Anticytokine autoantibody-associated immunodeficiency.

Anticytokine autoantibodies are an emerging mechanism of disease in previously healthy adults. Patients with these syndromes demonstrate a unique infectious phenotype associated with neutralizing autoantibodies that target a specific cytokine. Examples include anti-interferon (IFN)-γ autoantibodies and disseminated nontuberculous mycobacteria; anti-granulocyte macrophage colony-stimulating factor autoantibodies and cryptococcal meningitis; anti-interleukin (IL)-6 autoantibodies and staphylococcal skin infection; and anti-IL-17A, anti-IL-17F, or anti-IL-22 autoantibodies and mucocutaneous candidiasis in the setting of either APECED (autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy syndrome) or thymoma. Other anticytokine autoantibodies may contribute to an infectious phenotype such as anti-granulocyte colony stimulating factor and anti-IFN-α autoantibodies, although the strength of the association is less clear. Their identification not only affects disease management but also may uncover key mechanisms of host defense against specific organisms. Furthermore, it raises the possibility that currently idiopathic diseases will someday be explained by a yet unidentified anticytokine autoantibody. This review focuses on the current understanding, both clinical and mechanistic, of anticytokine autoantibody-associated immunodeficiency.

Inflammatory Ly6Chigh Monocytes Protect against Candidiasis through IL-15-Driven NK Cell/Neutrophil Activation.

Neutrophils play a crucial role in defense against systemic candidiasis, a disease associated with a high mortality rate in patients receiving immunosuppressive therapy, although the early immune mechanisms that boost the candidacidal activity of neutrophils remain to be defined in depth. Here, we used a murine model of systemic candidiasis to explore the role of inflammatory Ly6Chigh monocytes in NK cell-mediated neutrophil activation during the innate immune response against C. albicans. We found that efficient anti-Candida immunity required a collaborative response between the spleen and kidney, which relied on type I interferon-dependent IL-15 production by spleen inflammatory Ly6Chigh monocytes to drive efficient activation and GM-CSF release by spleen NK cells; this in turn was necessary to boost the Candida killing potential of kidney neutrophils. Our findings unveil a role for IL-15 as a critical mediator in defense against systemic candidiasis and hold promise for the design of IL-15-based antifungal immunotherapies.

Vertebral Candidiasis, the State of the Art: A Systematic Literature Review.

OBJECTIVE: In recent years, Candida spondylodiscitis has represented an increasingly emerging disease in clinical practice. This condition requires long-term antibiotic therapy and sometimes surgical treatments. The main purpose of this study is to investigate the epidemiology, clinical and radiological aspects, treatment protocols, and outcomes of Candida-mediated vertebral osteomyelitis. METHODS: A systematic review of the English literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.The research was conducted on Medline, Cochrane library, PubMed, and Scopus using as search terms "vertebral"; "spinal"; "infection"; "spondylodiscitis"; "discitis"; "osteomyelitis"; "Candida"; and "Candidosis." A case of vertebral candidiasis that was surgically managed was also reported. RESULTS: In total, 88 articles were included in our systematic review. Including the reported case, our analysis covered 113 cases of vertebral candidiasis. Candida albicans was isolated in 64 cases (56.1%), Candida tropicalis in 21 (18.4%), Candida glabrata in 14 (12.3%), and Candida parapsilosis in five (4.4%). The mean duration of the follow-up was 395 days. Finally, 87 (82%) patients completely recovered, ten (9.4%) died, and nine (8.5%) reported sequelae. CONCLUSION: This systematic review summarized the state of the art on vertebral candidiasis, describing data on its clinical features, diagnostic criteria and current limitations, and treatment alternatives and their outcomes.

Candida Infectious Endocarditis and Implantable Cardiac Device Infections.

Intravascular diseases due to Candida species, including endocarditis and cardiac device-associated infections, are rare yet devastating manifestations of invasive candidiasis affecting an already vulnerable population. Despite their significant associated morbidity and mortality, limited prospective data exist to inform the optimal diagnostic and therapeutic approaches to these entities. Herein, we review the existing literature pertaining to the epidemiology, diagnosis, and management of infectious endocarditis, rhythm management device infections, and circulatory support device infections caused by Candida species and suggest areas for future research.

