Antifungal activity of 2-chloro-N-phenylacetamide: a new molecule with fungicidal and antibiofilm activity against fluconazole-resistant Candida spp

Abstract In the current context of emerging drug-resistant fungal pathogens such as Candida albicans and Candida parapsilosis, discovery of new antifungal agents is an urgent matter. This research aimed to evaluate the antifungal potential of 2-chloro-N-phenylacetamide against fluconazole-resistant clinical strains of C. albicans and C. parapsilosis. The antifungal activity of 2-chloro-N-phenylacetamide was evaluated in vitro by the determination of the minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC), inhibition of biofilm formation and its rupture, sorbitol and ergosterol assays, and association between this molecule and common antifungal drugs, amphotericin B and fluconazole. The test product inhibited all strains of C. albicans and C. parapsilosis, with a MIC ranging from 128 to 256 µg.mL-1, and a MFC of 512-1,024 µg.mL-1. It also inhibited up to 92% of biofilm formation and rupture of up to 87% of preformed biofilm. 2-chloro-N-phenylacetamide did not promote antifungal activity through binding to cellular membrane ergosterol nor it damages the fungal cell wall. Antagonism was observed when combining this substance with amphotericin B and fluconazole. The substance exhibited significant antifungal activity by inhibiting both planktonic cells and biofilm of fluconazole-resistant strains. Its combination with other antifungals should be avoided and its mechanism of action remains to be established.

Resumo No atual contexto de patógenos fúngicos resistentes emergentes tais como Candida albicans e Candida parapsilosis, a descoberta de novos agentes antifúngicos é uma questão urgente. Esta pesquisa teve como objetivo avaliar o potencial antifúngico da 2-cloro-N-fenilacetamida contra cepas clínicas de C. albicans e C. parapsilosis resistentes a fluconazol. A atividade antifúngica da substância foi avaliada in vitro através da determinação da concentração inibitória mínima (CIM), concentração fungicida mínima (CFM), ruptura e inibição da formação de biofilme, ensaios de sorbitol e ergosterol, e associação entre esta molécula e antifúngicos comuns, anfotericina B e fluconazol. O produto teste inibiu todas as cepas de C. albicans e C. parapsilosis, com uma CIM variando de 128 a 256 µg.mL-1, e uma CFM de 512-1,024 µg.mL-1. Também inibiu até 92% da formação de biofilme e causou a ruptura de até 87% de biofilme pré-formado. A 2-cloro-N-fenilacetamida não promoveu atividade antifúngica pela ligação ao ergosterol da membrana celular fúngica, tampouco danificou a parede celular. Antagonismo foi observado ao combinar esta substância com anfotericina B e fluconazol. A substância exibiu atividade antifúngica significativa ao inibir tanto as células planctônicas quanto o biofilme das cepas resistentes ao fluconazol. Sua combinação com outros antifúngicos deve ser evitada e seu mecanismo de ação deve ser estabelecido.

Antifungal activity of 2-chloro-N-phenylacetamide: a new molecule with fungicidal and antibiofilm activity against fluconazole-resistant Candida spp / Atividade antifúngica de 2-cloro-N-fenilacetamida: uma nova molécula com atividade fungicida e anti-biofilme contra Candida spp. resistentes a fluconazol

In the current context of emerging drug-resistant fungal pathogens such as Candida albicans and Candida parapsilosis, discovery of new antifungal agents is an urgent matter. This research aimed to evaluate the antifungal potential of 2-chloro-N-phenylacetamide against fluconazole-resistant clinical strains of C. albicans and C. parapsilosis. The antifungal activity of 2-chloro-N-phenylacetamide was evaluated in vitro by the determination of the minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC), inhibition of biofilm formation and its rupture, sorbitol and ergosterol assays, and association between this molecule and common antifungal drugs, amphotericin B and fluconazole. The test product inhibited all strains of C. albicans and C. parapsilosis, with a MIC ranging from 128 to 256 µg.mL-1, and a MFC of 512-1,024 µg.mL-1. It also inhibited up to 92% of biofilm formation and rupture of up to 87% of preformed biofilm. 2-chloro-N-phenylacetamide did not promote antifungal activity through binding to cellular membrane ergosterol nor it damages the fungal cell wall. Antagonism was observed when combining this substance with amphotericin B and fluconazole. The substance exhibited significant antifungal activity by inhibiting both planktonic cells and biofilm of fluconazole-resistant strains. Its combination with other antifungals should be avoided and its mechanism of action remains to be established.

