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ESCMID* *Information in this manuscript was presented in part at ECCMID 2011. European Society for Clinical Microbiology and Infectious Diseases guideline for the diagnosis and management of Candida diseases 2012: developing European guidelines in clinical microbiology and infectious diseases
Abstract
Clin Microbiol Infect 2012; 18 (Suppl. 7): 1–8
The process to develop a guideline in a European setting remains a challenge. The ESCMID Fungal Infection Study Group (EFISG) successfully achieved this endeavour. After two face-to-face meetings, numerous telephone conferences, and email correspondence, an ESCMID task force (basically composed of members of the Society’s Fungal Infection Study Group, EFISG) finalized the ESCMID diagnostic and management/therapeutic guideline for Candida diseases. By appreciating various patient populations at risk for Candida diseases, four subgroups were predefined, mainly ICU patients, paediatric, HIV/AIDS and patients with malignancies including haematopoietic stem cell transplantation. Besides treatment recommendations, the ESCMID guidelines provide guidance for diagnostic procedures. For the guidelines, questions were formulated to phrase the intention of a given recommendation, for example, outcome. The recommendation was the clinical intervention, which was graded by a score of A–D for the ‘Strength of a recommendation’. The ‘level of evidence’ received a score of I–III. The author panel was approved by ESCMID, European Organisation for Research and Treatment of Cancer, European Group for Blood and Marrow Transplantation, European Society of Intensive Care Medicine and the European Confederation of Medical Mycology. The guidelines followed the framework of GRADE and Appraisal of Guidelines, Research, and Evaluation. The drafted guideline was presented at ECCMID 2011 and points of discussion occurring during that meeting were incorporated into the manuscripts. These ESCMID guidelines for the diagnosis and management of Candida diseases provide guidance for clinicians in their daily decision-making process.
... This is particularly important in the setting of HSCT and SOT, where patients are at increased risk of IFI due to immunosuppression. 15,[29][30][31][32][33] The ability to perform rapid microscopy can aid in the early identification of fungal pathogens, allowing for the timely initiation of appropriate antifungal IFI diagnostic and treatment capacities in Germany therapy. Similarly, the greater availability of culture methods, antibody detection, antigen detection and molecular tests in HSCT/SOT centres highlights their enhanced capacity for comprehensive diagnostic evaluation. ...
... 3 By rectifying these discrepancies and instituting strategies to augment the accessibility of essential antifungal agents, healthcare institutions can enhance their capacity to handle IFI across a wider range of patients, in line with current guidelines. 15,[30][31][32][33][34] This holds particular significance given the rising incidence of IFI among immunocompetent individuals, attributable to factors such as travel history to endemic regions, 35,36 burns 37 or traumatic injuries, 38 and more recently as a secondary infection to respiratory viral infections, including influenza-or severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-associated pulmonary aspergillosis. 9,39 The widespread availability of TDM, especially for posaconazole and voriconazole, in HSCT/SOT centres demonstrates their commitment to optimizing antifungal therapy. ...
... TDM allows for the measurement of antifungal drug concentrations in the patient's blood, ensuring that therapeutic levels are maintained and minimizing the risk of toxicity. 15,[30][31][32][33] This is particularly important for voriconazole, which has a narrow therapeutic window. ...
Introduction
In Germany, the growing incidence of invasive fungal infections (IFIs) is a significant health concern, particularly impacting individuals with compromised immune systems due to factors like increasing transplant recipients, an ageing population, and heightened use of immunosuppressive medications. Diagnosing IFI remains challenging, and the integration of biomarker assays into clinical practice is difficult. Antifungal resistance, exemplified by pan-antifungal-resistant Candida auris cases, adds complexity to treatment. This study aims to provide a concise overview of the diagnostic and treatment landscape for IFI in Germany, identifying areas for improvement and paving the way for targeted interventions.
Methods
Data were collected using an online electronic case report form from October 2021 to February 2023. The survey included questions about institutional practices related to fungal infection diagnosis and treatment, with invitations extended to researchers nationwide.
Results
The study surveyed 58 hospitals across Germany. Notably, 77.6% managed high-risk patients for IFI. While 86% had onsite microbiology labs, a significant difference was noted for high-risk patients (93% in specialized hospitals versus 62% in others). Microscopy services had 96% coverage, while overall access to culture was 96%. Antigen tests had 96% coverage, and antibody access was reported at 98%. PCR testing was available at 98%. Imaging access showed no significant access differences. Variability existed in amphotericin B formulations based on patient profiles. Therapeutic drug monitoring was more common in high-risk patient institutions (89.5% versus 50.0%). All analysed institutions reported access to surgery (100%).
Conclusions
Addressing identified disparities in diagnostic and therapeutic resources for IFI is crucial to improving patient outcomes. The study calls for ongoing research and collaboration to optimize strategies for the prevention and treatment of IFI, emphasizing the importance of equitable access to resources, especially in high-risk patient populations.
... (3) R-positive patients undergoing T cell-depleted autologous HSCT (eg, autoimmune disease) should receive prophylaxis for 3-6 months based on immunosuppressed nature of these transplant recipients C, III These recommendations have been graded according to the European Society of Clinical Microbiology and Infectious Diseases grading system (appendix p 3). 124 They apply both for adults and children, providing adaptation of the doses of anti-toxoplasma drugs. GVHD=graft-versus-host disease. ...
... Based on an extensive review of the literature and a list of questions with clinical impact prepared by the expert panel, guidelines were developed. The ECIL method for guideline development is summarised in the appendix (pp 1-2), along with the European Society of Clinical Microbiology and Infectious Diseases grading system (appendix p 3). 124 Toxoplasma disease is, however, often preventable. The pre-emptive approach using qPCR screening during the first months of transplant might identify early T gondii infection, which usually precedes the development of the disease. ...
... Pyrimethamine (200 mg single loading dose followed by 50-75 mg/day orally) plus folinic acid (10-25 mg/day) is the most effective agent for toxoplasma disease and should always be used in combination with a second active agent (1a) With sulfadiazine 4-6 g/day A, II, t (1b) With clindamycin 600 mg four times per day (orally or intravenously), in patients intolerant to sulfadiazine A, II, t (1c) With atovaquone (1500 mg/day orally) if intolerant to other regimens C, II, t(2)Trimethoprim-sulfamethoxazole (10-20 mg/kg per day and 50-100 mg/kg per day, respectively, orally or intravenously) with or without clindamycin (600 mg three to four times per day) can be used as an alternative regimen in settings where either pyrimethamine is not available or oral route is not feasible, irrespective of previous trimethoprim-sulfamethoxazole prophylaxisA, II, t(3)Atovaquone might also be used in combination with sulfadiazine (daily doses above) C, II, t (4) Minimum duration of therapy is 6 weeks or until clinical resolution, or both, and two negative PCR tests in blood, 7 days apart, or one qPCR negative in a previously qPCRpositive cerebrospinal fluid; longer courses might be required if clinical disease or radiological findings are extensive or response is incomplete at be carefully considered in patients with severe ocular toxoplasmosis or CNS disease with radiological midline shift, progression within 48 h of treatment or elevated intracranial pressure C, IIIRecommendations for toxoplasma secondary prophylaxis(1) Secondary prophylaxis of toxoplasmosis should be considered in patients who had toxoplasma infection or disease and who have ongoing risk factors for recurrence at the end of toxoplasmosis treatment (active GVHD or immunosuppression, or low CD4 counts); the choice of drugs for secondary prophylaxis depends on previous prophylaxis, the initial induction therapy and tolerance of the patient B, II, u These recommendations are graded for the level of proof and the strength of recommendation according to the European Society of Clinical Microbiology and Infectious Diseases grading system (appendix p 3).124 They apply both for adults and children, providing adaptation of the doses of anti-toxoplasma drugs. ...
... infections increased during the last decades as was the utilization of different antifungal agents [3]. Due to the high morbidity and mortality associated with such infections, appropriate empirical antifungal therapy plays an important role in survival [4,5]. ...
... Fluconazole administration was an independent risk factor for candidaemia due to C. glabrata (nomenclatural change to Nakaseomyces glabrataa), which is an azole non-susceptible species, and C. krusei (nomenclatural change to Pichia kudriavzevii), which is resistant to fluconazole [9][10][11]. Such an increase of fluconazole non-susceptible species combined with better outcomes of patients receiving echinocandins, resulted to a gradual increase in echinocandin administration [4,5,12]. ...
... Non-susceptibility to fluconazole was a common phenomenon (22.5 %), while echinocandin non-susceptibility was found only in 1.3 % [13]. In a Greek multicenter point-prevalence study, echinocandins were the most commonly used antifungals, in accordance to the 2012 European Society of Clinical Microbiology and Infectious Diseases guidelines [5,12]. ...
Introduction. Resistance rates to azoles and echinocandins of Candida spp. increased over the last decade.
Hypothesis/Gap Statement. Widespread use of antifungals could lead to development and dissemination of resistant Candida spp.
Aim. To identify risk factors for isolation of Candida spp. non-susceptible to either fluconazole or echinocandins.
Methodology. All patients hospitalized in the Intensive Care Unit (ICU) of the University General Hospital of Patras, Greece with Candida spp. isolated from clinical specimens during a ten-year period (2010–19) were included. Candida isolates were identified using Vitek-2 YST card. Consumption of antifungals was calculated.
Results. During the study period, 253 isolates were included. C. non-albicans predominated (64.4 %) with C. parapsilosis being the most commonly isolated (42.3 %) followed by C. glabrata (nomenclatural change to Nakaseomyces glabrataa; 8.7 %) and C. tropicalis (11.9 %). Among all isolates, 45.8 and 28.5 % were non-susceptible and resistant to fluconazole, respectively. Concerning echinocandins, 8.7 % of isolates were non-susceptible to at least one echinocandin (anidulafungin or micafungin) and 3.1 % resistant. Multivariate analysis revealed that hospitalization during 2015–19, as compared to 2010–14, isolate being non-albicans or non-susceptible to at least one echinocandin was associated with isolation of fluconazole non-susceptible isolate. Administration of echinocandin, isolate being C. glabrata or C. tropicalis, or Candida spp. non-susceptible to fluconazole were independently associated with isolation of Candida spp. non-susceptible to at least one echinocandin. Fluconazole’s administration decreased during the study period, whereas liposomal-amphotericin B’s and echinoncandins’ administration remained stable.
Conclusion. Fluconazole’s non-susceptibility increased during the study period, despite the decrease of its administration. Although echinocandins’ administration remained stable, non-susceptibility among Candida spp. increased.
... The optimal antifungal dosages vary by given patient populations and include both patient physical condition and type of treatment. Therefore, dosage recommendations are written in several guidelines and review articles, including aspergillosis and candidiasis in neonates [42], pediatrics [43], and adults [44,45]. These recommendations are summarized and simplified in Table 3. ...
... (IC) [42] Neonatals (IA) [43] Children (IC) [48] Children (IA) [43] Adults (IC) [44] HSCT (IA) [45] CMTH (IA) [45] NN (IA) [45] NH (IA) [ ...
... The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) published guidelines for the management of Aspergillus [45], Candida [44], Fusarium, and Scedosporium [56] infections. In these guidelines, the correct selection of an antifungal agent is based on the clinical experience, case studies, clinical trials, and population of patients. ...
We reviewed the licensed antifungal drugs and summarized their mechanisms of action, pharmacological profiles, and susceptibility to specific fungi. Approved antimycotics inhibit 1,3‐β‐D‐glucan synthase, lanosterol 14‐α‐demethylase, protein, and deoxyribonucleic acid biosynthesis, or sequestrate ergosterol. Their most severe side effects are hepatotoxicity, nephrotoxicity, and myelotoxicity. Whereas triazoles exhibit the most significant drug–drug interactions, echinocandins exhibit almost none. The antifungal resistance may be developed across most pathogens and includes drug target overexpression, efflux pump activation, and amino acid substitution. The experimental antifungal drugs in clinical trials are also reviewed. Siderophores in the Trojan horse approach or the application of siderophore biosynthesis enzyme inhibitors represent the most promising emerging antifungal therapies.
... Neither fluconazole nor caspofungin has been shown to reduce significantly in-vasive candidiasis-related mortality in critical care settings when prescribed as prophylaxis or empirical therapy [37][38][39][40]. Current guidelines and expert task forces recommend an echinocandin as an initial or empirical treatment rather than fluconazole based on decreased susceptibility of fungi to azoles worldwide and especially in critically ill patients [35,41,42]. An aggressive strategy for empirical coverage of fungal agents needs to be followed by appropriate de-escalation policy whenever possible [43]. ...
... Neither fluconazole nor caspofungin has been shown to reduce significan invasive candidiasis-related mortality in critical care settings when prescribed as prop laxis or empirical therapy [37][38][39][40]. Current guidelines and expert task forces recomme an echinocandin as an initial or empirical treatment rather than fluconazole based on creased susceptibility of fungi to azoles worldwide and especially in critically ill patie [35,41,42]. An aggressive strategy for empirical coverage of fungal agents needs to be lowed by appropriate de-escalation policy whenever possible [43]. ...
This comprehensive review aims to provide a practical guide for intensivists, focusing on enhancing patient care associated with nosocomial peritonitis (NP). It explores the epidemiology, diagnosis, and management of NP, a significant contributor to the mortality of surgical patients worldwide. NP is, per definition, a hospital-acquired condition and a consequence of gastrointestinal surgery or a complication of other diseases. NP, one of the most prevalent causes of sepsis in surgical Intensive Care Units (ICUs), is often associated with multi-drug resistant (MDR) bacteria and high mortality rates. Early clinical suspicion and the utilization of various diagnostic tools like biomarkers and imaging are of great importance. Microbiology is often complex, with antimicrobial resistance escalating in many parts of the world. Fungal peritonitis and its risk factors, diagnostic hurdles, and effective management approaches are particularly relevant in patients with NP. Contemporary antimicrobial strategies for treating NP are discussed, including drug resistance challenges and empirical antibiotic regimens. The importance of source control in intra-abdominal infection management, including surgical and non-surgical interventions, is also emphasized. A deeper exploration into the role of open abdomen treatment as a potential option for selected patients is proposed, indicating an area for further investigation. This review underscores the need for more research to advance the best treatment strategies for NP.
... 26,35 Guidelines set by ECMM, ISHAM (International Society for Human and Animal Mycology), ASM (American Society for Microbiology), and MSG-ERC (Mycoses Study Group Education and Research Consortium) strongly recommend cultures for invasive fungal infection diagnosis. [25][26][27][28][29][30][32][33][34][35][36] Most of the European institutions (99%) could process isolates, which is 10 percentage points more than Asian institutions (89·2%), 41 and 20% more compared with Latin American and Caribbean institutions (78·0%). 17 Within Europe, we observed that the availability of tests for specific identification varied according to country GDP. ...