Appropriate Source Control and Antifungal Therapy are Associated with Improved Survival in Critically Ill Surgical Patients with Intra-abdominal Candidiasis.

BACKGROUND: Intra-abdominal candidiasis (IAC) is the predominant type of invasive candidiasis with high mortality in surgical intensive care patients. The purpose of this study was to investigate the impact of appropriate source control and antifungal therapy on the outcomes of critically ill surgical patients with IAC. METHODS: This was a retrospective single-center cohort study. Adult surgical patients who were admitted to the intensive care unit and diagnosed with IAC from January 1, 2003, to December 31, 2016, were enrolled. The patients' data including risk factors of IAC, infection-related information, antifungal treatment and 30-day outcomes were collected. The primary endpoint was 30-day mortality. A COX proportional hazards model was used to analyze the association between appropriate treatment and 30-day survival. RESULTS: A total of 82 patients were included in the analysis. Of these, 45 (54.9%) were complicated with septic shock at IAC diagnosis. Types of IAC included peritonitis (61.0%), intra-abdominal abscesses (23.2%) and biliary tract infections (15.9%). Of the included patients, 53 (64.6%) received appropriate source control and 44 (53.7%) appropriate antifungal therapy. Compared with patients with neither of these treatments, appropriate source control (HR 0.08, 95% CI 0.02-0.30; P < 0.001), appropriate antifungal therapy (HR 0.14, 95% CI 0.04-0.55; P = 0.005), and a combination of these treatments (HR 0.02, 95% CI 0.00-0.08; P < 0.001) were associated with reduced risk of death within 30 days after IAC diagnosis. CONCLUSION: For critically ill surgical patients with IAC, both appropriate source control and appropriate antifungal therapy were associated with reduced risk of 30-day mortality, and the protective effects of the two appropriate treatments were additive.

Pharmacists' clinical competency towards oral mucosal diseases: Results from a mystery shopper study.

OBJECTIVES: To investigate the clinical advices pharmacists would give to patients who present with various oral mucosal lesions. SUBJECTS AND METHODS: One hundred and twenty pharmacists in three major cities in the United Arab Emirates (UAE) were approached by senior dental students acting as mystery shoppers. Pharmacists were shown an image of one of four oral mucosal lesions representing candidosis, aphthous ulcer, erosive lichen planus and squamous cell carcinoma (SCC). Pharmacists' referral pattern and choices of medications were recorded and assessed against demographic variables. RESULTS: Eighty-eight per cent (88%) of pharmacists dispensed a non-prescription medication to treat the oral lesions, including SCC, while only 12% recommended that the lesion shown to them be assessed by a clinician. Among all referral recommendations, 32% were for SCC (p = .006). Geographical proximity of a clinic to the pharmacy was a significant factor in determining pharmacists' referral recommendation (p = .036). CONCLUSION: Most pharmacists dispensed a medication for oral mucosal lesions, including potentially malignant and malignant ones, without referring patients to a medical or dental practitioner. Pharmacists should be aware of the serious nature of some oral mucosal lesions and the necessity to refer those cases to a qualified practitioner for proper clinical assessment.

Quinine Improves the Fungicidal Effects of Antimicrobial Blue Light: Implications for the Treatment of Cutaneous Candidiasis.