No atual contexto de patógenos fúngicos resistentes emergentes tais como Candida albicans e Candida parapsilosis, a descoberta de novos agentes antifúngicos é uma questão urgente. Esta pesquisa teve como objetivo avaliar o potencial antifúngico da 2-cloro-N-fenilacetamida contra cepas clínicas de C. albicans e C. parapsilosis resistentes a fluconazol. A atividade antifúngica da substância foi avaliada in vitro através da determinação da concentração inibitória mínima (CIM), concentração fungicida mínima (CFM), ruptura e inibição da formação de biofilme, ensaios de sorbitol e ergosterol, e associação entre esta molécula e antifúngicos comuns, anfotericina B e fluconazol. O produto teste inibiu todas as cepas de C. albicans e C. parapsilosis, com uma CIM variando de 128 a 256 µg.mL-1, e uma CFM de 512-1,024 µg.mL-1. Também inibiu até 92% da formação de biofilme e causou a ruptura de até 87% de biofilme pré-formado. A 2-cloro-N-fenilacetamida não promoveu atividade antifúngica pela ligação ao ergosterol da membrana celular fúngica, tampouco danificou a parede celular. Antagonismo foi observado ao combinar esta substância com anfotericina B e fluconazol. A substância exibiu atividade antifúngica significativa ao inibir tanto as células planctônicas quanto o biofilme das cepas resistentes ao fluconazol. Sua combinação com outros antifúngicos deve ser evitada e seu mecanismo de ação deve ser estabelecido.

Clinical treatment and management of invasive fungal disease in recipients of solid organ transplantation / 器官移植

With widespread application of solid organ transplantation (SOT), the incidence of postoperative invasive fungal disease (IFD) in SOT recipients has been increased year by year. In recent years, the awareness of preventive antifungal therapy for SOT recipients has been gradually strengthened. However, the problem of fungal resistance has also emerged, leading to unsatisfactory efficacy of original standardized antifungal regimens. Drug-drug interaction and hepatorenal toxicity induced by drugs are also challenges facing clinicians. In this article, the characteristics of drug-drug interaction and hepatorenal toxicity among triazole, echinocandin and polyene antifungal drugs and immunosuppressants were reviewed, and postoperative preventive strategies for IFD in different types of SOT recipients and treatment strategies for IFD caused by infection of different pathogens were summarized, aiming to provide reference for physicians in organ transplantation and related disciplines.

Cost-effectiveness analysis and budgetary impact of anidulafungin treatment for patients with candidemia and other forms of invasive candidiasis in Brazil

ABSTRACT Candidemia and other forms of invasive candidiasis (C/IC) are serious conditions, especially for immunosuppressed individuals with prolonged hospitalization in intensive care units (ICU). This study analyzed the incremental cost-effectiveness and budgetary impact (BI) of treatment for IC with anidulafungin compared to amphotericin B lipid complex (ABLC) and amphotericin B deoxycholate (ABD) or conventional amphotericin B (CAB), in the Brazilian Unified Health System (SUS). A decision model was conducted with a time horizon of two weeks from the perspective of SUS. The primary effectiveness endpoints were survival and treatment response rate. All patients were followed up until successful therapy or death. BI analysis was performed based on the measured demand method. A five-year time horizon was adopted based on the number of hospitalizations (per 1,000 hospitalizations). For effectiveness measured in the successful response rate (SRR), anidulafungin dominated the ABLC and ABD formulations. In the results of the analysis with the effectiveness measured according to survival, anidulafungin had a better cost-effectiveness ratio (R$988.26/survival) compared to ABD (R$16,359.50/survival). The BI estimate related to the incorporation of anidulafungin suggests savings of approximately 148 million reais in 5 years when comparing it to ABD. The economic evaluation of anidulafungin and its comparators found it to be cost-effective. The consensus of international scientific societies recommends it as a first-line drug for IC, and its incorporation by SUS would be important.