... Isavuconazole and voriconazole are the recommended antifungals for invasive aspergillosis; 27,35 however, they were only available in 78% and 20% of institutions with a GDP of less than $30 000, respectively. Echinocandins, which are strongly recommended for the treatment of candidemia, 36 were available in only 72% of countries with the lowest GDP. Liposomal amphotericin B, isavuconazole, and posaconazole are the preferred options for mucormycosis; 26,29 however, in countries with a GDP of less than $30 000 these were available in 20-50% of the reporting institutions. ...
... 17 Although some tests are not available in all institutions, there is always at least one test that allows timely diagnosis of the most common invasive fungal infections. [18][19][20][21][22][23][24][25][26][27][28][29] Nevertheless, it should be noted that all Austrian hospitals are above the European average for each of the parameters analysed, both for diagnosis and treatment. 16 This puts Austria in one of the best situations to fight invasive fungal infections properly. ...
... 12 General access to all antifungals described as first-line treatment for the most common invasive fungal infections is ensured in Austria, following recommendations of the WHO and the global guidelines programme. [18][19][20][21][22][23][24][25][26][27][28][29]31 In this work, we had to face some limitations. Firstly, there is the limitation of the number of institutions. ...
Introduction
Immunosuppression after chemotherapy, stem cell transplantation or solid organ transplantation are the main risk factors for invasive fungal infections in Austria. Here, we aim to describe the status of laboratory mycology and the access to antifungal treatment in Austria.
Methods
Between October and November 2021, hospitals were contacted to participate in our online survey: www.clinicalsurveys.net/uc/IFI_management_capacity/. Centres were required to provide information on their institutional profile; self-assessment of burden of invasive fungal infections; access to microscopy, culture, serology, antigen detection and molecular testing; and availability of antifungal agents and therapeutic drug monitoring.
Results
Responses were collected from university hospitals and laboratories in Graz, Innsbruck, Linz and Vienna. The four hospitals can provide tertiary care and were highly specialised, including management of patients with severe immunosuppression. All sites consider the incidence of invasive fungal infections to be moderate. Access to microscopy, culture, serology, antigen detection and molecular testing is provided regardless of laboratory. The maximum capacity to identify fungi varies from institution to institution. All currently marketed antifungal agents are available at the four sites.
Conclusion
Austria is currently well equipped to deal with the emerging threat of invasive fungal infections. However, hospitals may consider preparing for the potential endemicity of certain infections in the near future.
... 26,35 Guidelines set by ECMM, ISHAM (International Society for Human and Animal Mycology), ASM (American Society for Microbiology), and MSG-ERC (Mycoses Study Group Education and Research Consortium) strongly recommend cultures for invasive fungal infection diagnosis. [25][26][27][28][29][30][32][33][34][35][36] Most of the European institutions (99%) could process isolates, which is 10 percentage points more than Asian institutions (89·2%), 41 and 20% more compared with Latin American and Caribbean institutions (78·0%). 17 Within Europe, we observed that the availability of tests for specific identification varied according to country GDP. ...
... Isavuconazole and voriconazole are the recommended antifungals for invasive aspergillosis; 27,35 however, they were only available in 78% and 20% of institutions with a GDP of less than $30 000, respectively. Echinocandins, which are strongly recommended for the treatment of candidemia, 36 were available in only 72% of countries with the lowest GDP. Liposomal amphotericin B, isavuconazole, and posaconazole are the preferred options for mucormycosis; 26,29 however, in countries with a GDP of less than $30 000 these were available in 20-50% of the reporting institutions. ...
Access to the appropriate tools is crucial for early diagnosis and clinical management of invasive fungal infections. This Review aims to describe the invasive fungal infection diagnostic capacity of Europe to better understand the status and the most pressing aspects that need improvement. To our knowledge, this is the first time that the mycological diagnostic capability and access to antifungal treatments of institutions has been evaluated at a pan-European level. Between Nov 1, 2021, and Jan 31, 2022, 388 institutions in Europe self-assessed their invasive fungal infection management capability. Of the 388 participating institutions from 45 countries, 383 (99%) had access to cultures, 375 (97%) to microscopy, 363 (94%) to antigen-detection assays, 329 (85%) to molecular tests (mostly PCR), and 324 (84%) to antibody tests for diagnosis and management. With the exception of microscopy, there were considerable differences in access to techniques among countries according to their gross domestic product. At least one triazole was available in 363 (94%) of the institutions, one echinocandin in 346 (89%), and liposomal amphotericin B in 301 (78%), with country gross domestic product-based differences. Differences were also observed in the access to therapeutic drug monitoring. Although Europe is well prepared to manage invasive fungal infections, some institutions do not have access to certain diagnostic tools and antifungal drugs, despite most being considered essential by WHO. These limitations need to be overcome to ensure that all patients receive the best diagnostic and therapeutic management.
... Ces molécules ont une activité à large spectre, sont très bien tolérés et ne sont généralement pas sujet à des interactions médicamenteuses nécessitant un ajustement posologique. En raison de l'émergence de la résistance aux azolés, les échinocandines sont devenus le traitement de première intention lors d'une infection fongique chez des patients de réanimation selon les recommandations européennes [3,4]. ...
... Recommandations de l'ESCMID 2012[3].L'administration d'un traitement précoce et adapté est essentielle dans la survie du patient. ...
Le sepsis joue un rôle fondamental dans l’altération de la pharmacocinétique (PK) des anti-infectieux, responsable d’un risque de sous ou surdosage chez des patients de réanimation pouvant conduire à un échec thérapeutique. La compréhension de la variabilité PK des anti-infectieux est essentielle afin de proposer une posologie adéquate. De plus, développer un modèle animal de sepsis permettrait d’améliorer la compréhension des altérations PK des anti-infectieux induites par le choc septique.Ce projet de thèse a pour but d’évaluer la capacité du modèle porcin de sepsis à prédire la PK d’anti-infectieux chez l’humain. Pour ce faire, étudier des molécules déjà connues permettrait de confirmer dans un premier temps sa transposition à l’Homme. Les échinocandines, traitement de première intention en cas d’infection fongique, sont au centre de ce projet. Au préalable, des études complémentaires chez des patients de réanimation ont été menées afin d’approfondir nos connaissances sur leur PK dans des situations à risque, comme le recours à des thérapies d’épuration extra-rénale et dans le cadre d’une péritonite secondaire, où la diffusion péritonéale des échinocandines est déterminante pour éradiquer l’infection fongique. Enfin, la PK de la micafungine a été étudiée sur un modèle porcin septique, dont la physiologie est très proche de l’humain, afin de la comparer à celle retrouvée chez les patients septiques. Ces études ont été réalisées à l’aide de modélisation par approche de population.Ces travaux ont mis en exergue la nécessité d’augmenter la posologie des échinocandines chez les patients de réanimation sous peine d’échec thérapeutique. Les thérapies d’épuration extra-rénale, quant à elles, n’altèrent pas la PK des échinocandines. Leur diffusion au sein de la cavité péritonéale, site infectieux fréquent des espèces Candida, est modérée mais serait suffisante afin d’éradiquer l’infection fongique en prenant en compte les CLSI breakpoints. Enfin, la PK de la micafungine chez le modèle porcin septique est similaire à celle retrouvée chez l’humain en considérant une relation allométrique du poids de l’espèce appliquée au volume de distribution central de la micafungine. Ces résultats encourageants tendent à justifier la transposabilité du modèle porcin à l’humain. Si cette hypothèse s’avère exacte, le modèle porcin septique pourrait être utilisé pour l’étude de nouveaux anti-infectieux lors des phases précliniques, afin d’estimer une posologie adéquate chez des patients de réanimation.
... 5,[7][8][9] In view of the epidemiological shift to non-albicans Candida infections with their high severity of illness, infectious disease specialists have published several evidence-based guidelines for the diagnosis and treatment of Candida diseases. 12,13 The guidelines emphasise that infectious disease specialists play an essential role in promoting adherence to recommended treatments, as well as in implementing antifungal management policies designed to increase survival rates. [14][15][16] The European Confederation of Medical Mycology published a simple and rapid scoring system for antifungal management and guideline adherence. ...
... 21 Diagnoses and treatments for candidaemia were based on the current recommendations of the guidelines and of the European Society of Clinical Microbiology and Infectious Diseases. 12,13 The EQUAL Candida score was used to qualify the degree of adherence to the guidelines. 17 ...
Background:
Candida tropicalis is the most common non-albicans Candida species found in Asia-Pacific countries, including Thailand. The pathogen is known for its great virulence, which causes a high case-fatality rate. Associations between case fatality and patient characteristics, infectious disease unit consultation, and EQUAL Candida score were investigated.
Methods:
This retrospective cohort study was conducted with 160 cases of C. tropicalis bloodstream infection between 2015 and 2019 at a single, large, tertiary centre in Thailand. Clinical characteristics, clinical presentations, patient outcomes (30-day case-fatality rate) and independent predictive factors were analysed.
Results:
The 30-day case-fatality rate was 68.1%. The median of the EQUAL Candida score was 8. Independent factors for the prediction of case fatality were septic shock (hazard ratio, 1.84), the use of mechanical ventilation (hazard ratio, 2.03) and the EQUAL Candida score (hazard ratio, 0.75).
Conclusions:
The predictive factors for 30-day case fatality were septic shock, mechanical ventilation use and the EQUAL Candida score. It is recommended that the EQUAL score be considered for patients infected with C. tropicalis candidaemia to reduce the case-fatality rate.
... Therefore, micafungin has higher safety and less drug interaction compared to other antifungal agents such as triazoles and amphotericin B [4]. At present, micafungin is strongly recommended for prophylaxis therapy in neutropenic patients receiving HSCT [5][6][7][8][9]. The aim of this study was to assess the efficacy and safety of micafungin for antifungal prophylaxis during neutropenia after transplantation. ...
... Several studies demonstrated that micafungin is either similar or superior to fluconazole for prophylaxis of fungal infections among patients undergoing HSCT [13,18]. A meta-analysis by Lee et al. also showed that micafungin was significantly associated with higher treatment success, lower rates of IFIs, and fewer adverse reactions compared with triazoles [5]. Different doses of micafungin were shown to be effective for IFIs prophylaxis in patients with hematological malignancy [19]. ...
Objectives: The objective of the study was to assess the tolerability and effectiveness of micafungin prophylaxis during the neutropenic phase in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Methods We conducted a retrospective study of 73 consecutive adults receiving antifungal prophylaxis with micafungin bridged to voriconazole/itraconazole in our center from July 2013 to March 2018. Clinical and transplant-related demographics and data on fungal infection post-transplant were collected. Results Micafungin was effective in 71 (97.3%) leukopenic patients. The fungal-free survival was 91.8%, 80.6%, and 77.6% respectively at 30, 60, and 100 days after HSCT. All patients had no micafungin-related adverse events. Conclusions The utility of micafungin bridged to voriconazole/ itraconazole for antifungal prophylaxis after HSCT is beneficial.
... Serum mannan-antigen(mannan-Ag), anti-mannan antibody(antimannan-Ab) and 1,3 beta-D-glucan(BDG) are among the biomarkers commercially available for the detection of IC. Their accuracy to predict the occurrence of IFI [8][9][10][11][12][13] has already been assessed in several studies (table S1). ...
... BDG, owing to early positivity in ICU patients has, in particular, quite good sensitivity and negative predictive value [14][15][16][17][18]. The BDG test is also proposed to rule out the diagnosis of IC in adult patients at risk of infection [11,19] and its accuracy is considered to be greater than that of the colonization index in predicting IC [20]. However, very few studies have been performed in ICU patients, for whom the probability of IC is the highest. ...
Background
We aimed to assess the prognostic value of repeated measurements of serum (1-3)-β-D-glucan(BDG), mannan-antigen(mannan-Ag) and anti-mannan antibodies(anti-mannan-Ab) on the occurrence of Invasive Candidiasis(IC) in a high risk non-immunocompromised population.
Methods
It is a preplanned ancillary analysis of the EMPIRICUS Randomized Clinical Trial, including non-immunocompromised critically ill patients with ICU-acquired sepsis, multiple Candida colonization, multiple organ failure, exposed to broad-spectrum antibacterial agents. BDG(>80 and >250 pg/mL), mannan-Ag(>125 pg/mL) and anti-mannan-Ab(>10 AU) were collected repeatedly. We used cause-specific hazard models. Biomarkers were assessed at baseline in the whole cohort(cohort 1). Baseline covariates and/or repeated measurements and/or increased of biomarkers were then studied in the subgroup of patients who were still alive at day 3 and free of IC(cohort 2).
Results
234 patients were included and 215 were still alive and free of IC at day 3. IC developed in 27(11.5%) and day-28 mortality was 29.1%. Finally, only BDG>80 pg/ml at inclusion was associated with an increased risk of IC(CSHR[IC]=4.67, CI95% 1.61-13.5) but not death (CSHR[death]=1.20, CI95% 0.71-2.02).
Conclusions
Among high risk patients, a first measurement of BDG over 80 pg/mL was strongly associated with the occurrence of IC. Neither a cut off-of 250 pg/mL nor repeated measurements of fungal biomarkers seemed to be useful to predict the occurrence of IC. The cumulative risk of IC in the placebo group if BDG>80 pg/ml was 25.39% questioning about the potential interest of empirical therapy in this subgroup.
... Moreover, the effectiveness of various antifungal medicines necessitates the need for early and precise diagnosis. Microscopy, selective culture, and/or biochemical methods are used to diagnose candidiasis in the past (Cuenca-Estrella et al., 2012;Arendrup et al., 2014). All of these procedures necessitate the isolation and cultivation of the infective agent from clinical specimens, which takes around 48 hours for most pathogenic yeasts but may take longer for some samples or species. ...
... The statistical package SPSS V.25 and Stata V.17 will be used. The analysis will be carried out according to the Standards for Reporting of Diagnostic Accuracy initiative) 16 guidelines. ...
Introduction
The evaluation of staging and activity of invasive fungal infection (IFI) is used to adjust the type and duration of antifungal therapy (AT). Typically anatomy-based imaging is used. Positron emission tomography/CT with ¹⁸ F-fluorodeoxyglucose ( ¹⁸ F-FDG PET/CT) not only evaluates more than one body area in one session, but adds functional information to the anatomic data provided by usual imaging techniques and can potentially improve staging of IFI and monitoring of the response to therapy. Our objective is to analyse the impact of the systematic use of ¹⁸ F-FDG PET/CT in IFI diagnostic and therapeutic management.
