR1 Protects Mice from Systemic Candidiasis of Hematogenous Origin.

Systemic candidiasis is a leading cause of nosocomial bloodstream infection with a high mortality rate despite treatment. Immune-based strategies are needed to improve outcomes. We previously reported that genetic deficiency in the chemokine receptor CCR1 improves survival and ameliorates tissue damage in Candida-infected mice. Here, we found that treatment of immunocompetent Candida-infected mice with the CCR1-selective antagonist BL5923 improves survival, decreases the kidney fungal burden, and protects from renal tissue injury.

Cell Intrinsic Galectin-3 Attenuates Neutrophil ROS-Dependent Killing of Candida by Modulating CR3 Downstream Syk Activation.

Invasive candidiasis is a leading cause of nosocomial bloodstream infection. Neutrophils are the important effector cells in host resistance to candidiasis. To investigate the modulation of neutrophil fungicidal function will advance our knowledge on the control of candidiasis. While recombinant galectin-3 enhances neutrophil phagocytosis of Candida, we found that intracellular galectin-3 downregulates neutrophil fungicidal functions. Co-immunoprecipitation and immunofluorescence staining reveal that cytosolic gal3 physically interacts with Syk in neutrophils after Candida stimulation. Gal3−/− neutrophils have higher level of Syk activation as well as greater abilities to generate reactive oxygen species (ROS) and kill Candida than gal3+/+ cells. While galectin-3 deficiency modulates neutrophil and macrophage activation and the recruitment of monocytes and dendritic cells, the deficiency does not affect the numbers of infiltrating neutrophils or macrophages. Galectin-3 deficiency ameliorates systemic candidiasis by reducing fungal burden, renal pathology, and mortality. Adoptive transfer experiments demonstrate that cell intrinsic galectin-3 negatively regulates neutrophil effector functions against candidiasis. Reducing galectin-3 expression or activity by siRNA or gal3 inhibitor TD139 enhances human neutrophil ROS production. Mice treated with TD139 have enhanced ability to clear the fungus. Our work unravels the mechanism by which galectin-3 regulates Syk-dependent neutrophil fungicidal functions and raises the possibility that blocking gal3 in neutrophils may be a promising therapeutic strategy for treating systemic candidiasis.

Multidrug-Resistant Candida haemulonii and C. auris, Tel Aviv, Israel.

Candida auris and C. haemulonii are closely related, multidrug-resistant emerging fungal pathogens that are not readily distinguishable with phenotypic assays. We studied C. auris and C. haemulonii clinical isolates from 2 hospitals in central Israel. C. auris was isolated in 5 patients with nosocomial bloodstream infection, and C. haemulonii was found as a colonizer of leg wounds at a peripheral vascular disease clinic. Liberal use of topical miconazole and close contact among patients were implicated in C. haemulonii transmission. C. auris exhibited higher thermotolerance, virulence in a mouse infection model, and ATP-dependent drug efflux activity than C. haemulonii. Comparison of ribosomal DNA sequences found that C. auris strains from Israel were phylogenetically distinct from isolates from East Asia, South Africa and Kuwait, whereas C. haemulonii strains from different countries were closely interrelated. Our findings highlight the pathogenicity of C. auris and underscore the need to limit its spread.