BACKGROUND AND OBJECTIVE: Candida albicans is an opportunistic fungal pathogen of clinical importance and is the primary cause of fungal-associated wound infections, sepsis, or pneumonia in immunocompromised individuals. With the rise in antimicrobial resistance, it is becoming increasingly difficult to successfully treat fungal infections using traditional antifungals, signifying that alternative non-traditional approaches must be explored for their efficacy. STUDY DESIGN/MATERIALS AND METHODS: We investigated the combination of antimicrobial blue light (aBL) and quinine hydrochloride (Q-HCL) for improved inactivation of C. albicans, in vitro and in vivo, relative to either monotherapy. In addition, we evaluated the safety of this combination therapy in vivo using the TUNEL assay. RESULTS: The combination of aBL (108 J/cm2 ) with Q-HCL (1 mg/mL) resulted in a significant improvement in the inactivation of C. albicans planktonic cells in vitro, where a 7.04 log10 colony forming units (CFU) reduction was achieved, compared with aBL alone that only inactivated 3.06 log10 CFU (P < 0.001) or Q-HCL alone which did not result in a loss of viability. aBL + Q-HCL was also effective at inactivating 48-hour biofilms, with an inactivation 1.73 log10 CFU at the dose of 108 J/cm2 aBL and 1 mg/mL Q-HCL, compared with only a 0.73 or 0.66 log10 CFU by aBL and Q-HCL alone, respectively (P < 0.001). Transmission electron microscopy revealed that aBL + Q-HCL induced morphological and ultrastructural changes consistent with cell wall and cytoplasmic damage. In addition, aBL + Q-HCL was effective at eliminating C. albicans within mouse abrasion wounds, with a 2.47 log10 relative luminescence unit (RLU) reduction at the dose of 324 J/cm2 aBL and 0.4 mg/cm2 Q-HCL, compared with a 1.44 log10 RLU reduction by aBL alone. Q-HCL or nystatin alone did not significantly reduce the RLU. The TUNEL assay revealed some apoptotic cells before and 24 hours following treatment with aBL + Q-HCL. CONCLUSION: The combination of aBL + Q-HCL was effective at eliminating C. albicans both in vitro and in vivo. A comprehensive assessment of toxicity (cytotoxicity and genotoxicity) is required to fully determine the safety of aBL + Q-HCL therapy at different doses. In conclusion, the combination of aBL and Q-HCL may be a viable option for the treatment of cutaneous candidiasis. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Non-thermal atmospheric plasma treatment of onychomycosis in an in vitro human nail model.

BACKGROUND: Onychomycosis affects almost 6% of the world population. Topical azoles and systemic antifungal agents are of low efficacy and can have undesirable side effects. An effective, non-invasive therapy for onychomycosis is an unmet clinical need. OBJECTIVE: Determine the efficacy threshold of non-thermal atmospheric plasma (NTAP) to treat onychomycosis in an in vitro model. METHODS: A novel toe/nail-plate model using cadaver nails and agarose media inoculated with Candida albicans was exposed to a range of NTAP doses. RESULTS: Direct exposure of C albicans and Trichophyton mentagrophytes to 12 minutes of NTAP results in complete killing at doses of 39 and 15 kPulses, respectively. Onset of reduced viability of C albicans to NTAP treatment through the nail plate occurs at 64 kPulses with 10× and 100× reduction at 212 and 550 kPulses, respectively. CONCLUSIONS: NTAP is an effective, non-invasive therapeutic approach to onychomycosis that should be evaluated in a clinical setting.

Ozone Treatment Unveils the Veil of Candida parapsilosis Infection in the Knee Joint: A Case Report and Literature Review.

Candida infection is common, while Candida parapsilosis infection in the knee joint is rare. Local symptoms of Candida infections in the knee are atypical, rarely associated with systemic symptoms, and difficult to distinguish from other types of knee arthritis. We here report a special case of C. parapsilosis infections in the knee joint. A patient had previously undergone knee puncture in a private clinic for the treatment of osteoarthritis and developed a left knee joint infection with C. parapsilosis. However, the patient only showed more severe local knee symptoms, and there was no systemic manifestation associated with any Candida infection. Surprisingly, after receiving ozone lavage, the patient showed symptoms of a systemic infection such as fever and chills. There was no positive finding in the blood cultures. Finally, the synovial fluid cultures showed a C. parapsilosis infections. After antifungal treatment and another knee ozone therapy, the patient did not experience recurrence of the infections. It is suggested that in this special case, the strong sterilization with ozone caused the destruction of C. parapsilosis, leading to a transient systemic toxin reaction. In addition, we reviewed the 17 cases of C. parapsilosis infections that have been reported thus far.

Acute ischemic stroke treated with mechanical thrombectomy and fungal endocarditis: A case report and systematic review of the literature.