Methods and analysis
Multicentre prospective cohort study of IFI with performance of systematic ¹⁸ F-FDG PET/CT at diagnosis and follow-up that will be carried out in 14 Spanish tertiary hospitals. It is planned to include 224 patients with IFI over a 2-year study period. Findings and changes in management before and after ¹⁸ F-FDG PET/CT will be compared. Additionally, the association of initial quantitative ¹⁸ F-FDG PET/CT parameters with response to therapy will be evaluated.
The primary endpoint is to compare the yield of ¹⁸ F-FDG PET/CT with standard management without ¹⁸ F-FDG PET/CT in IFI at initial assessment (staging) and in monitoring the response to treatment.
The impact of the results of ¹⁸ F-FDG PET/CT on the diagnostic-therapeutic management of patients with IFI (added value), as well as the prognostic ability of different quantification parameters of ¹⁸ F-FDG PET/CT will be secondary endpoints.
Ethics and dissemination
The Clinical Research Ethics Committee of Puerta de Hierro-Majadahonda University Hospital approved the protocol of the study at the primary site. We plan to publish the results in high-impact journals.
Trial registration number
NCT05688592 .
... The diagnostic criteria of candidemia were based on the guidelines for diagnosing and treating candidiasis: the expert consensus issued by the Chinese Adult Candidiasis Diagnosis and Management Expert Consensus Group [13]. These criteria were also in accordance with the European Society of Clinical Microbiology and Infectious Diseases ESCMID* guidelines for the diagnosis and management of Candida diseases 2012 [14,15] and the Infectious Diseases Society of America Clinical Practice Guidelines for the Management of Candidiasis: 2016 Update [16]. All patients aged ≥ 18 years who presented to the three tertiary hospitals with candidemia from 2016 to 2021 were investigated; only the first episode was included in our analysis. ...
Background
Data on persistent candidemia (PC), a recognized complication of candidemia, are lacking in China. This study aimed to investigate the clinical characteristics and risk factors for the mortality of PC among adults in China.
Methods
This 6-year retrospective study analyzed the prevalence, species distribution, antifungal susceptibility, risk factors, and patient mortality of PC among adults in three regional tertiary teaching hospitals in China from 2016 to 2021. We collected electronic laboratory records data of PC and non-PC patients and used the Student test or Mann–Whitney U test for a retrospective study. Logistic regression was used to identify risk factors associated with persistent candidemia.
Results
The definition of PC was fulfilled by 36 patients (13.7%, 36/263). The mean age of the patients was 59.9 years (60 years for patients with PC; 59.8 years for those with non-PC; P > 0.05) and 131 (60.1%) were men [16 with PC (44.4%), 115 with non-PC (63.2%), P < 0.05]. The mean annual incidence was 0.15/1000 admissions (including PC 0.03/1000 admissions vs. non-PC 0.12/1000 admissions, P < 0.05). Candida parapsilosis (14/36, 38.9%) and Candida albicans (81/182, 44.5%) were the predominant pathogens in patients with PC and non-PC, respectively. Most isolates were susceptible to flucytosine (99.0%) and amphotericin B (99.5%), and the activity of antifungal agents against Candida species was not statistically significantly different between patients with PC and non-PC (P > 0.05). The 30-day mortality rate was 20.2% (16.7% with PC vs. 20.9% with non-PC, P > 0.05). Multivariable regression analysis showed that use of broad-spectrum antibiotics (odds ratio (OR), 5.925; 95% confidence interval (CI), 1.886–18.616, P = 0.002), fluconazole (OR, 3.389; 95% CI, 1.302–8.820, P = 0.012) and C. parapsilosis infection (OR, 6.143; 95% CI, 2.093–18.031, P = 0.001) were independent predictors of PC, sex (male) (OR, 0.199; 95% CI, 0.077–0.518, P = 0.001) was the protective factor for PC. Respiratory dysfunction (OR, 5.763; 95% CI, 1.592–20.864, P = 0.008) and length of hospital stay(OR, 0.925; 95% CI, 0.880–0.973, P = 0.002) were independent predictors of 30-day mortality in patients with non-PC. C. tropicalis bloodstream infection (OR, 12.642; 95% CI, 1.059–150.951; P = 0.045) was an independent predictor of 30-day mortality in patients with PC.
Conclusions
The epidemiological data of patients with PC and non-PC were different in the distribution of Candida species, the mean annual incidence and independent predictors of 30-day mortality. Flucytosine and amphotericin B could be used as first-choice drugs in the presence of PC infections.
... The level of recommendation by the EADV Mycology Task Force working group on MF was determined using a grading system ranging from A to D, employed by the European Society for Clinical Microbiology and Infectious Diseases. 17,18 The recommendations are as follows: ...
Malassezia is a lipophilic yeast that is a part of the human mycobiome. Malassezia folliculitis appears when the benign colonization of the hair follicles, by the Malassezia yeasts, becomes symptomatic with pruritic papules and pustules. Although Malassezia folliculitis is common in hospital departments, diagnosing and treating it varies among dermatologists and countries. The European Academy of Dermatology and Venereology Mycology Task Force Malassezia folliculitis working group has, therefore, sought to develop these recommendations for the diagnosis and management of Malassezia folliculitis. Recommendations comprise methods for diagnosing Malassezia folliculitis, required positive findings before starting therapies and specific treatment algorithms for individuals who are immunocompetent, immunocompromised or who have compromised liver function. In conclusion, this study provides a clinical strategy for diagnosing and managing Malassezia folliculitis.
... The diagnostic criteria of candidemia were based on the guidelines for diagnosing and treating candidiasis: the expert consensus issued by the Chinese Adult Candidiasis Diagnosis and Management Expert Consensus Group [11]. These criteria were also in accordance with the European Society of Clinical Microbiology and Infectious Diseases ESCMID* guidelines for the diagnosis and management of Candida diseases 2012 [12,13] and the Infectious Diseases Society of America Clinical Practice Guidelines for the Management of Candidiasis: 2016 Update [14]. All patients aged ≥ 18 years who presented to the three tertiary hospitals with candidemia from 2016 to 2021 were investigated; only the rst episode was included in our analysis. ...
Background: Data on persistent candidemia (PC), a recognized complication of candidemia, are lacking in China. This study aimed to investigate the clinical characteristics and risk factors for the mortality of PC among adults in China.
Methods: This 6-year retrospective study analyzed the prevalence, species distribution, antifungal susceptibility, risk factors, and patient mortality of PC among adults in three regional tertiary teaching hospitals in China from 2016 to 2021. PC was defined as the isolation of the same Candida species from positive blood culture for ≥5 days following the initiation of antifungal therapy.
Results: The definition of PC was fulfilled by 36 patients (13.7%, 36/263). The mean age of the patients was 59.9 years (60 years for patients with PC; 59.8 years for those with non-PC; P > 0.05), and 131 (60.1%) were men [16 with PC (44.4%), 115 with non-PC (63.2%), P < 0.05]. The mean annual incidence was 0.15/1000 admissions (including PC 0.03/1000 admissions vs non-PC 0.12/1000 admissions, P < 0.05). Candida parapsilosis(14/36, 38.9%) and Candida albicans (81/182, 44.5%) were the predominant pathogens in patients with PC and non-PC, respectively. Most isolates were susceptible to flucytosine (99.0%) and amphotericin B (99.5%), and the activity of antifungal agents against Candida species was not statistically significantly different between patients with PC and non-PC (P> 0.05). The 30-day mortality rate was 20.2% (16.7% with PC vs 20.9% with non-PC, P > 0.05). Multivariable regression analysis showed that use of broad-spectrum antibiotics, and fluconazole were independent predictors of PC, sex (male) was the protective factor for PC. Respiratory dysfunction and length of hospital stay were independent predictors of 30-day mortality in patients with non-PC. C. tropicalis bloodstream infection (odds ratio, 12.642; 95% confidence interval, 1.059–150.951; P = 0.045) was an independent predictor of 30-day mortality in patients with PC.
Conclusions: The epidemiological data of patients with PC and non-PC were different in the distribution of Candida species, the mean annual incidence, and independent predictors of 30-day mortality. Flucytosine and amphotericin B could be used as first-choice drugs in the presence of PC infections.
... These drugs are fungicidal against most Candida spp. and represent the first choice to treat systemic Candida infections [8,9]. Pyrimidines (i.e., 5-flucytosine) and allylamines (i.e., terbinafine) act by inhibiting protein and ergosterol synthesis, respectively. ...
Candida spp. is the major causative agent of fungal infections in hospitalized patients and the fourth most common cause of nosocomial bloodstream infection (BSI). The availability of standardized methods for testing the in vitro activity of antifungals along with the expanding of antifungal armamentarium, the rising of drug-resistance and the persistence of a high mortality rate in systemic candidiasis have led to an increased interest in combination therapy. Therefore, we aimed to review the scientific literature concerning the antifungal combinations against Candida. A literature search performed in PubMed yielded 92 studies published from 2000 to 2021: 29 articles referring to in vitro studies, six articles referring to either in vitro and in vivo (i.e., animal models) studies and 57 clinical articles. Pre-clinical studies involved 735 isolates of Candida species and 12 unique types of antifungal combination approaches including azoles plus echinocandins (19%), polyenes plus echinocandins (16%), polyenes plus azoles (13%), polyenes plus 5-flucytosine ([5-FC], 13%), azoles plus 5-FC (11%) and other types of combinations (28%). Results varied greatly, often being species-, drug- and methodology-dependent. Some combinatorial regimens exerted a synergistic effect against difficult-to-treat Candida species (i.e., azoles plus echinocandins; polyenes plus 5-FC) or they were more effective than monotherapy in prevent or reducing biofilm formation and in speeding the clearance of infected tissues (i.e., polyenes plus echinocandins). In 283 patients with documented Candida infections (>90% systemic candidiasis/BSI), an antifungal combination approach could be evaluated. Combinations included: azoles plus echinocandins (36%), 5-FC-combination therapies (24%), polyenes plus azoles (18%), polyenes plus echinocandins (16%) and other types of combination therapy (6%). Case reports describing combination therapies yielded favorable response in most cases, including difficult-to-treat fungal infections (i.e., endocarditis, osteoarticular infections, CNS infections) or difficult-to-treat fungal pathogens. The only randomized trial comparing amphotericin-B deoxycholate (AMB) plus FLU vs. AMB alone for treatment of BSI in nonneutropenic patients showed that the combination trended toward improved success and more-rapid clearance from the bloodstream. In summary, antifungal combinations against Candida have produced great interest in the past two decades. To establish whether this approach can become a reliable treatment option, additional in vitro and clinical data are warranted.
... IFDs consisted mainly of fungemia (49%), PJP (20%), and IA (19%) confirming the previous ranking in France (15), but mucormycosis is now more often diagnosed than cryptococcosis. Despite the availability of new diagnostic procedures and publications of guidelines (23,24), the global 3-month mortality remained unchanged over the 7 years, as recently shown for yeast fungemia (25). Overall, the global incidence was 2.21 IFDs/10,000 hospitalization days, with a significant increase over time (Fig. 1A). ...
ABSTRACT The French National Reference Center for Invasive Mycoses and Antifungals leads an active and sustained nationwide surveillance program on probable and proven invasive fungal diseases (IFDs) to determine their epidemiology in France. Between 2012 and 2018, a total of 10,886 IFDs were recorded. The incidence increased slightly over time (2.16 to 2.36/10,000 hospitalization days, P = 0.0562) in relation with an increase of fungemia incidence (1.03 to 1.19/10,000, P = 0.0023), while that of other IFDs remained stable. The proportion of ≥65-year-old patients increased from 38.4% to 45.3% (P
... Members of the expert subgroups approved the final set of recommendations. For grading of the strength of recommendation and the level of evidence, the European Society of Clinical Microbiology and Infectious Disease (ESCMID) grading system [1] was used (Table 1). ...
The 9th web-based European Conference on Infections in Leukemia (ECIL-9), held September 16-17, 2021, reviewed the risk of infections and febrile neutropenia associated with more recently approved immunotherapeutic agents and molecular targeted drugs for the treatment of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Novel antibody based treatment approaches (inotuzumab ozogamicin, gemtuzumab ozogamicin, flotetuzumab), isocitrate dehydrogenases inhibitors (ivosidenib, enasidenib, olutasidenib), FLT3 kinase inhibitors (gilteritinib, midostaurin, quizartinib), a hedgehog inhibitor (glasdegib) as well as a BCL2 inhibitor (venetoclax) were reviewed with respect to their mode of action, their immunosuppressive potential, their current approval and the infectious complications and febrile neutropenia reported from clinical studies. Evidence-based recommendations for prevention and management of infectious complications and specific alerts regarding the potential for drug-drug interactions were developed and discussed in a plenary session with the panel of experts until consensus was reached. The set of recommendations was posted on the ECIL website for a month for comments from members of EBMT, EORTC, ICHS and ELN before final approval by the panelists. While a majority of these agents are not associated with a significantly increased risk when used as monotherapy, caution is required with combination therapy such as venetoclax plus hypomethylating agents, gemtuzumab ozogamicin plus cytotoxic drugs or midostaurin added to conventional AML chemotherapy.
... Therapy for specific microorganisms was applied according to the guidelines (e.g. Mycobacterium spp., Candida spp., Brucella spp.) [5][6][7]. ...
Purpose
Vertebral osteomyelitis (VO) is a severe clinical entity associated with significant morbidity and mortality. Several studies have showed that successful treatment of VO patients leads to significantly improved quality of life (QoL). Nevertheless, QoL levels of these patients remained below those of the general population. There are rarely studies focusing on predicting factors for favourable QoL after surgically treated VO. The aim of this study was to identify factors influencing positively the QoL of patients undergoing surgery for VO.
Methods
We conducted a prospective monocentric study including surgically treated VO patients from 2008 to 2016. Data were collected before (T0) and 1 year (T1) after surgery. Primary outcome was favourable QoL defined as back pain with disability restricting normal life activity with a cutoff value ≥ 12 on Oswestry Disability Index (ODI).
Ethics
Ethical approval was given by the Faculty of Medicine at the University of Cologne (09-182).
Results
A total of 119 patients surviving 1 year after surgically treated VO were analysed. Favourable QoL was achieved in 35/119 patients. On multivariate analysis, younger age (hazard ratio = HR: 0.95; 95% CI 0.91–0.99; p = 0.022), lower albumin (HR: 0.9; 0.83–0.98; p = 0.019) an ASA score ≤ 2 (HR:4.24; 95%CI 1.42–12.68; p = 0.010), and a lower preoperative leg pain on the VAS (HR: 0.86; 95% CI 0.76–0.97; p = 0.018) were identified as independent risk factors for favourable QoL. Interestingly, the absence of neurological deficits was not predictive for a favourable outcome by means of QoL.