Invasive candidiasis in the elderly: a single-center, retrospective cohort study / 中华老年医学杂志

Objective:To investigate the clinical and mycological characteristics, treatment and prognosis of invasive candidiasis(IC)in the elderly.Methods:This retrospective study included aged patients(≥65 years)admitted to the Peking University First Hospital between January, 2010 and December, 2019, who were diagnosed with IC based on positive culture results.The infecting strains were re-identified and their antifungal drug resistance was tested.The clinical and mycological characteristics, treatment and prognosis information of the elderly patients were collected and compared with those of non-elderly adults.Results:A total of 99 aged patients were included, with a median age of 78(70-83)years and a male-to-female ratio of 2.1∶1.0.The elderly accounted for 62.7%(99/158)of the adult IC patients.Compared with their younger counterparts, elderly patients were more likely to need medium-to long-term hospitalization and intensive care unit(ICU)stay, and to show concurrent heart failure, respiratory failure or renal failure, to require mechanical ventilation, and to show deep-seated bacterial infections and multifocal Candida colonization, especially for those with previous fluconazole exposure( P<0.05). Bloodstream was the most common Candida transmission route(71/99, 71.7%)and Candida albicans was the most prevalent species(47/99, 47.5%). Antifungal resistance was highest for fluconazole(17/117, 14.5%)and voriconazole(15/117, 12.8%). No significant difference was found between elderly patients and non-elderly patients in terms of infected sites, Candida species, and antifungal resistance( P>0.05). A total of 86 patients(86.9%)received systemic antifungal treatment and fluconazole was the most commonly used drug(35/86, 40.7%). The thirty-day all-cause mortality in aged IC patients was 32.6%(29/89), significantly higher than in younger patients( P=0.022). Logistic regression analysis revealed that advanced age( OR=1.12, 95% CI: 1.06-1.20, P<0.001), renal failure( OR=4.81; 95% CI: 1.65-14.03; P=0.004), and a high Candida score( OR=1.81, 95% CI: 1.06-3.11, P=0.031)significantly increased the risk of death. Conclusions:Elderly patients were the main affected population of IC, and the mortality of IC steadily increases with age.Treatment for aged IC patients should be proactive and cautious.

A Ten-year Retrospective Study of Invasive Candidiasis in a Tertiary Hospital in Beijing / 生物医学与环境科学（英文）

Objective@#This study aimed to evaluate the epidemiological, clinical and mycological characteristics of invasive candidiasis (IC) in China.@*Methods@#A ten-year retrospective study including 183 IC episodes was conducted in a tertiary hospital in Beijing, China.@*Results@#The overall incidence of IC from 2010-2019 was 0.261 episodes per 1,000 discharges. Candidemia (71.0%) was the major infective pattern; 70.3% of the patients tested positive for @*Conclusion@#The incidence of IC has declined in the recent five years.

Uso de Quinolonas como Factor de Riesgo para Infección Oportunista Severa por Cándida en Pacientes Adultos Críticamente Enfermos

Resumen Introducción: Candida es uno de los microorganismos mayormente aislado de los hemocultivos positivos, mostrando un aumento de su prevalencia a nivel mundial debido a múltiples factores de riesgo siendo unos de los más importantes el uso de antibioticoterapia de espectro ampliado, como las quinolonas usados en pacientes críticos hospitalizados en salas de cuidado intensivo, de los cuales la literatura es tangencial en su relación con el desarrollo de candidiasis invasiva. Materiales y metodos: se realizó una búsqueda exhaustiva en las bases de datos biomédicas MEDLINE, PubMed, ScienceDirect, Scopus, Embase, utilizando la estrategia de búsqueda: "Candidemia AND Quinolones AND Adult" sin embargo también se usaron otras estrategias para aumentar la sensibilidad como: "Invasive candidiasis AND Quinolones" y "Candidemia OR Invasive candidiasis AND risk factors" incluyendo los idiomas inglés, español, francés y portugués, se tuvieron en cuenta artículos tipo: [Randomized Controlled Trial], [Clinical Trial], [Controlled Clinical Trial] y [Review] Resultados: la literatura biomédica es escasa en cuanto a la descripción de la relación entre el uso de quinolinas como factor de riesgo para desarrollar candidiasis invasiva, sin embargo se encontraron ocho estudios con significancia estadística importante que muestran una relación estrecha entre el fenómeno propuesto. Conclusiónes: Las quinolonas de uso sistémico como Ciprofloxacino, son un factor de riesgo confirmado asociado a infecciones invasivas por hongos tipo Candida.