Fungal endocarditis is a rare clinical form of infective endocarditis. The main etiology of FE is Candida albicans but also Candida parapsilosis and the overall mortality is high. We report a case of an acute ischemic stroke treated by mechanical thrombectomy, with the histopathological analysis of the retrieved clot followed by the confirmation of fungal endocarditis. An extensive review of the literature has been proposed and three key points concerning the fungal endocarditis predisposing factors, the relation between thrombolysis and hemorrhagic risk and, finally, the importance of clot analysis have been discussed.

Synergistic Antifungal Effect of Amphotericin B-Loaded Poly(Lactic-Co-Glycolic Acid) Nanoparticles and Ultrasound against Candida albicans Biofilms.

Candida albicans is a human opportunistic pathogen that causes superficial and life-threatening infections. An important reason for the failure of current antifungal drugs is related to biofilm formation, mostly associated with implanted medical devices. The present study investigated the synergistic antifungal efficacy of low-frequency and low-intensity ultrasound combined with amphotericin B (AmB)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (AmB-NPs) against C. albicans biofilms. AmB-NPs were prepared by a double-emulsion method and demonstrated lower toxicity than free AmB. We then established biofilms and treated them with ultrasound and AmB-NPs separately or jointly in vitro and in vivo The results demonstrated that the activity, biomass, and proteinase and phospholipase activities of biofilms were decreased significantly after the combination treatment of AmB-NPs with 42 kHz of ultrasound irradiation at an intensity of 0.30 W/cm2 for 15 min compared with the controls, with AmB alone, or with ultrasound treatment alone (P < 0.01). The morphology of the biofilms was altered remarkably after joint treatment based on confocal laser scanning microscopy (CLSM), especially in regard to reduced thickness and loosened structure. Furthermore, the same synergistic effects were found in a subcutaneous catheter biofilm rat model. The number of CFU from the catheter exhibited a significant reduction after joint treatment with AmB-NP and ultrasound for seven continuous days, and CLSM and scanning electron microscopy (SEM) images revealed that the biofilm on the catheter surface was substantially eliminated. This method may provide a new noninvasive, safe, and effective therapy for C. albicans biofilm infection.

Candida auris: what have we learned so far?

PURPOSE OF REVIEW: The increasing prevalence of fungal infections due to Candida species has been well described in critically ill patient populations, but in recent years a new species, Candida auris has received attention from the medical community worldwide. We aim to summarize the current knowledge related to C. auris, as new identification techniques, novel antifungal agents and more experience with outbreak management have been published in the past few years. RECENT FINDINGS: C. auris has been described in several countries, arising independently in separate clades. Its resistance to multiple antifungals and persistent colonization of patients and medical surfaces have become a therapeutic and infection control challenge. Recent elucidation of some of the molecular mechanisms related to pathogenicity and studies of in-vitro efficacy of novel antifungal agents can better guide therapy. SUMMARY: As C. auris continues to cause outbreaks worldwide, newer, and more efficient identification techniques, novel antifungals, and more knowledge in effective infection control techniques will allow better clinical outcomes in the management and control of invasive fungal disease.

Fungal prosthetic aortic valve endocarditis and endarteritis: An unusual cause of aortic root vegetations.

Fungal endocarditis is a relatively rare occurrence with high morbidity and mortality. Patients may have an indolent and non-specific course requiring a high index of suspicion to make a diagnosis. Here, we present the case of a 33-year-old patient who presented with fevers and acute lower limb ischemia requiring a 4-compartment fasciotomy caused by septic emboli from Candida albicans endocarditis. The patient had a large vegetation in the ascending aorta associated with a mycotic aneurysm, which is an exceedingly rare location for a vegetation. We also review the literature and summarize the typical echocardiographic appearance and vegetation locations in fungal endocarditis.

Novel Therapies for Biofilm-Based Candida spp. Infections.