Conclusion
One-third of surgically treated VO patients (29%) in our cohort achieved favourable QoL by means of ODI. Our findings can facilitate an estimation of the prognosis when informing the patient before surgery, and underscore that spine disability questionnaires, such as ODI, measuring QoL, are mandatory to evaluate comprehensively the outcome of this entity.
... . The sequential events in the disease progression are outlined in Figure 2 [11]- [15] . In the tissue specimens, the Grocott- [28]. Lately, this disease is associated with COVID-19 that also predisposes to the immunosuppressed state aiding rapid dissemination of the infection increasing both morbidity and mortality [43], [44] ...
Mucormycosis, a rare but life-threatening fungal disease, is challenging to diagnose and treat. Presently, COVID-19 associated mucormycosis reported high morbidity and mortality, extravagant treatment costs, and a shortage of antifungal drugs. From the global perspective, the surge in mucormycosis cases signifies a higher number of immunosuppressed patients, improved diagnostics, and improper use of antifungal prophylaxis against Mucorales. Further, the growth and infectivity of fungal spores are intensified by acidic blood pH, low oxygen level, and high glucose and iron level in serum resulting in angioinvasion, thrombosis and, tissue necrosis. So, early and precise diagnosis, settling primarily associated risk factors, surgery in localized infection, judicious use of antifungal agents, controlling nosocomial infection, maintaining personal hygiene, and strictly monitoring blood sugar are crucial preventive measures for Mucorales. If not, other opportunistic fungi such as Aspergillus, Candida, or any Zygomycetes may result in an epidemic as COVID-19 mucormycosis. We searched various scholarly literature using keywords: black fungus, mucormycosis, COVID-19 mucormycosis in PubMed, Scopus and Google Scholar databases, summarized the clinical features of mucormycosis and highlighted the reason for an abrupt lethal outbreak in COVID-19 patients.
... Invasive candidiasis usually presents as fever and worsening of clinical conditions in critically-ill and/ or immune-suppressed patients. Signs and symptoms of candidiasis occurring at skin or mucosal surfaces could also be present, as well as signs suggesting a central-line associated infection (Cornely et al., 2012). However, the majority of subjects do not show specific symptoms, and the diagnosis relies on the microbiological isolation of Candida spp. ...
COVID-19 is frequently associated with the onset of secondary infections, especially in severe cases treated in the intensive care unit. While bacterial pathogens are the most frequently encountered causative agents, several factors put SARS-CoV-2 infected patients at a heightened risk of invasive fungal infections, which have been recognized as a substantial cause of morbidity and mortality in this population. Moreover, the frequent occurrence of these complications in severely ill subjects and the absence of pathognomonic features, together with the emergence of fungal species with reduced susceptibility to first-line treatments and the difficult to manage safety profile of several antifungal drugs, demand an additional focus on these rare but challenging complications. In this review, we will summarize the currently available literature on fungal superinfections in COVID-19 patients, exploring the pathogenesis, epidemiology, clinical features, treatment, and outcomes.
... Gaining widespread consensus in the diagnosis of yeast infections has long been a challenge [1]. As the mortality associated with invasive diseases remains high, it is imperative that diagnostic tests are developed and utilized to give both timely and accurate results, enabling effective therapy to be swiftly initiated [2]. ...
Purpose of Review
The use of molecular tests to aid the diagnosis of invasive yeast infection, in particular invasive candidosis, has been described for over two decades, yet widespread application is limited, and diagnosis remains heavily dependent on classical microbiology. This article will review developments from the past decade in attempt to build on existing knowledge. It will highlight clinical performance and limitations while reviewing developments on recognized procedures; it will also provide insight into novel approaches incorporated in response to clinical demand (e.g. C. auris and antifungal resistance) or technological advances (e.g. next-generation sequencing).
Recent Findings
Limited methodological standardization and, until recently, unavailability of commercial options have hindered the integration of molecular diagnostics for yeasts. The development of certain, novel commercial methods has received considerable evaluation allowing a greater understanding of individual assay performance, but widespread multicentre evaluation of most commercial kits is lacking. The detection of emerging pathogens (e.g. C. auris) has been enhanced by the development of molecular tests. Molecular methods are providing a better understanding of the mycobiome, mechanisms of resistance and epidemiology/phylogeny.
Summary
Despite over two decades of use, the incorporation of molecular methods to enhance the diagnosis of yeast infections remains limited to certain specialist centres. While the development of commercial tests will provide stimulus for broader application, further validation and reduced costs are required. Over the same period of time, Aspergillus PCR has become more widely accepted driven by international efforts to standardize methodology; it is critical that yeast PCR follows suit. Next-generation sequencing will provide significant information on the mycobiome, antifungal resistance mechanism and even broad-range detection directly from the specimen, which may be critical for the molecular detection of yeasts other than Candida species, which is currently limited.
... 50% to 80% of patients with ocular fungal involvement may initially be asymptomatic (or unable to communicate) [66,67]. Consecutively, current guidelines recommend an ophthalmological examination of all patients with candidaemia [68,69]. However, more recent studies have reported lower OC rates, from 2.9% to 12.8%, and the necessity for routine ophthalmology consultation has been challenged [70][71][72][73]. ...
is is a literature review of 31 case series of endogenous endophthalmitis (EE) published in the last ten years, identified from a literature search of several databases (PubMed, EMBASE, and the Cochrane Library). While diabetes mellitus and malignancies remain the most frequently associated medical conditions, intravenous drug use is a significant risk factor (especially in the last years, in studies from Western countries). Ophthalmologic screening is recommended for candidaemia, but not in patients with sepsis of other aetiologies (however, the physician treating patients with sepsis must be well aware of EE). e most frequent Gram-positive microorganisms that cause EE are Staphylococcus and Streptococcus; the most frequent Gram-negative organism is Pseudomonas, and yeasts, probably Candida, usually cause fungal infections. In all-cause EE, prognostic factors of better visual outcomes are initial VA better than counting fingers, performing a pars plana vitrectomy (PPV), performing an intravitreal injection within the first 24 hours after clinical diagnosis, and the presence of a focal type of EE. In endogenous fungal endophthalmitis, more than 1/4 of patients have bilateral involvement. Blood samples have a low rate of positivity. Yeasts remain the most prevalent cause. Many authors report using azoles and echinocandins for systemic therapy (and voriconazole for intravitreal injections). Although PPV was performed in small proportions of eyes, the anatomical success rate is quite high. Klebsiella pneumoniae is an important cause of EE in Southeast Asia (and probably an emergent etiology in other regions), which is frequently associated with diabetes. ere is a robust association with pyogenic liver abscess (PLA) (but in up to half of the cases, the diagnosis of EE precedes that of PLA). Blood cultures have a high diagnostic yield, while vitreous samples have a low yield. K. pneumoniae may carry antibiotic resistance. Anatomical and functional success rates are small, but they may be improved with PPV.
... The fungal specimen data were collected from inpatients with candidaemia in the Affiliated Hospital of Southwest Medical University (Luzhou, China), which is a 3200-bed tertiary care teaching hospital with 43 wards and approximately 120,000 annual admissions, from January 2013 to December 2019. The diagnostic criteria of candidaemia were based on the guidelines for the diagnosis and treatment of Candidiasis: the expert consensus issued by the Chinese Medical Association [12]; these criteria were also in accordance with the European Society of Clinical Microbiology and Infectious Diseases (ESCMID)* guidelines for the diagnosis and management of Candida diseases 2012 [13,14] and the Infectious Diseases Society of America (IDSA) Guidelines for the Management of Candidiasis: 2016 Update [15]. For each patient, only the first episode was included in our analysis. ...
Background:
There are no current national estimates of the candidaemia burden in China, and epidemiological candidaemia data from the underdeveloped region of China are lacking.
Methods:
A 7-year retrospective study was carried out to analyse the prevalence, species distribution, antifungal susceptibility, risk factors and inpatient mortality of candidaemia among paediatric and adult patients in a regional tertiary teaching hospital in China.
Results:
During the seven-year study period, a total of 201 inpatients with candidaemia were identified. The median age of the patients was 65 years (range, 1 day to 92 years), and 114 of the patients (56.7%) were male. The mean annual incidence of candidaemia was 0.26 cases per 1000 admissions (0.42 cases per 1000 paediatric admissions vs 0.24 cases per 1000 adult admissions, P < 0.05). Candida albicans was the most common fungal species (81/201, 40.3%) in all patients, Candida glabrata was the most common fungal species (18/35, 51.4%) in paediatric patients. Most isolates were susceptible to flucytosine (99.0%) and amphotericin B (99.0%), and the activity of antifungal agents against Candida species was no significant difference in satisfaction between paediatric and adult patients (P > 0.05). The all-cause mortality rate was 20.4% (paediatric patients: 11.4% vs adult patients:22.3%, P > 0.05). Fewer univariate predictors of poor outcomes were identified for paediatric patients than for adult patients (4 vs 11 predictors). Respiratory dysfunction and septic shock were independent predictors of 30-day mortality for all patients.
Conclusions:
The epidemiological data of candidaemia in paediatric and adult patients are only different in the distributions of Candida species and the mean annual incidence of candidaemia. Flucytosine and amphotericin B can be used as first-choice agents when no antifungal susceptibility test results are available.
... Candida PCR also had a significantly higher positivity rate (85%) compared with blood culture (38%) for patients with proven or probable IC [42]. Despite the findings of the respective meta-analysis, guidelines for defining IFD do not recommended PCR, due to limited standardization, compounded by the sparsity of well-validated commercial tests and subsequent lack of clinical evidence of an optimal process [43]. The MICAFEM study group aimed to evaluate serum PCR and blood culture in a prospective noninterventional multicentre study. ...
Purpose of Review
This review has incorporated the knowledge and experience of the leads of each of the laboratory working parties of the fungal PCR initiative in order to provide up-to-date information on the performance and developments of PCR methods for the detection of fungi that commonly cause invasive fungal disease (IFD).
Recent Findings
Molecular diagnosis of IFD enhances the current repertoire of mycological investigations. Providing superior sensitivity and turn-around-time over classical approaches, yet maintaining the benefits of classical tests (e.g. species level identification and identifying resistance). Standardization for Aspergillus PCR is almost complete; the recent release of commercial PCR assays for a wide range fungi (Aspergillus, Candida, Pneumocystis, Mucorales and Pan-fungal) and availability of external quality control schemes (e.g. Quality Control of Molecular Diagnostics for Aspergillus, Candida, Pneumocystis) means that fungal PCR testing is robust and ready for use, globally.
Summary
Further work is needed to ascertain the utility of PCR in routine practice and to determine whether combining it with other biomarkers is an optimal strategy. PCR for detecting Mucorales sp. and on tissue, together with direct antifungal resistance detection in body fluids, may increase its diagnostic value across the board. This and the ability to diagnose Pneumocystis pneumonia and invasive candidiasis would go a long way towards attaining the long-held ambition of medical mycology to provide a comprehensive range of tests that can be relied upon to diagnose, at least, the common IFD. In short, PCR has a clear future and is close to achieving its full potential in our laboratories.
... The guideline follows the structure and definitions of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Guidelines on Candidiasis and the ESCMID/ECMM guidelines on rare invasive fungal infections, 2,5 which are in accordance with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) and Appraisal of Guidelines for Research & Evaluation (AGREE) systems. 6,7 Mucormycosis is a rare disease for which only one small randomised trial has been conducted, 8 and meta-analyses are therefore not applicable. ...
... The guideline follows the structure and definitions of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Guidelines on Candidiasis and the ESCMID/ECMM guidelines on rare invasive fungal infections, 2,5 which are in accordance with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) and Appraisal of Guidelines for Research & Evaluation (AGREE) systems. 6,7 Mucormycosis is a rare disease for which only one small randomised trial has been conducted, 8 and meta-analyses are therefore not applicable. ...
... Currently, molecular techniques based on PCR are not recommended nor have they been approved for clinical diagnosis purposes [45]. Despite this, the third objective of this study was to identify the yeast species by directly extracting the DNA from eight types of clinical samples. ...
Candida species are one of the most important causes of human infections, especially in hospitals and among immunocompromised patients. The correct and rapid etiological identification of yeast infections is important to provide adequate therapy, reduce mortality, and control outbreaks. In this study, Candida species were identified in patients with suspected fungal infection, and phenotypic and genotypic identification methods were compared. A total of 167 axenic fungal cultures and 46 clinical samples were analyzed by HardyCHROM ® , MicroScan ® (Omron Microscan Systems Inc, Renton, WA, USA), and PCR-RFLP (Restriction Fragment Length Polymorphisms). The species of the C. albicans complex were the most frequent, followed by C. tropicalis and C. glabrata. Less common but clinically relevant species of Candida were also isolated. The comparison between the three methods was concordant, especially for the most common Candida species. Fungal DNA amplification was successful in all clinical samples.
... The guideline follows the structure and definitions of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Guidelines on Candidiasis and the ESCMID/ECMM guidelines on rare invasive fungal infections, 2,5 which are in accordance with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) and Appraisal of Guidelines for Research & Evaluation (AGREE) systems. 6,7 Mucormycosis is a rare disease for which only one small randomised trial has been conducted, 8 and meta-analyses are therefore not applicable. ...
Mucormycosis is a difficult to diagnose rare disease with high morbidity and mortality. Diagnosis is often delayed, and disease tends to progress rapidly. Urgent surgical and medical intervention is lifesaving. Guidance on the complex multidisciplinary management has potential to improve prognosis, but approaches differ between health-care settings. From January, 2018, authors from 33 countries in all United Nations regions analysed the published evidence on mucormycosis management and provided consensus recommendations addressing differences between the regions of the world as part of the "One World One Guideline" initiative of the European Confederation of Medical Mycology (ECMM). Diagnostic management does not differ greatly between world regions. Upon suspicion of mucormycosis appropriate imaging is strongly recommended to document extent of disease and is followed by strongly recommended surgical intervention. First-line treatment with high-dose liposomal amphotericin B is strongly recommended, while intravenous isavuconazole and intravenous or delayed release tablet posaconazole are recommended with moderate strength. Both triazoles are strongly recommended salvage treatments. Amphotericin B deoxycholate is recommended against, because of substantial toxicity, but may be the only option in resource limited settings. Management of mucormycosis depends on recognising disease patterns and on early diagnosis. Limited availability of contemporary treatments burdens patients in low and middle income settings. Areas of uncertainty were identified and future research directions specified.