Abstract Introduction: Candida is one of the microorganisms most frequently isolated from positive blood cultures, showing an increase in its prevalence worldwide due to multiple risk factors, one of the most important being the use of extended-spectrum antibiotic therapy, such as quinolones used in critical patients in intensive care wards, of which the literature is tangential in its relationship with the development of invasive candidiasis, Methods: a search of biomedical databases MEDLINE, PubMed, ScienceDirect, Scopus, Embase, was performed using the search strategy: "Candidemia AND Quinolones AND Adult" other strategies were also used to increase sensitivity such as: "Invasive candidiasis AND Quinolones" and "Candidemia OR Invasive candidiasis AND risk factors" including English, Spanish, French and Portuguese languages, articles type were taken into account: [Randomized Controlled Trial], [Clinical Trial], [Controlled Clinical Trial] and [Review]. Results: The biomedical literature is scarce regarding the description of the relationship between the use of quinolones as a risk factor for developing invasive candidiasis; however, eight studies were found with important statistical significance that show a close relationship between the proposed phenomenon. Conclusion: Systemic quinolones such as Ciprofloxacin are a confirmed risk factor associated with invasive fungal infections such as Candida.

Estudo do potencial antifúngico e do mecanismo de ação do timol contra cepas de Candida parapsilosis resistentes ao fluconazol e a anfotericina B / Study of the antifungal potential and mechanism of action of thymol against strains of Candida parapsilosis resistant to fluconazole and amphotericin B

Objetivo: investigar a suscetibilidade de cepas fúngicas de Candida parapsilosis isoladas de sangue humano frente ao timol, bem como seu mecanismo de ação. Metodologia: foram utilizadas técnicas de microdiluição em placas de 96 poços para determinar a concentração inibitória mínima (CIM) e concentração fungicida mínima (CFM). Além disso, foram realizados testes com o sorbitol e o ergosterol para investigar a ação do timol na parede e na membrana celular fúngica respectivamente. Resultados: nos testes de CIM e CFM, foi observado que as cepas de C. parapsilosis são resistentes ao fluconazol e a anfotericina B, no entanto, o timol desempenhou efeito fungicida com razão CFM/CIM entre 1 e 2. Além disso, a CIM do timol não aumentou quando o sorbitol ou o ergosterol foi adicionado no meio, sugerindo fortemente que este monoterpeno não age na parede celular fúngica ou por ligação ao ergosterol na membrana plasmática. Conclusão: portanto, esses resultados contribuem para a elucidação do mecanismo de ação do timol, sugerindo outros possíveis alvos de interação fármaco-receptor. No entanto, mais investigações de caráter enzimático e molecular em modelos in vitro são necessários para que se possa elucidar completamente o modo de ação desse promissor monoterpeno.

Objective: to investigate the susceptibility of fungal strains of Candida parapsilosis isolated from human blood against thymol, as well as its mechanism of action. Methodology: microdilution techniques were used in 96-well plates to determine minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC). In addition, tests were performed with sorbitol and ergosterol to investigate the action of thymol on the wall and on the fungal cell membrane respectively. Results: in the CIM and CFM tests, it was observed that C. parapsilosis strains are resistant to fluconazole and amphotericin B, however, thymol had a fungicidal effect with MFC/MIC ratio between 1 and 2. In addition, thymol MIC did not increase when sorbitol or ergosterol was added in the medium, strongly suggesting that this monoterpene does not act on the fungal cell wall or by binding to ergosterol on the plasma membrane. Conclusion: therefore, these results contribute to the elucidation of the mechanism of action of thymol, suggesting other possible targets of drug-receptor interaction. However, further investigations of enzymatic and molecular character in in vitro models are necessary to fully elucidate the mode of action of this promising monoterpene.