The presence of fungal infections continue to grow worldwide, mostly in immunosuppressed patients, and in individuals with continued antimicrobial treatments. Candida spp. are the most common yeasts involved in these disorders, being associated with a high rate of antifungal resistance and an increased ability to form biofilms, which make the treatment of these infections difficult. This review aims to present and discuss the main biofilm-related infections cause by several Candida spp. and novel therapies that are currently available in the clinical, scientific and academic environment. New drugs with promising antifungal activity, natural approaches (e.g. probiotics, essential oils, plant extracts, honey) and a final consideration on alternative methodologies, such as photodynamic therapy are presented and discussed.

Native Joint Septic Arthritis: Comparison of Outcomes with Medical and Surgical Management.

OBJECTIVE: To determine whether there are differences in the outcomes of native joint septic arthritis (SA) in adults, based on medical versus surgical management. METHODS: A 10-year retrospective single-center study was conducted of patients admitted to a tertiary care hospital between January 1, 2006 and December 31, 2015 with a diagnosis of SA to compare outcomes based on the management approach taken: medical (bedside closed-needle joint aspiration) versus surgical (arthrotomy/arthroscopy). Evaluated outcomes included joint recovery, time to recovery, length of stay, disposition to home versus rehabilitation unit, recurrence of SA in the same joint, and mortality. RESULTS: Of 118 confirmed cases of SA, 48 were in prosthetic joints and 70 were in native joints, and 61 met our inclusion criteria. Forty-one (67%) patients received surgery, and 20 (33%) received closed-needle aspiration. There was no statistically significant difference in long-term outcomes between the two groups at 12 months. Patients managed medically were more likely to experience full recovery at 3 months and were less likely to need short-term rehabilitation. CONCLUSIONS: Medical management with closed-needle aspiration may be an adequate approach to the treatment of native joint infections.

Candida glabrata-Induced Refractory Infectious Arthritis: A Case Report and Literature Review.

The incidence of deep fungal infection due to non-albicans Candida species (especially Candida glabrata) has significantly increased in recent decades. Candida glabrata is an opportunistic pathogen of low virulence which mainly invades the gastrointestinal, genitourinary, and respiratory tracts, but has rarely been reported as complication of articular surgery in the literature. We present a case of knee fungal arthritis caused by C. glabrata after a minimally invasive arthroscopic surgery. In this case, the patient's knee got infected after arthroscopic treatment for a recurrent popliteal cyst, and she was unable to be cured by either debridement or antifungal drugs. Mycological and molecular identification of the necrotic tissues isolate revealed C. glabrata as etiologic agent. We originally planned to conduct a debridement once again, but it was found that the articular cartilage was extensively damaged during the operation. Besides, the magnetic resonance imaging of the affected knee also showed that the infection had invaded the subchondral bone. So we treated this case with a two-stage primary total knee arthroplasty with an antibiotic-laden cement spacer block. After a 10-month follow-up, the patient had completely recovered and has not experienced any recurrence to date. In addition, we review 21 cases of C. glabrata-induced infectious arthritis described to date in the literature.

Prosthetic Joint Infections Caused by Candida Species: A Systematic Review and a Case Series.

The purpose of this study was to evaluate the efficacy of echinocandins in the treatment of Candida prosthetic joint infection (PJI) based on published literature and on patients we examined. A structured literature review of multiple databases was conducted to identify patients who received echinocandins for Candida PJIs. Additionally, we describe here the first cases of PJIs due to C. parapsilosis, successfully treated with prolonged anidulafungin therapy. Out of 17 patients, 12 were female and the mean age at diagnosis was 66.0 years. No risk factors associated with Candida PJIs were found in four patients (23.5%). Infection sites included the knee (n = 10, 62.5%), the hip (n = 6, 35.3%) and the shoulder (n = 1, 5.9%). The most frequently isolated Candida species were C. albicans (n = 7, 41.2%) and C. glabrata (n = 7, 41.2%), followed by C. parapsilosis (n = 2, 11.8%) and C. freyschussii (n = 1, 5.9%). All patients were cured with the combination of systemic antifungal therapy and surgical interventions. Two-stage exchange arthroplasty and resection arthroplasty were performed in five and nine patients, respectively. The most frequently used echinocandins were caspofungin (n = 11, 64.7%), followed by anidulafungin (n = 4, 23.5%) and micafungin (n = 2, 11.8%). The median duration (days) of echinocandin therapy was as follows: caspofungin (25.5, range 8-56), micafungin (14.0, range 4-56) and anidulafungin (58, range 14-90). This study supports the effective role of echinocandins, as well as the potential advantage of surgical intervention in the treatment of Candida PJIs. Furthermore, it provides fundamental data on the safety of long-term echinocandin therapy.