... Sabouraud dextrose agar (Acumedia; Michigan, USA) was used for the culture, and identification of the species was performed by conventional methods (Dalmou method) with micromorphologic features, ID32C (bioMerieux; France) with carbohydrate assimilation features and MALDI-TOFF MS with proteomic features. Antifungal susceptibilities were investigated via E-test method, and minimum inhibitor concentration levels were used according to the CLSI guideline (6,7). ...
Objectives:
Candida species are among the most important causes of hospital acquired blood borne infections, and with high rates of mortality and morbidity, these infections are still a major problem today. History of gastrointestinal surgery, administration of total parenteral nutrition and/or wide spectrum antibiotics and immune suppression following organ transplantations are considered serious risk factors for these infections. This study aimed to evaluate the patients from our general surgery department with diagnosed candidemia; by means of strain, treatment and prognosis.
Material and methods:
Patients with positive blood cultures for Candida species who were treated in the wards and Ege University Faculty of Medicine general surgery department of surgical intensive care units of our between 2012 and 2017 were retrospectively analyzed by means of strain, treatment and prognosis.
Results:
A total of 50 patients were enrolled in the study. Mean age was 58.96 years and 54% of the patients were female. There were nine patients with organ transplantation (four liver and five kidney transplantations), six with intestinal perforation and three with anastomotic leakage. Isolated strains were Candida albicans (36%; 18/50), Candida tropicalis (14%; 7/50), Candida glabrata (12%; 6/50), Candida parapsilosis (8%; 4/50), Candida kefyr (6%; 3/50), Candida krusei (4%; 2/50), Candida pulcherrima (2%; 1/50), Cryptococcus neoformans (2%, 1/50), Geotrichum capitatum (2%, 1/50), Candida spp. (unidentified, 14%; 7/50) with decreasing frequency. The highest antifungal sensitivity rates (> 90%) were measured for amphotericin B, voriconazole and echinocandins among all isolates. One-month mortality rate was 43.4% (20/46). Documented eradication was achieved among 24 of the 33 patients who had control blood culture samples (72.7%), and mean eradication time was 7.6 days. Echocardiography was performed in 14% (7/50) and ophthalmic examination in 8% (4/50).
Conclusion:
Although C. albicans appears to be the dominant strain in patients with candidemia, frequencies of other strains are increasing. Early diagnosis and treatment of patients with candidemia is of vital importance due to high mortality and morbidity rates.
... The candida score and Ostrozky score can be helpful in excluding patients who are not likely to benefit from antifungal therapy rather than selecting those who will benefit from such therapy, thus restricting the irrational use of antifungal agents [51]. We followed the IDSA and ESCMID guidelines, which recommend the use of echinocandins for critically ill patients not previously exposed to azoles or infected with a non-albicans Candida spp as a result of a broader spectrum and greater efficacy than traditional antifungals [52,53]. Poves-Alavrez et al., conversely, found that 30-day mortality was not modified by antifungal treatment [10]. ...
Lymphopenia has been related to increased mortality in septic patients. Nonetheless, the impact of lymphocyte count on candidemia mortality and prognosis has not been addressed. We conducted a retrospective study, including all admitted patients with candidemia from 2007 to 2016. We examined lymphocyte counts during the first 5 days following the diagnosis of candidemia. Multivariable logistic regression analysis was performed to determine the relationship between lymphocyte count and mortality. Classification and Regression Tree analysis was used to identify the best cut-off of lymphocyte count for mortality associated with candidemia. From 296 cases of candidemia, 115 died, (39.8% 30-day mortality). Low lymphocyte count was related to mortality and poor outcome (p < 0.001). Lymphocyte counts < 0.703 × 109 cells/L at diagnosis (area under the curve (AUC)-ROC, 0.783 ± 0.042; 95% confidence interval (CI), 0.700–0.867, p < 0.001), and lymphocyte count < 1.272 × 109 cells/L five days later (AUC-ROC, 0.791 ± 0.038; 95%CI, 0.716–0.866, p < 0.001) increased the odds of mortality five-fold (odds ratio (OR), 5.01; 95%CI, 2.39–10.93) at time of diagnosis, and three-fold (OR, 3.27; 95%CI, 1.24–8.62) by day 5, respectively. Low lymphocyte count is an independent predictor of mortality in patients with candidemia and might serve as a biomarker for predicting candidemia-associated mortality and poor outcome.
... The two internationally accepted standard AFST methods are EUCAST [2] and CLSI [3]. They allow the categorization of isolates as susceptible, intermediate, or resistant [4] and AFST according to these guidelines has become standard procedure to guide antifungal therapy [5]. ...
Antifungal susceptibility testing (AFST) of clinical isolates is a tool in routine diagnostics to facilitate decision making on optimal antifungal therapy. The minimal inhibitory concentration (MIC)-phenomena (trailing and paradoxical effects (PXE)) observed in AFST complicate the unambiguous and reproducible determination of MICs and the impact of these phenomena on in vivo outcome are not fully understood. We aimed to link the MIC-phenomena with in vivo treatment response using the alternative infection model Galleria mellonella. We found that Candida albicans strains exhibiting PXE for caspofungin (CAS) had variable treatment outcomes in the Galleria model. In contrast, C. albicans strains showing trailing for voriconazole failed to respond in vivo. Caspofungin- and voriconazole-susceptible C. albicans strains responded to the respective antifungal therapy in vivo. In conclusion, MIC data and subsequent susceptibility interpretation of strains exhibiting PXE and/or trailing should be carried out with caution, as both effects are linked to drug adaptation and treatment response is uncertain to predict.
... Inappropriate selection of antifungals and dosing [124,125] Insufficient plasma and tissue drug levels despite correct dosing because of unpredictable pharmacokinetics with high inter-and intrapatient variability [126,127] Absence of therapeutic drug monitoring (TDM) where recommended (e.g., intravenous and oral voriconazole, and posaconazole oral suspension [128][129] [130] Incorrect intake procedures [131,132] Incorrect handling or antifungal therapy of fungal biofilms on vascular devices or foreign bodies [133,134] [135] [133,[136][137][138][139] , including incomplete source control, for example catheter management ...
Breakthrough invasive fungal infections (IFI) have emerged as a significant problem in patients receiving systemic antifungals; however, consensus criteria for defining breakthrough IFI are missing. This position paper establishes broadly applicable definitions of breakthrough IFI for clinical research. Representatives of the Mycoses Study Group Education and Research Consortium (MSG‐ERC) and the European Confederation of Medical Mycology (ECMM) reviewed the relevant English literature for definitions applied and published through 2018. A draft proposal for definitions was developed, and circulated to all members of the two organizations for comment and suggestions. The authors addressed comments received, and circulated the updated document for approval. Breakthrough IFI was defined as any IFI occurring during exposure to an antifungal drug, including fungi outside the spectrum of activity of an antifungal. The time of breakthrough IFI was defined as the first attributable clinical sign or symptom, mycological finding or radiological feature. The period defining breakthrough IFI depends on pharmacokinetic properties and extends at least until one dosing interval after drug discontinuation. Persistent IFI describes IFI that is unchanged/stable since treatment initiation with ongoing need for antifungal therapy. It is distinct from refractory IFI, defined as progression of disease and therefore similar to non‐response to treatment. Relapsed IFI occurs after treatment, and is caused by the same pathogen at the same site, although dissemination can occur. These proposed definitions are intended to support the design of future clinical trials and epidemiological research in clinical mycology, with the ultimate goal of increasing the comparability of clinical trial results. This article is protected by copyright. All rights reserved.
... An executive summary was prepared and submitted to Clinical Microbiology and Infection in 2017 and published in 2018 after peer review [25]. The methods to evaluate the quality of evidence and to reach group consensus recommendations have been previously described [26]. A modified United States Preventive Service Task Force (USPSFT) grading system https://www.uspreventiveservicestaskforce.org/Page/Name/ ...
Scope:
Presenting symptoms, distributions and patterns of diseases and vulnerability to invasive aspergillosis (IA) are similar between children and adults. However, differences exist in the epidemiology and underlying conditions, the usefulness of newer diagnostic tools, the pharmacology of antifungal agents and in the evidence from interventional phase 3 clinical trials. Therefore, the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and the European Confederation of Medical Mycology (ECMM) have developed a paediatric-specific guideline for the diagnosis and management of IA in neonates and children.
Methods:
Review and discussion of the scientific literature and grading of the available quality of evidence was performed by the paediatric subgroup of the ESCMID-ECMM-European Respiratory Society (ERS) Aspergillus disease guideline working group, which was assigned the mandate for the development of neonatal- and paediatric-specific recommendations.
Questions:
Questions addressed by the guideline included the epidemiology of IA in neonates and children; which paediatric patients may benefit from antifungal prophylaxis; how to diagnose IA in neonates and children; which antifungal agents are available for use in neonates and children; which antifungal agents are suitable for prophylaxis and treatment of IA in neonates and children; what is the role of therapeutic drug monitoring of azole antifungals; and which management strategies are suitable to be used in paediatric patients. This guideline provides recommendations for the diagnosis, prevention and treatment of IA in the paediatric population, including neonates. The aim of this guideline is to facilitate optimal management of neonates and children at risk for or diagnosed with IA.
Antifungal stewardship refers to the rational use of antifungal agents. Historically, in some instances, the misuse or overuse of antifungal agents has predisposed patients to an elevated risk of systemic side-effects and treatment resistance, as well as increased healthcare costs. Superficial mycoses, such as onychomycosis, are sometimes treated without any diagnostic testing and is associated with a high likelihood of self-diagnosis and self-treatment, potentially leading to the emergence of resistance against commonly used antifungals like terbinafine. Practitioners need to ensure that a proper clinical diagnosis is backed up by appropriate testing. This may include the traditional light microscopy and culture; additionally, molecular techniques (such as polymerase chain reaction, terbinafine gene mutational analysis) and antifungal susceptibility testing are considerations as appropriate. The choice of antifungal agent should be guided by what is the standard of care in the location where the clinician practices as well as more broadly state and national prescription patterns. Recently, reports of treatment resistance concerning both superficial and deep fungal infections have added another layer of difficulty to clinical practice. This review aims to explore the phenomenon of antifungal drug resistance, and highlights the importance of adopting antifungal stewardship programs. We provide an overview of treatment resistance and mechanisms of resistance reported thus far in dermatophytes. Challenges of performing antifungal susceptibility testing and therapeutic drug monitoring are discussed, as well as principles, recommendations and future directions of antifungal stewardship programs.
Immunosuppressed patients, transplant recipients, and those with acute or chronic respiratory disease are at increased risk for invasive fungal infections in Argentina. Although the national public system guarantees universal access to health care for all citizens, little is known about the quality of available diagnostic and treatment armamentarium for invasive fungal infections in the country. Between June and August 2022, infectious diseases clinicians from each of the 23 provinces and the Autonomous City of Buenos Aires were contacted to describe local access to fungal diagnostic tools and antifungal agents. The information collected included different aspects such as hospital characteristics, patients admitted and wards, access to diagnostic tools, estimated infection incidence and treatment capacity. Thirty responses were collected from facilities throughout Argentina. Most institutions were governmental (77%). A mycology department was available in 83% of them. Histopathology was available in almost 93% of the sites, while automated methods and galactomannan tests were available in 57%, each; 53% of the sites had access to MALDI-TOF-MS through regional reference laboratories and PCR was present in 20% of the sites. Susceptibility testing was available in 63% of the laboratories. Candida spp. (24%), Cryptococcus spp. (20%), Aspergillus spp. (18%), and Histoplasma spp. (16%) were described as the main pathogens. Fluconazole was the only antifungal agent available in all institutions. This was followed by amphotericin B deoxycholate (83%) and itraconazole (80%). If an antifungal agent was not available on site, 60% of the patients could receive adequate antifungal treatment within the first 48 hours upon request. Although there are no significant differences in access to diagnostic and clinical management of invasive fungal infections among the Argentinean centres studied, national awareness-raising initiatives led by policymakers could help to improve their general availability.
Candidemia remains a major public health challenge due to its high mortality rates, especially in developing countries. Monitoring epidemiological trends may provide insights for better clinical outcomes. This study aimed to describe trends in the epidemiology, therapeutic practices, and mortality in candidemia through a retrospective comparative analysis between two surveillance cohorts of all candidemic adults at eleven tertiary hospitals in Brazil, from 2010–2011 (Period I) versus 2017–2018 (Period II). A total of 616 cases were diagnosed, with 247 being from Period II. These patients were more likely to have three or more coexisting comorbidities [72 (29.1%) vs. 60 (16.3%), p < 0.001], had a prior history of in-hospital admissions more often [102 (40.3%) vs. 79 (21.4%), p = 0.001], and presented with candidemia earlier after admission, within 15 days (0–328) vs. 19 (0–188), p = 0.01. Echinocandins were more frequently prescribed [102 (41.3%) vs. 50 (13.6%), p = 0.001], but time to antifungal initiation [2 days (0–14) vs. 2 (0–13), p = 0.369] and CVC removal within 48 h [90/185 (48.6%) vs. 148/319 (46.4%), p = 0.644] remained unchanged. Additionally, many patients went untreated in both periods I and II [87 (23.6%) vs. 43 (17.4%), p = 0.07], respectively. Unfortunately, no improvements in mortality rates at 14 days [123 (33.6%) vs. 93 (37.7%), p = 0.343] or at 30 days [188 (51.4%) vs. 120 (48.6%), p = 0.511] were observed. In conclusion, mortality rates remain exceedingly high despite therapeutic advances, probably associated with an increase in patients’ complexity and suboptimal therapeutic interventions. Management strategies should be tailored to suit epidemiological changes, expedite diagnosis to reduce the number of untreated eligible patients and guarantee early antifungal initiation and source control.
Background: Data on persistent candidemia (PC), a recognized complication of candidemia, are lacking in China. This study aimed to investigate the clinical characteristics and risk factors for the mortality of PC among adults in China.
Methods: This 6-year retrospective study analyzed the prevalence, species distribution, antifungal susceptibility, risk factors, and patient mortality of PC among adults in three regional tertiary teaching hospitals in China from 2016 to 2021. PC was defined as the isolation of the same Candida species from positive blood culture for ≥5 days following the initiation of antifungal therapy.