Meta-analysis of the Efficacy and Safety of Echinocandins as Antifungal Agents in the Prevention of Invasive Candidiasis / 中国药房

ABSTRACT OBJECTIVE：To systematically evaluate the efficacy and safety of echinococcins in the prevention of invasive candidiasis，and to provide evidence-based reference for clinical treatment. METHODS：Retrieved from PubMed，Embase， Medline，Cochrane library，CJFD，VIP and Wanfang database，randomized controlled trials（RCTs）about the effectiveness and safety of echinococcins （trial group） versus conventional fungal drugs （amphotericin B and triazole antifungal agents，control group）in the prevention of invasive candidiasis were collected during database establishment to Jul. 2019. After data extraction of clinical studies met inclusion criteria and quality evaluation with Cochrane system evaluator manual 5.0.2，Meta-analysis was performed for breakthrough invasive fungal infection rate，fungal infection mortality rate，all-cause mortality rate and the incidence of drug withdrawal due to adverse reactions by using Rev Man 5.2 statistical software. RESULTS：Totally 7 RCTs were included， involving 3 219 patients. Results of Meta-analyses indicated that the incidence of breakthrough invasive fungal infection [OR＝0.58， 95％CI（0.40，0.85），P＝0.004]，fungal infection mortality rate[OR＝0.68，95％CI（0.51，0.92），P＝0.01] and the incidence of drug withdrawal due to adverse reactions [OR＝0.52，95％CI（0.40，0.67），P＜0.001] in trial groups were significantly lower than control group，with statistical significance. There was no statistical significance in the all-cause mortality rate [OR＝0.84，95％CI（0.67， 1.05），P＝0.13]. CONCLUSIONS：Compared with amphotericin B and triazole antifungal agents，echinococcins used for the prevention of invasive candidiasis can reduce the incidence of breakthrough invasive fungal infection，fungal infection mortality rate and the incidence of drug withdrawal due to adverse reactions

Consensus statement on the management of invasive candidiasis in Indian scenario

Invasive fungal infections in critically ill patients are associated with increased morbidity and mortality. Candida species are among the most common causes of nosocomial bloodstream infections and of invasive infections in intensive care units (ICUs). The high mortality mandates early identification of invasive candidiasis which is vital to initiate appropriate and timely treatment and improve outcomes. Delaying the initiation of treatment could result in an increase in mortality which can be avoided by usage of more rapid diagnostic techniques. There are multiple diagnostic tests including culture and non-culture tests like 1,3-β-D-glucan and newer techniques like MALDI-TOF which are available to diagnose candidemia but each with their drawbacks. Additionally, there are various guidelines like IDSA and ESCMID on treatment which aim to minimize death, late complications from deep-seated candidiasis and rise of drug- resistant Candida strains. Through this consensus statement prepared by a panel of experts, all of whom are senior intensivists, infectious disease specialists and microbiologists, we aim to address the major aspects of management of invasive candidiasis in the Indian population as per the authors opinions, backed by published evidence and supported by the latest clinical guidelines.

Colombian consensus on the diagnosis, treatment, and prevention of Candida Spp. disease in children and adults, / Consenso Colombiano Para el Diagnóstico, Tratamiento y Prevención de la Enfermedad por Candida Spp. en Niños y Adultos

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.