Prosthetic Valve Candida spp. Endocarditis: New Insights Into Long-term Prognosis-The ESCAPE Study.

Background: Prosthetic valve endocarditis caused by Candida spp. (PVE-C) is rare and devastating, with international guidelines based on expert recommendations supporting the combination of surgery and subsequent azole treatment. Methods: We retrospectively analyzed PVE-C cases collected in Spain and France between 2001 and 2015, with a focus on management and outcome. Results: Forty-six cases were followed up for a median of 9 months. Twenty-two patients (48%) had a history of endocarditis, 30 cases (65%) were nosocomial or healthcare related, and 9 (20%) patients were intravenous drug users. "Induction" therapy consisted mainly of liposomal amphotericin B (L-amB)-based (n = 21) or echinocandin-based therapy (n = 13). Overall, 19 patients (41%) were operated on. Patients <66 years old and without cardiac failure were more likely to undergo cardiac surgery (adjusted odds ratios [aORs], 6.80 [95% confidence interval [CI], 1.59-29.13] and 10.92 [1.15-104.06], respectively). Surgery was not associated with better survival rates at 6 months. Patients who received L-amB alone had a better 6-month survival rate than those who received an echinocandin alone (aOR, 13.52; 95% CI, 1.03-838.10). "Maintenance" fluconazole therapy, prescribed in 21 patients for a median duration of 13 months (range, 2-84 months), led to minor adverse effects. Conclusion: L-amB induction treatment improves survival in patients with PVE-C. Medical treatment followed by long-term maintenance fluconazole may be the best treatment option for frail patients.

Candida auris.

PURPOSE OF REVIEW: To give an update on the recent emergence of Candida auris. RECENT FINDINGS: C. auris is a pathogen, that evades present therapeutic options, that is highly virulent, causes disease in all types of patients, and spreads easily in the environment and among patients, thereby posing an imminent threat to our patients. The fact that C. auris, in addition, is more resilient to environmental disinfection and frequently misclassified during microbiological diagnostics only heightens its potential as a 'perfect villain.' SUMMARY: Healthcare institutions, especially hospitals, need to ensure that their diagnostic and infection control policies to handle C. auris are in place.

Lactobacillus paracasei 28.4 reduces in vitro hyphae formation of Candida albicans and prevents the filamentation in an experimental model of Caenorhabditis elegans.

The objective of this study was to evaluate the influence of microbe-microbe interactions to identify a strain of Lactobacillus that could reduce the filamentation of Candida albicans ATCC 18804 using in vitro and in vivo models. Thus presenting a probiotic effect against the fungal pathogen. First, we analyzed the ability of 25 clinical isolates of Lactobacillus to reduce filamentation in C. albicans in vitro. We found that L. paracasei isolate 28.4 exhibited the greatest reduction of C. albicans hyphae (p = 0.0109). This reduction was confirmed by scanning electron microscopy analysis. The influence of C. albicans filamentation was found to be contributed through reduced gene expression of filament associated genes (TEC1 and UME6). In an in vivo study, prophylactic provisions with L. paracasei increased the survival of Caenorhabditis elegans worms infected with C. albicans (p = 0.0001) by 29%. Prolonged survival was accompanied by the prevention of cuticle rupture of 27% of the worms by filamentation of C. albicans, a phenotype that is characteristic of C. albicans killing of nematodes, compared to the control group. Lactobacillus paracasei isolate 28.4 reduced the filamentation of C. albicans in vitro by negatively regulating the TEC1 and UME6 genes that are essential for the production of hyphae. Prophylactic provision of Lactobacillus paracasei 28.4 protected C. elegans against candidiasis in vivo. L. paracasei 28.4 has the potential to be employed as an alternative method to control candidiasis.