Results: The definition of PC was fulfilled by 36 patients (13.7%, 36/263). The mean age of the patients was 59.9 years (60 years for patients with PC; 59.8 years for those with non-PC; P > 0.05), and 131 (60.1%) were men [16 with PC (44.4%), 115 with non-PC (63.2%), P < 0.05]. The mean annual incidence was 0.15/1000 admissions (including PC 0.03/1000 admissions vs non-PC 0.12/1000 admissions, P < 0.05). Candida parapsilosis(14/36, 38.9%) and Candida albicans (81/182, 44.5%) were the predominant pathogens in patients with PC and non-PC, respectively. Most isolates were susceptible to flucytosine (99.0%) and amphotericin B (99.5%), and the activity of antifungal agents against Candida species was not statistically significantly different between patients with PC and non-PC (P> 0.05). The 30-day mortality rate was 20.2% (16.7% with PC vs 20.9% with non-PC, P > 0.05). Multivariable regression analysis showed that use of broad-spectrum antibiotics, and fluconazole were independent predictors of PC, sex (male) was the protective factor for PC. Respiratory dysfunction and length of hospital stay were independent predictors of 30-day mortality in patients with non-PC. C. tropicalis bloodstream infection (odds ratio, 12.642; 95% confidence interval, 1.059–150.951; P = 0.045) was an independent predictor of 30-day mortality in patients with PC.
Conclusions: The epidemiological data of patients with PC and non-PC were different in the distribution of Candida species, the mean annual incidence, and independent predictors of 30-day mortality. Flucytosine and amphotericin B could be used as first-choice drugs in the presence of PC infections.
Shwachman-Diamond syndrome is a rare disorder that can develop malignant and non-malignant haematological complications. Overall, 10-20% of Shwachman-Diamond patients need hematopoietic stem cell transplantation (HSCT), but most centres have a limited experience and different approaches. The European Society for Blood and Marrow Transplantation-Severe Aplastic Anaemia Working Party promoted an expert consensus to propose recommendations regarding key issues in the management of Shwachman-Diamond patients with hematological complications.
The main items identified as relevant for improving survival were: the importance of regular and structured haematologic follow-up, the potential reduction of transplant-related mortality by using reduced-intensity conditioning regimens, the limitation of total body irradiation, particularly for non-malignant severe cytopenia/bone marrow failure, the early diagnosis of clonal malignant evolution and early recognition of an indication for HSCT. Finally, the poor results of HSCT in patients with acute myeloid leukaemia, irrespective of cytoreductive chemotherapy treatment received prior to transplantation, highlights the need for innovative approaches.
In this study, a cholesterol-dependent C. glabrata clinical isolate that confers azole and AmB resistance was investigated using artificial intelligence (AI) technologies and cloud computing applications. This is the first of the known cholesterol-dependent C. glabrata isolate to be found in Turkey.
Since echinocandins are recommended as first line therapy for invasive candidiasis, detection of resistance, mainly due to alteration in FKS protein, is of main interest. EUCAST AFST recommends testing both MIC of anidulafungin and micafungin, and breakpoints (BPs) have been proposed to detect echinocandin-resistant isolates. We analyzed MIC distribution for all three available echinocandins of 2,787 clinical yeast isolates corresponding to 5 common and 16 rare yeast species, using the standardized EUCAST method for anidulafungin and modified for caspofungin and micafungin (AM3-MIC). In our database, 64 isolates of common pathogenic species were resistant to anidulafungin, according to the EUCAST BP, and/or to caspofungin, using our previously published threshold (AM3-MIC ≥ 0.5 mg/L). Among these 64 isolates, 50 exhibited 21 different FKS mutations. We analyzed the capacity of caspofungin AM3-MIC and anidulafungin MIC determination in detecting isolates with FKS mutation. They were always identified using caspofungin AM3-MIC and the local threshold while some isolates were misclassified using anidulafungin MIC and EUCAST threshold. However, both methods misclassified four wild-type C. glabrata as resistant. Based on a large data set from a single center, the use of AM3-MIC testing for caspofungin looks promising in identifying non-wild-type C. albicans, C. tropicalis and P. kudiravzevii isolates, but additional multicenter comparison is mandatory to conclude on the possible superiority of AM3-MIC testing compared to the EUCAST method.
Background:
Candidemia and Candida-associated catheter-related bloodstream infections (CRBSIs) are the significant cause of mortality and morbidity in patients with malignancy.
Methods:
A retrospective analysis including all pediatric hematologic/oncologic malignancies patients with CRBSIs treated in Dr. Behçet Uz Children Diseases and Surgery Training and Research Hospital between the period of 2009 and 2020.
Results:
During the study period, 53 children with CRBSIs associated with Candida species were included. The most common malignancy was acute lymphoblastic leukemia (45.3%) and acute myeloid leukemia (15.1%). A total of 56 Candida isolates were present including non-albicans Candida species (80.4%) and Candida albicans (19.6%). The most common isolated Candida species was Candida parapsilosis (42.9%) and followed by C. albicans (19.6%). The ratio of azole prophylaxis was significantly higher in patients with the non-albicans Candida group (P=0.031). Candida-related endocarditis (vegetation) was present in 2 (3.8%) patients, and the overall rate of hepatosplenic candidiasis was 3.8%. Seven days Candida attributable mortality was 7.5% (4 patients) and 30 days Candida attributable mortality was 11.3% (6 patients). The Candida species responsible for the Candida-related deaths were as following: Candida tropicalis (n=3), C. parapsilosis (n=2), and C. lusitanae (n=1).
Conclusion:
In pediatric cancer patients with Candida-associated CRBSIs, evaluation of the patient for organ involvement including liver and spleen ultrasonography and cardiac involvement with echocardiography are essential regardless of the patients' clinical picture.
Paediatric patients with cancer and those undergoing allogeneic haematopoietic cell transplantation have an increased susceptibility to invasive fungal diseases. In addition to differences in underlying conditions and comorbidities relative to adults, invasive fungal diseases in infants, children, and adolescents are unique in terms of their epidemiology, the validity of current diagnostic methods, the pharmacology and dosing of antifungal agents, and the absence of phase 3 clinical trials to provide data to guide evidence-based interventions. To re-examine the state of knowledge and to further improve invasive fungal disease diagnosis, prevention, and management, the 8th European Conference on Infections in Leukaemia (ECIL-8) reconvened a Paediatric Group to review the literature and to formulate updated recommendations according to the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and European Confederation of Medical Mycology (ECMM) grading system, which are summarised in this Review.
Background: There are no current national estimates of the candidaemia burden in China, and epidemiological candidaemia data from the underdeveloped region of China are lacking.
Methods: A 7-year retrospective study was carried out to analyse the prevalence, species distribution, antifungal susceptibility, risk factors and inpatient mortality of candidaemia among paediatric and adult patients in a regional tertiary teaching hospital in China.
Results: During the seven-year study period, a total of 201 inpatients with candidaemia were identified. The median age of the patients was 65 years (range, 1 day to 92 years), and 114 of the patients (56.7%) were male. The mean annual incidence of candidaemia was 0.26 cases per 1,000 admissions (0.42 cases per 1,000 paediatric admissions vs 0.24 cases per 1,000 adult admissions, P<0.05). Candida albicans was the most common fungal species (81/201, 40.3%) in all patients, Candida glabrata was the most common fungal species (18/35, 51.4%) in paediatric patients. Most isolates were susceptible to flucytosine (99.0%) and amphotericin B (99.0%), and the activity of antifungal agents against Candida species was no significant difference in satisfaction between paediatric and adult patients(P>0.05). The all-cause mortality rate was 20.4% (paediatric patients: 11.4% vs adult patients:22.3%, P>0.05). Fewer univariate predictors of poor outcomes were identified for paediatric patients than for adult patients (4 vs 11 predictors). Respiratory dysfunction and septic shock were independent predictors of 30-day mortality for all patients.
Conclusions: The epidemiological data of candidaemia in paediatric and adult patients are only different in the distributions of Candida species and the mean annual incidence of candidaemia. Flucytosine and amphotericin B can be used as first-choice agents when no antifungal susceptibility test results are available.
Candida species are one of the most important causes of human infections, especially in hospitals and among immunocompromised patients. The correct and rapid etiological identification of yeast infections is important to provide adequate therapy, reduce mortality and control outbreaks. In this study, Candida species were identified in patients with suspected fungal infection, and phenotypic and genotypic identification methods were compared. A total of 167 axenic fungal cultures and 46 clinical samples were analyzed by HardyCHROM®, MicroScan®, and PCR-RFLP. The species of the C. albicans complex were the most frequent, followed by C. tropicalis and C. glabrata. Less common but clinically relevant species of Candida were also isolated. The comparison between the three methods was concordant, especially for the most common Candida species. Fungal DNA amplification was successful in all clinical samples.
Persons employed in microbiological laboratories constitute a group of employees who are particularly exposed to the wide spectrum of harmful biological agents. The work of a microbiologist requires extreme caution, as well as compliance with research procedures and health and safety regulations. The direct threat to the health of employees of microbiological laboratories are, among others, microbiological waste. Proper disposal as well as inactivation of these wastes has an impact on the quality of air inside laboratories. Therefore, it is extremely important to monitor the microbiological quality of air in laboratory rooms. This paper presents the results of measurements of concentrations of microbiological air pollutants in a laboratory storing and utilizing microbiological waste, located in the SilesianVoivodship. Bioaerosol samples were collected using a 6-stage Andersen impactor, with cut-off diameters of 7.0, 4.7, 3.3, 2.1, 1.1 and 0.65 μm (Thermo Fisher Scientific, Waltham, MA, USA). It has been shown that exposure to biological agents does not pose a direct threat to the health of workers in the laboratory under test, however, long-term inhalation of biological aerosols in this room may cause adverse health effects, especially in people sensitive to this type of air pollution. In order to ensure proper air quality in the analyzed laboratory, it is necessary to haveadequate ventilation and intensive ventilation of the room.Keywords: bioaerosol, bacterial aerosol, microbiological waste, indoor air quality (IAQ).
Cytomegalovirus is one of the most important infections to occur after allogeneic haematopoietic stem cell transplantation (HSCT), and an increasing number of reports indicate that cytomegalovirus is also a potentially important pathogen in patients treated with recently introduced drugs for hematological malignancies. Expert recommendations have been produced by the 2017 European Conference on Infections in Leukaemia (ECIL 7) after a review of the literature on the diagnosis and management of cytomegalovirus in patients after HSCT and in patients receiving other types of therapy for haematological malignancies. These recommendations cover diagnosis, preventive strategies such as prophylaxis and pre-emptive therapy, and management of cytomegalovirus disease. Antiviral drugs including maribavir and letermovir are in development and prospective clinical trials have recently been completed. However, management of patients with resistant or refractory cytomegalovirus infection or cytomegalovirus disease is a challenge. In this Review we summarise the reviewed literature and the recommendations of the ECIL 7 for management of cytomegalovirus in patients with haematological malignancies.
Invasive Candidiasis (IC) and candidemia (as its most frequent manifestation) have become the main cause of opportunistic mycosis at hospital settings. This study, made by members of the Colombian Association of Infectious Diseases (ACIN), was aimed at providing a set of recommendations for the management, follow-up and prevention of IC / candidemia and mucous membrane candida infection in adult, pediatric and neonatal patients in a hospital setting, including the hemato-oncological and critical care units. All the data obtained through an exhaustive search were reviewed and analyzed in a comprehensive manner by all the members of the group, and the recommendations issued are being made after a careful review of the scientific literature available and the consensus of all specialists involved; the emergence of Candida Spp. problem is highlighted and a correct orientation to health professionals regarding the management of patients with candidiasis is provided in a rational and practical way, emphasizing patient evaluation, diagnostic strategies, prophylaxis, empirical treatment, directed treatment and preventative therapy.
Invasive fungal diseases (IFDs) continue to cause considerable morbidity and mortality in patients with haematological malignancy. Diagnosis of IFD is difficult, with the sensitivity of the gold standard tests (culture and histopathology) often reported to be low, which may at least in part be due to sub-optimal sampling or subsequent handling in the routine microbiological laboratory. Therefore, a working group of the European Conference in Infections in Leukaemia was convened in 2009 with the task of reviewing the classical diagnostic procedures and providing recommendations for their optimal use. The recommendations were presented and approved at the ECIL-3 conference in September 2009. Although new serological and molecular tests are examined in separate papers, this review focuses on sample types, microscopy and culture procedures, antifungal susceptibility testing and imaging. The performance and limitations of these procedures are discussed and recommendations are provided on when and how to use them and how to interpret the results.
Invasive fungal infections (IFIs) are life-threatening complications in patients with hemato-oncological malignancies, and early diagnosis is crucial for outcome. The compound 1,3-β-D-glucan (BG), a cell wall component of most fungal species, can be detected in blood during IFI. Four commercial BG antigenemia assays are available (Fungitell, Fungitec-G, Wako, and Maruha). This meta-analysis from the Third European Conference on Infections in Leukemia (ECIL-3) assessed the performance of BG assays for the diagnosis of IFI in hemato-oncological patients.
Studies reporting the performance of BG antigenemia assays for the diagnosis of IFI (European Organization for Research and Treatment of Cancer and Mycoses Study Group criteria) in hemato-oncological patients were identified. The analysis was focused on high-quality cohort studies with exclusion of case-control studies. Meta-analysis was performed by conventional meta-analytical pooling and bivariate analysis.
Six cohort studies were included (1771 adult patients with 414 IFIs of which 215 were proven or probable). Similar performance was observed among the different BG assays. For the cutoff recommended by the manufacturer, the diagnostic performance of the BG assay in proven or probable IFI was better with 2 consecutive positive test results (diagnostic odds ratio for 2 consecutive vs one single positive results, 111.8 [95% confidence interval {CI}, 38.6-324.1] vs 16.3 [95% CI, 6.5-40.8], respectively; heterogeneity index for 2 consecutive vs one single positive results, 0% vs 72.6%, respectively). For 2 consecutive tests, sensitivity and specificity were 49.6% (95% CI, 34.0%-65.3%) and 98.9% (95% CI, 97.4%-99.5%), respectively. Estimated positive and negative predictive values for an IFI prevalence of 10% were 83.5% and 94.6%, respectively.
Different BG assays have similar accuracy for the diagnosis of IFI in hemato-oncological patients. Two consecutive positive antigenemia assays have very high specificity, positive predictive value, and negative predictive value. Because sensitivity is low, the test needs to be combined with clinical, radiological, and microbiological findings.
Candidemia and invasive candidiasis (C/IC) are life-threatening opportunistic infections that add excess morbidity, mortality and cost to the management of patients with a range of potentially curable underlying conditions. The Association of Medical Microbiology and Infectious Disease Canada developed evidence-based guidelines for the approach to the diagnosis and management of these infections in the ever-increasing population of at-risk adult patients in the health care system. Over the past few years, a new and broader understanding of the epidemiology and pathogenesis of C/IC has emerged and has been coupled with the availability of new antifungal agents and defined strategies for targeting groups at risk including, but not limited to, acute leukemia patients, hematopoietic stem cell transplants and solid organ transplants, and critical care unit patients. Accordingly, these guidelines have focused on patients at risk for C/IC, and on approaches of prevention, early therapy for suspected but unproven infection, and targeted therapy for probable and proven infection.