La Candidiasis Invasora (CI) y la candidemia, como su manifestación más frecuente, se ha convertido en la principal causa de micosis oportunista a nivel hospitalario. Este manuscrito realizado por miembros de la Asociación Colombiana de Infectología (ACIN), tuvo como objetivo proporcionar un conjunto de recomendaciones para manejo, seguimiento y prevención de la CI/candidemia y de la infección candidiásica de mucosas, en población adulta, pediátrica y neonatal, en un entorno hospitalario, incluyendo las unidades hemato-oncológicas y unidades de cuidado crítico. Todos los datos obtenidos mediante una búsqueda exhaustiva, fueron revisados y analizados de manera amplia por todos los miembros del grupo, y las recomendaciones emitidas se elaboraron luego de la evaluación de la literatura científica disponible, y el consenso de todos los especialistas involucrados, reconociendo el problema de la emergencia de las infecciones por Candida Spp. y brindando una correcta orientación a los profesionales de la salud sobre el manejo de pacientes con enfermedad candidiásica, de una forma racional y práctica, enfatizando en la evaluación del paciente, estrategias de diagnóstico, profilaxis, tratamiento empírico, tratamiento dirigido y terapia preventiva.

Diagnosis of Invasive Fungal Infections in Children

Invasive fungal infections are important causes of morbidity and mortality particularly in high-risk patients. Recognizing such infectionsis often difficult because of non-specific symptoms and clinical signs. Timely diagnosis is also a challenge due to difficulty in obtainingadequate volume of samples, need for anaesthesia to perform certain diagnostic procedures, and insufficient data and experiencerelated to fungal biomarkers and molecular detection tests. This results in widespread use of empiric broad spectrum antifungal agentswith the consequent emergence of drug-resistant strains. This review focusses on the definition, clinical and microbial profile anddiagnostic modalities for invasive fungal infections.

Evaluation of Candida Score: a bedside scoring system for early antifungal therapy in non-neutropenic critically ill patients

Background: Invasive Candida infections are the most common invasive fungal infections. Multiple site colonization plays a major role. Further decrease in host immunity (e.g. neutropenia, diabetes mellitus etc.) aggravates local invasion and dissemination which finally leads to candidemia. Hence the study was done to evaluate “Candida Score” in non-neutropenic critically ill patients for early antifungal therapy.Methods: In this prospective observational cohort study, all critically ill patients having sepsis or septic shock on admission or during their stay in ICU stay were included in the study. The components of “Candida Score” like severe sepsis, total parenteral nutrition, surgery, and multifocal Candida colonization were as per Leone et al. Clinical sepsis was given score of 2 if present and 0 if absent. The other variables were given score 01 if present and 0 if absent. The score more than 2.5 is considered significant.Results: Out of 78 patients admitted in the ICU a total of 26 blood culture positives were reported. The prevalence of Candidemia (based on culture) was 23.1% (n=06). The strains isolated were Candida non albicans (n=4, 66.7%) and Canida albicans (n=2, 33.3%). Candida was isolated in different samples other than blood culture of 26(33.33%). The most common specimen with Candida isolation was from urine (n=14, 60.87%), followed by endotracheal aspiration and sputum (n=3, 13% each) and BAL fluid (n=1, 04.3%). Among the isolates Candida non albicans (n=12, 52.2%) was more prevalent than Candida albicans (n=11, 47.8%). The prevalence was maximum for the age group of 60 to 69 years (42.31%) followed by 70 to 79 yrs and 50-59 yrs. Among all patients, 14 patients were referred in our hospital and 12 of them had a prolonged ICU stay (>10 Days). The patients with the Candida score ≥2.5 were 06 in numbers, of which 66.7% were having score 3 followed by one each of having score 4 and 5. Out of these 06 patients 04 received antifungal treatment. One patient with Candida score more than 03 succumbed to death without having antifungal treatment.Conclusions: Early identification of invasive candidiasis with the use of “Candida Score” in critically ill patients may help to initiate antifungal interventions and even help the treating physician or intensivist to formulate the more effective treatment algorithms.