Invasive fungal infections (IFIs) are a primary cause of morbidity and mortality in patients with hematological malignancies. Establishing a definite diagnosis of IFI in immunocompromised patients is particularly challenging and time consuming, but delayed initiation of antifungal treatment increases mortality. The limited overall outcome has led to the strategy of initiating either 'empirical' or 'preemptive' antifungal therapy before the final diagnosis. However, diagnostic procedures have been vastly improved in recent years. Particularly noteworthy is the introduction of newer imaging techniques and non-culture methods, including antigen-based assays, metabolite detection and molecular detection of fungal DNA from body fluid samples. Though varying widely in cancer patients, the risk of IFI is highest in those with allogeneic stem cell transplantation and those with acute leukemia. The AGIHO presents recommendations for the diagnosis of IFIs with risk-adapted screening concepts for febrile episodes in patients with haemato-oncological disorders.
Neutrophils play an important role in immunological function. Neutropenic patients are vulnerable to infection, and except fever is present, inflammatory reactions are scarce in many cases. Additionally, because infections can worsen rapidly, early evaluation and treatments are especially important in febrile neutropenic patients. In cases in which febrile neutropenia is anticipated due to anticancer chemotherapy, antibiotic prophylaxis can be used, based on the risk of infection. Antifungal prophylaxis may also be considered if long-term neutropenia or mucosal damage is expected. When fever is observed in patients suspected to have neutropenia, an adequate physical examination and blood and sputum cultures should be performed. Initial antibiotics should be chosen by considering the risk of complications following the infection; if the risk is low, oral antibiotics can be used. For initial intravenous antibiotics, monotherapy with a broad-spectrum antibiotic or combination therapy with two antibiotics is recommended. At 3-5 days after beginning the initial antibiotic therapy, the condition of the patient is assessed again to determine whether the fever has subsided or symptoms have worsened. If the patient's condition has improved, intravenous antibiotics can be replaced with oral antibiotics; if the condition has deteriorated, a change of antibiotics or addition of antifungal agents should be considered. If the causative microorganism is identified, initial antimicrobial or antifungal agents should be changed accordingly. When the cause is not detected, the initial agents should continue to be used until the neutrophil count recovers.
Accurate diagnosis is a fundamental aspect of appropriate healthcare. However, clinicians need guidance when implementing diagnostic tests given the number of tests available and resource constraints in healthcare. Practitioners of health often feel compelled to implement recommendations in guidelines, including recommendations about the use of diagnostic tests. However, the understanding about diagnostic tests by guideline panels and the methodology for developing recommendations is far from completely explored. Therefore, we evaluated the factors that guideline developers and users need to consider for the development of implementable recommendations about diagnostic tests.
Using a critical analysis of the process, we present the results of a case study using the Grading of Recommendations Applicability, Development and Evaluation (GRADE) approach to develop a clinical practice guideline for the diagnosis of Cow Milk Allergy with the World Allergy Organization.
To ensure that guideline panels can develop informed recommendations about diagnostic tests, it appears that more emphasis needs to be placed on group processes, including question formulation, defining patient-important outcomes for diagnostic tests, and summarizing evidence. Explicit consideration of concepts of diagnosis from evidence-based medicine, such as pre-test probability and treatment threshold, is required to facilitate the work of a guideline panel and to formulate implementable recommendations.
This case study provides useful guidance for guideline developers and clinicians about what they ought to demand from clinical practice guidelines to facilitate implementation and strengthen confidence in recommendations about diagnostic tests. Applying a structured framework like the GRADE approach with its requirement for transparency in the description of the evidence and factors that influence recommendations facilitates laying out the process and decision factors that are required for the development, interpretation, and implementation of recommendations about diagnostic tests.
Invasive fungal infections are on the rise. Echinocandins are a relatively new class of antifungal drugs that act by inhibition of a key enzyme necessary for integrity of the fungal cell wall. Currently there are three available agents: caspofungin, micafungin and anidulafungin.
While the individual echinocandin antifungals have a different spectrum of licensed indications, basically all of them are available for the treatment of candidemia and invasive candidiasis. Antifungal treatment modalities basically include in therapy for suspected or proven infection and prophylaxis. All three drugs are comparatively expensive. Therefore a systematic review of the literature was performed to investigate the following aspects:
• General aspects of cost-effectiveness in the treatment of invasive fungal infections
• Cost-effectiveness of the treatment with the above-mentioned antifungals
• Cost-effectiveness in two settings: therapy and prophylaxis
Early initiation of antifungal therapy, adjustment after availability of microbiological results, duration of therapy, success and occurrence of severe complications (e.g renal failure) are the most important cost drivers in antifungal therapy.
Considering the specific antifungals, for caspofungin the best evidence for cost-effectiveness is found in treatment of invasive candidiasis and in empiric therapy of suspected infections. Favourable economic data are available for micafungin as a cost-effective alternative to LAmB for prophylaxis in patients with hematopoietic stem cell transplantation (HSCT). For anidulafungin, cost-effectiveness was demostrated in a pharmacoeconomic model. Net savings - yet not significant - were observed in a retrospective chart review of 234 patients. Generally, however, most analyses are still based on pharmacoeconomic modelling rather than direct analysis of trial data or real-life clinical populations.
As an overall conclusion, using caspofungin, micafungin, or anidulafungin is not more expensive than using other established therapies. Micafungin has proven to be cost-effective in prophylaxis if the local fungal epidemiology indicates a high level of resistance to fluconazole. Switch strategies involving early initiation of broadly active therapy with switch to cheaper alternatives according to microbiology results and clinical status and early initiation of an appropriate therapy have been proven to be cost-efficient independent of the antifungal agent.
Key points
► AGREE II (Appraisal of Guidelines, for Research, and Evaluation), which comprises 23 items and a user's manual, offers refinements of a new way to develop, report, and evaluate practice guidelines. ► Key changes from the original version include a new seven-point response scale, with modifications to half of the items, and a new user's manual. ► AGREE II is available online at the AGREE Research Trust website (www.agreetrust.org).
In 2005, several groups, including the European Group for Blood and Marrow Transplantation, the European Organization for Treatment and Research of Cancer, the European Leukemia Net and the Immunocompromised Host Society created the European Conference on Infections in Leukemia (ECIL). The main goal of ECIL is to elaborate guidelines, or recommendations, for the management of infections in leukemia and stem cell transplant patients. The first sets of ECIL slides about the management of invasive fungal disease were made available on the web in 2006 and the papers were published in 2007. The third meeting of the group (ECIL 3) was held in September 2009 and the group updated its previous recommendations. The goal of this paper is to summarize the new proposals from ECIL 3, based on the results of studies published after the ECIL 2 meeting: (1) the prophylactic recommendations for hematopoietic stem cell transplant recipients were formulated differently, by splitting the neutropenic and the GVHD phases and taking into account recent data on voriconazole; (2) micafungin was introduced as an alternative drug for empirical antifungal therapy; (3) although several studies were published on preemptive antifungal approaches in neutropenic patients, the group decided not to propose any recommendation, as the only randomized study comparing an empirical versus a preemptive approach showed a significant excess of fungal disease in the preemptive group.
We undertook research to improve the AGREE instrument, a tool used to evaluate guidelines. We tested a new seven-point scale, evaluated the usefulness of the original items in the instrument, investigated evidence to support shorter, tailored versions of the tool, and identified areas for improvement.
We report on one component of a larger study that used a mixed design with four factors (user type, clinical topic, guideline and condition). For the analysis reported in this article, we asked participants to read a guideline and use the AGREE items to evaluate it based on a seven-point scale, to complete three outcome measures related to adoption of the guideline, and to provide feedback on the instrument's usefulness and how to improve it.
Guideline developers gave lower-quality ratings than did clinicians or policy-makers. Five of six domains were significant predictors of participants' outcome measures (p < 0.05). All domains and items were rated as useful by stakeholders (mean scores > 4.0) with no significant differences by user type (p > 0.05). Internal consistency ranged between 0.64 and 0.89. Inter-rater reliability was satisfactory. We received feedback on how to improve the instrument.
Quality ratings of the AGREE domains were significant predictors of outcome measures associated with guideline adoption: guideline endorsements, overall intentions to use guidelines, and overall quality of guidelines. All AGREE items were assessed as useful in determining whether a participant would use a guideline. No clusters of items were found more useful by some users than others. The measurement properties of the seven-point scale were promising. These data contributed to the refinements and release of the AGREE II.
We established a program of research to improve the development, reporting and evaluation of practice guidelines. We assessed the construct validity of the items and user's manual in the beta version of the AGREE II.
We designed guideline excerpts reflecting high-and low-quality guideline content for 21 of the 23 items in the tool. We designed two study packages so that one low-quality and one high-quality version of each item were randomly assigned to each package. We randomly assigned 30 participants to one of the two packages. Participants reviewed and rated the guideline content according to the instructions of the user's manual and completed a survey assessing the manual.
In all cases, content designed to be of high quality was rated higher than low-quality content; in 18 of 21 cases, the differences were significant (p < 0.05). The manual was rated by participants as appropriate, easy to use, and helpful in differentiating guidelines of varying quality, with all scores above the mid-point of the seven-point scale. Considerable feedback was offered on how the items and manual of the beta-AGREE II could be improved.
The validity of the items was established and the user's manual was rated as highly useful by users. We used these results and those of our study presented in part 1 to modify the items and user's manual. We recommend AGREE II (available at www.agreetrust.org) as the revised standard for guideline development, reporting and evaluation.
Prior analyses suggest that empiric fluconazole for ICU patients with sepsis is cost-effective. Using updated estimates of efficacy and cost, Zilberberg and colleagues compare the use of micafungin with that of fluconazole. The authors conclude that micafungin is an attractive alternative to fluconazole. This conclusion is driven by recent reduction in micafungin's cost and by better activity of micafungin against azole-resistant Candida species. Their results are limited by inflated estimates of efficacy, life expectancy and risk of Candida sepsis. This commentary explores the rationale for early anti-Candida strategies in the ICU and highlights the contribution and limitations of the article by Zilberberg and colleagues.
Guidelines for the management of patients with invasive candidiasis and mucosal candidiasis were prepared by an Expert Panel
of the Infectious Diseases Society of America. These updated guidelines replace the previous guidelines published in the 15
January 2004 issue of Clinical Infectious Diseases and are intended for use by health care providers who care for patients who either have or are at risk of these infections.
Since 2004, several new antifungal agents have become available, and several new studies have been published relating to the
treatment of candidemia, other forms of invasive candidiasis, and mucosal disease, including oropharyngeal and esophageal
candidiasis. There are also recent prospective data on the prevention of invasive candidiasis in high-risk neonates and adults
and on the empiric treatment of suspected invasive candidiasis in adults. This new information is incorporated into this revised
document.
There is no widely accepted standard for antifungal prophylaxis in patients with hematologic malignancies. The Infectious Diseases Working Party of the German Society for Haematology and Oncology assigned a committee of hematologists and infectious disease specialists to develop recommendations. Literature data bases were systematically searched for clinical trials on antifungal prophylaxis. The studies identified were shared within the committee. Data were extracted by two of the authors (OAC and MSi). The consensus process was conducted by email communication. Finally, a review committee discussed the proposed recommendations. After consensus was established the recommendations were finalized. A total of 86 trials were identified including 16,922 patients. Only a few trials yielded significant differences in efficacy. Fluconazole 400 mg/d improved the incidence rates of invasive fungal infections and attributable mortality in allogeneic stem cell recipients. Posaconazole 600 mg/d reduced the incidence of IFI and attributable mortality in allogeneic stem cell recipients with severe graft versus host disease, and in patients with acute myelogenous leukemia or myelodysplastic syndrome additionally reduced overall mortality. Aerosolized liposomal amphotericin B reduced the incidence rate of invasive pulmonary aspergillosis. Posaconazole 600 mg/d is recommended in patients with acute myelogenous leukemia/myelodysplastic syndrome or undergoing allogeneic stem cell recipients with graft versus host disease for the prevention of invasive fungal infections and attributable mortality (Level A I). Fluconazole 400 mg/d is recommended in allogeneic stem cell recipients until development of graft versus host disease only (Level A I). Aerosolized liposomal amphotericin B is recommended during prolonged neutropenia (Level B II).
Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. Early antifungal treatment is mandatory to improve survival. Today, a number of effective and better-tolerated but more expensive antifungal agents compared to the former gold standard amphotericin B deoxycholate are available. Clinical decision-making must consider results from numerous studies and published guidelines, as well as licensing status and cost pressure. New developments in antifungal prophylaxis improving survival rates result in a continuous need for actualization. The treatment options for invasive Candida infections include fluconazole, voriconazole, and amphotericin B and its lipid formulations, as well as echinocandins. Voriconazole, amphotericin B, amphotericin B lipid formulations, caspofungin, itraconazole, and posaconazole are available for the treatment of invasive aspergillosis. Additional procedures, such as surgical interventions, immunoregulatory therapy, and granulocyte transfusions, have to be considered. The Infectious Diseases Working Party of the German Society of Hematology and Oncology here presents its 2008 recommendations discussing the dos and do-nots, as well as the problems and possible solutions, of evidence criteria selection.
During a comparative trial of amphotericin B vs. fluconazole for treatment of candidemia in nonneutropenic patients, data on the management of intravascular catheters were collected. Complete records were available for 91% of the 206 study patients. For the subset of patients with a catheter in place at the time of their first positive blood culture, removal and replacement of all intravascular catheters without exchange over a guidewire from a preexisting line on or before the first day the study drug was administered were associated with a reduction in the subsequent mean duration (+/- SE) of candidemia, from 5.6 +/ -0.8 days to 2.6 +/- 0.5 days (P < .001).
Infections due to Candida species are the most common of the fungal infections. Candida species produce a broad range of infections, ranging from nonlife-threatening mucocutaneous illnesses to invasive process that may involve virtually any organ. Such a broad range of infections requires an equally broad range of diagnostic and therapeutic strategies. This document summarizes current knowledge about treatment of multiple forms of candidiasis and is the guideline of the Infectious Diseases Society of America (IDSA) for the treatment of candidiasis. Throughout this document, treatment recommendations are scored according to the standard scoring scheme used in other IDSA guidelines to illustrate the strength of the underlying data. The document covers 4 major topical areas. The role of the microbiology laboratory. To a greater extent than for other fungi, treatment of candidiasis can now be guided by in vitro susceptibility testing. The guidelines review the available information supporting current testing procedures and interpretive breakpoints and place these data into clinical context. Susceptibility testing is most helpful in dealing with infection due to non-albicans species of Candida. In this setting, especially if the patient has been treated previously with an azole antifungal agent, the possibility of microbiological resistance must be considered. Treatment of invasive candidiasis. In addition to acute hematogenous candidiasis, the guidelines review strategies for treatment of 15 other forms of invasive candidiasis. Extensive data from randomized trials are really available only for therapy of acute hematogenous candidiasis in the nonneutropenic adult. Choice of therapy for other forms of candidiasis is based on case series and anecdotal reports. In general, both amphotericin B and the azoles have a role to play in treatment. Choice of therapy is guided by weighing the greater activity of amphotericin B for some non-albicans species (e.g., Candida krusei) against the lesser toxicity and ease of administration of the azole antifungal agents. Flucytosine has activity against many isolates of Candida but is not often used. Treatment of mucocutaneous candidiasis. Therapy for mucosal infections is dominated by the azole antifungal agents. These drugs may be used topically or systemically and have been proven safe and efficacious. A significant problem with mucosal disease is the propensity for a small proportion of patients to suffer repeated relapses. In some situations, the explanation for such a relapse is obvious (e.g., relapsing oropharyngeal candidiasis in an individual with advanced and uncontrolled HIV infection), but in other patients the cause is cryptic (e.g., relapsing vaginitis in a healthy woman). Rational strategies for these situations are discussed in the guidelines and must consider the possibility of induction of resistance over time. Prevention of invasive candidiasis. Prophylactic strategies are useful if the risk of a target disease is sharply elevated in a readily identified group of patients. Selected patient groups undergoing therapy that produces prolonged neutropenia (e.g., some bone-marrow transplant recipients) or who receive a solid-organ transplant (e.g., some liver transplant recipients) have a sufficient risk of invasive candidiasis to warrant prophylaxis.
Candida species are the most common cause of fungal infections. Candida species produce infections that range from non-life-threatening mucocutaneous illnesses to invasive processes that may involve virtually any organ. Such a broad range of infections requires an equally broad range of diagnostic and therapeutic strategies. These guidelines summarize current knowledge about treatment of multiple forms of candidiasis for the Infectious Diseases Society of America (IDSA). Throughout this document, treatment recommendations are rated according to the standard scoring scheme used in other IDSA guidelines to illustrate the strength of the supporting evidence and quality of the underlying data ( table 1). This document covers the following 4 major topical areas.
The GRADE system can be used to grade the quality of evidence and strength of recommendations for diagnostic tests or strategies. This article explains how patient-important outcomes are taken into account in this processSummary pointsAs for other interventions, the GRADE approach to grading the quality of evidence and strength of recommendations for diagnostic tests or strategies provides a comprehensive and transparent approach for developing recommendationsCross sectional or cohort studies can provide high quality evidence of test accuracyHowever, test accuracy is a surrogate for patient-important outcomes, so such studies often provide low quality evidence for recommendations about diagnostic tests, even when the studies do not have serious limitationsInferring from data on accuracy that a diagnostic test or strategy improves patient-important outcomes will require the availability of effective treatment, reduction of test related adverse effects or anxiety, or improvement of patients’ wellbeing from prognostic informationJudgments are thus needed to assess the directness of test results in relation to consequences of diagnostic recommendations that are important to patientsIn this fourth article of the five part series, we describe how guideline developers are using GRADE to rate the quality of evidence and move from evidence to a recommendation for diagnostic tests and strategies. Although recommendations on diagnostic testing share the fundamental logic of recommendations on treatment, they present unique challenges. We will describe why guideline panels should be cautious when they use evidence of the accuracy of tests (“test accuracy”) as the basis for recommendations and why evidence of test accuracy often provides low quality evidence for making recommendations.Testing makes a variety of contributions to patient careClinicians use tests that are usually referred to as “diagnostic”—including signs and symptoms, imaging, biochemistry, pathology, and psychological testing—for various purposes.1 These purposes include identifying physiological derangements, establishing prognosis, monitoring illness and response to treatment, and diagnosis. This article …
The Infectious Diseases Working Party of the German Society of Haematology and Oncology presents their guidelines for the treatment of fungal infections in patients with hematological and oncological malignancies. These guidelines are evidence-based, considering study results, case reports and expert opinions, using the evidence criteria of the Infectious Diseases Society of America (IDSA). The recommendations for major fungal complications in this setting are summarized here. The primary choice of therapy for chronic candidiasis should be fluconazole, reserving caspofungin or amphotericin B (AmB) for use in case of progression of the Candida infection. Patients with candidemia (except C. krusei or C. glabrata) who are in a clinically stable condition without previous azole prophylaxis should receive fluconazole, otherwise AmB or caspofungin. Voriconazole is recommended for the first-line treatment of invasive aspergillosis. The benefit of a combination of AmB and 5-flucytosine has not been demonstrated except in patients with cryptococcal meningitis. Mucormycosis is relatively rare. The drug therapy of choice consists of AmB, desoxycholate or liposomal formulation, in the highest tolerable dosage. Additional surgical intervention has been shown to achieve a lower fatality rate than with antifungal therapy alone. The role of interventional strategies, cytokines/G-CSF, and granulocyte transfusions in invasive fungal infections are further reviewed. These guidelines offer actual standards and discussions on the treatment of oropharyngeal and esophageal candidiasis, invasive candidiasis, cryptococcosis and mould infections.
Neutrophils play an important role in immunological function. Neutropenic patients are vulnerable to infection, and except fever is present, inflammatory reactions are scarce in many cases. Additionally, because infections can worsen rapidly, early evaluation and treatments are especially important in febrile neutropenic patients. In cases in which febrile neutropenia is anticipated due to anticancer chemotherapy, antibiotic prophylaxis can be used, based on the risk of infection. Antifungal prophylaxis may also be considered if long-term neutropenia or mucosal damage is expected. When fever is observed in patients suspected to have neutropenia, an adequate physical examination and blood and sputum cultures should be performed. Initial antibiotics should be chosen by considering the risk of complications following the infection; if the risk is low, oral antibiotics can be used. For initial intravenous antibiotics, monotherapy with a broadspectrum antibiotic or combination therapy with two antibiotics is recommended. At 3 5 days after beginning the initial antibiotic therapy, the condition of the patient is assessed again to determine whether the fever has subsided or symptoms have worsened. If the patient's condition has improved, intravenous antibiotics can be replaced with oral antibiotics; if the condition has deteriorated, a change of antibiotics or addition of antifungal agents should be considered. If the causative microorganism is identified, initial antimicrobial or antifungal agents should be changed accordingly. When the cause is not detected, the initial agents should continue to be used until the neutrophil count recovers.
During a comparative trial of amphotericin B vs. fluconazole for treatment of candidemia in nonneutropenic patients, data
on the management of intravascular catheters were collected. Complete records were available for 91% of the 206 study patients.
For the subset of patients with a catheter in place at the time of their first positive blood culture, removal and replacement
of all intravascular catheters without exchange over a guidewire from a preexisting line on or before the first day the study
drug was administered were associated with a reduction in the subsequent mean duration (±SE) of candidemia, from 5.6 ± 0.8
days to 2.6 ± 0.5 days (P < .001).
These guidelines resume different issues related to the clinical management of invasive candidosis in the immunossuppressed patients. They are based on the recommendations of the different Drug's Agencies.
To cite this article: Brożek JL, Akl EA, Compalati E, Kreis J, Terracciano L, Fiocchi A, Ueffing E, Andrews J, Alonso-Coello P, Meerpohl JJ, Lang DM, Jaeschke R, Williams JW Jr, Phillips B, Lethaby A, Bossuyt P, Glasziou P, Helfand M, Watine J, Afilalo M, Welch V, Montedori A, Abraha I, Horvath AR, Bousquet J, Guyatt GH, Schünemann HJ, for the GRADE Working Group. Grading quality of evidence and strength of recommendations in clinical practice guidelines. Part 3 of 3. The GRADE approach to developing recommendations. Allergy 2011; 66: 588–595.AbstractThis is the third and last article in the series about the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to grading the quality of evidence and the strength of recommendations in clinical practice guidelines and its application in the field of allergy. We describe the factors that influence the strength of recommendations about the use of diagnostic, preventive and therapeutic interventions: the balance of desirable and undesirable consequences, the quality of a body of evidence related to a decision, patients’ values and preferences, and considerations of resource use. We provide examples from two recently developed guidelines in the field of allergy that applied the GRADE approach. The main advantages of this approach are the focus on patient important outcomes, explicit consideration of patients’ values and preferences, the systematic approach to collecting the evidence, the clear separation of the concepts of quality of evidence and strength of recommendations, and transparent reporting of the decision process. The focus on transparency facilitates understanding and implementation and should empower patients, clinicians and other health care professionals to make informed choices.
Use of various induction regimens, of novel immunosuppressive agents, and of newer prophylactic strategies continues to change the pattern of infections among solid organ transplant (SOT) recipients. Although invasive fungal infections (IFIs) occur at a lower incidence than bacterial and viral infections in this population, they remain a major cause of morbidity and mortality worldwide. In March 2008, a panel of Italian experts on fungal infections and organ transplantation convened in Castel Gandolfo (Rome) to develop consensus guidelines for the diagnosis, prevention, and treatment of IFIs among SOT recipients. We discussed the definitions, microbiological and radiological diagnoses, prophylaxis, empirical treatment, and therapy of established disease. Throughout the consensus document, recommendations as clinical guidelines were rated according to the standard scoring system of the Infectious Diseases Society of America and the United Stated Public Health Service.
This article introduces the approach of GRADE to rating quality of evidence. GRADE specifies four categories-high, moderate, low, and very low-that are applied to a body of evidence, not to individual studies. In the context of a systematic review, quality reflects our confidence that the estimates of the effect are correct. In the context of recommendations, quality reflects our confidence that the effect estimates are adequate to support a particular recommendation. Randomized trials begin as high-quality evidence, observational studies as low quality. "Quality" as used in GRADE means more than risk of bias and so may also be compromised by imprecision, inconsistency, indirectness of study results, and publication bias. In addition, several factors can increase our confidence in an estimate of effect. GRADE provides a systematic approach for considering and reporting each of these factors. GRADE separates the process of assessing quality of evidence from the process of making recommendations. Judgments about the strength of a recommendation depend on more than just the quality of evidence.
These guidelines resume different issues related to the clinical management of invasive candidosis in the immunossuppressed patients. They are based on the recommendations of the different Drug’s Agencies.
The GRADE approach to grading the quality of evidence and strength of recommendations provides a comprehensive and transparent approach for developing clinical recommendations about using diagnostic tests or diagnostic strategies. Although grading the quality of evidence and strength of recommendations about using tests shares the logic of grading recommendations for treatment, it presents unique challenges. Guideline panels and clinicians should be alert to these special challenges when using the evidence about the accuracy of tests as the basis for clinical decisions. In the GRADE system, valid diagnostic accuracy studies can provide high quality evidence of test accuracy. However, such studies often provide only low quality evidence for the development of recommendations about diagnostic testing, as test accuracy is a surrogate for patient-important outcomes at best. Inferring from data on accuracy that using a test improves outcomes that are important to patients requires availability of an effective treatment, improved patients' wellbeing through prognostic information, or - by excluding an ominous diagnosis - reduction of anxiety and the opportunity for earlier search for an alternative diagnosis for which beneficial treatment can be available. Assessing the directness of evidence supporting the use of a diagnostic test requires judgments about the relationship between test results and patient-important consequences. Well-designed and conducted studies of allergy tests in parallel with efforts to evaluate allergy treatments critically will encourage improved guideline development for allergic diseases.
The GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach provides guidance to grading the quality of underlying evidence and the strength of recommendations in health care. The GRADE system's conceptual underpinnings allow for a detailed stepwise process that defines what role the quality of the available evidence plays in the development of health care recommendations. The merit of GRADE is not that it eliminates judgments or disagreements about evidence and recommendations, but rather that it makes them transparent. This first article in a three-part series describes the GRADE framework in relation to grading the quality of evidence about interventions based on examples from the field of allergy and asthma. In the GRADE system, the quality of evidence reflects the extent to which a guideline panel's confidence in an estimate of the effect is adequate to support a particular recommendation. The system classifies quality of evidence as high, moderate, low, or very low according to factors that include the study methodology, consistency and precision of the results, and directness of the evidence.
We determined the prescription rates of medications for the secondary prevention of ischaemic heart disease and left ventricular systolic dysfunction in stable dialysis patients. In patients with established ischaemic heart disease, statins, beta-blockers and renin–angiotensin–aldosterone system blockers were substantially underprescribed. Furthermore, beta-blockers and renin–angiotensin–aldosterone system blockers were prescribed in less than half of those with left ventricular systolic dysfunction. Contraindications to treatment were infrequent and did not explain these findings.
Practice guidelines for the treat-ment of candidiasis. Infectious diseases society of America
- Walsh Tj Sobel
Rex JH, Walsh TJ, Sobel JD et al. Practice guidelines for the treat-ment of candidiasis. Infectious diseases society of America. Clin Infect Dis 2000; 30: 662–678.
Diagnosis and management of Candida diseases 2012 ª2012 The Authors Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases
- Cmi Ullmann
CMI
Ullmann et al. Diagnosis and management of Candida diseases 2012
ª2012 The Authors
Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18 (Suppl. 7), 1–8
Primary prophylaxis of invasive fungal infections in patients with hematologic malignancies
- Oa Cornely
- A Bohme
- D Buchheidt
Cornely OA, Bohme A, Buchheidt D et al. Primary prophylaxis of invasive
fungal infections in patients with hematologic malignancies.
Treatment of fungal infections in hematology and oncology?guidelines of the infectious diseases working party (AGIHO) of the German society of hematology and oncology (DGHO) Ann Hematol2003
- A Bohme
- M Ruhnke
- D Buchheidt
- Etal
beta-Glucan antigenemia assay for the diagnosis of invasive fungal infections in patients with hematological malignancies: a systematic review and meta-analysis of cohort studies from the third european conference on infections in leukemia (ECIL-3) Clin Infect Dis2012
- F Lamoth
- M Cruciani
- C Mengoli
- Etal
Grading quality of evidence and strength of recommendations in clinical practice guidelines. Part 1 of 3. An overview of the GRADE approach and grading quality of evidence about interventions
- Jl Brozek
- Ea Akl
- P Alonso-Coello
- Etal
Practice guidelines for the treatment of candidiasis. Infectious diseases society of America
- Rex