The Efficacy and Safety of Echinocandins to Invasive Candidiasis in Pediatric Patients: A Systematic Review and Meta-Analysis / 中国药学杂志

OBJECTIVE: To review systematically the efficacy and safety of echinocandins to invasive candidiasis in pediatric patients. METHODS: Databases including multiple databases were searched electronically for randomized controlled trials (RCTs) of echinocandins to invasive candidiasis in pediatric patients up to September 2018. Two reviewers independently screened literatures according to the inclusion and exclusion criteria, extracted data, and assessed the methodological quality of the included studies. Then Meta-analysis was performed using Rev Man 5.3 software. RESULTS: A total of 5 RCTs involving 1 190 patients were included. There were 598 patients in the echinocandins group and 592 patients in the control group. Micafungin and caspofungin were retrieved. Fluconazole, and amphotericin B liposome and amphotericin B deoxycholate were used to treat the patient in control group. The RESULTS: of Meta-analysis showed that there was significant difference between experimental group and control group on the overall effectiveness. Subgroup analysis showed that there were significant difference between caspofungin and control group, also between micafungin and control group. There was significant difference between echinocandins and control group on the subgroup analysis of empiric therapy. There were significant difference between experimental group and control group on the discontinuation due to adverse events. Subgroup analysis showed that there was significant difference between caspofungin and control group. CONCLUSION: According to recent analysis, the efficacy and safety of echinocandins in children with invasive candidiasis infections is superior to fluconazole and/or amphotericin B.

Role of serum (1 3)--ß-d-glucan assay in early diagnosis of invasive fungal infections in a neonatal intensive care unit / O papel do (1 3)-ß-d-glucano no soro no diagnóstico precoce de infecções fúngicas invasivas em uma unidade de terapia intensiva neonatal

Abstract Objectives: To study the microbiological pattern of late onset neonatal sepsis cultures and to assess the diagnostic performance of serum (1,3)-β-d-glucan level for early diagnosis of invasive fungemia in high-risk infants admitted to a neonatal intensive care unit. Methods: A prospective multicenter clinical trial conducted on infants at high risk for invasive fungal infections, with suspected late onset sepsis, admitted to a neonatal intensive care unit at Mansoura University Children's Hospital and Mansoura General Hospital between March 2014 and February 2016. Results: A total of 77 newborn infants with high risk of invasive fungal infection were classified based on blood culture into three groups: no fungemia (41 neonates with proven bacterial sepsis), suspected fungemia (25 neonates with negative blood culture), and definite fungemia group (11 neonates with culture-proven Candida). The growing organisms were Klebsiella spp. (14/54); Escherichia coli (12/54); Staphylococcus spp. (12/54; coagulase-negative Staphylococcus [9/54]; Staphylococcus aureus [3/54]); Pseudomonas aerouginosa (3/54); and Proteus spp. (2/54). Moreover, 11/54 presented Candida. Serum (1,3)-β-d-glucan concentration was significantly lower in the no fungemia group when compared with the definite fungemia group. The best cut-off value of (1,3)-β-d-glucan was 99 pg/mL with sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 63.6%, 95.1%, 77.8%, 90.7%, and 88.5%, respectively. Conclusion: (1,3)-β-d-glucan assay has a limited sensitivity with excellent specificity and negative predictive value, which allow its use as an aid in exclusion of invasive neonatal fungal infection. Accurate diagnosis and therapeutic decisions should be based on combining (1,3)-β-d-glucan assay with other clinical, radiological, and microbiological findings.

Resumo Objetivos: Estudar o padrão microbiológico das culturas de sepse neonatal de início tardio e avaliar o desempenho diagnóstico do nível de (1,3)-β-D-glucano no soro para diagnóstico precoce de fungemia invasiva em neonatos de alto risco internados em uma unidade de terapia intensiva neonatal. Métodos: Ensaio clínico multicêntrico prospectivo conduzido em neonatos internados em uma unidade de terapia intensiva neonatal com suspeita de sepse de início tardio que estavam em risco de infecções fúngicas invasivas no hospital universitário infantil de Almançora e no hospital geral de Almançora entre março de 2014 e fevereiro de 2016. Resultados: Foram classificados 77 neonatos recém-nascidos com risco de infecção fúngica invasiva, com base na hemocultura, em: grupo sem fungemia, incluindo 41 neonatos com sepse bacteriana comprovada, grupo com suspeita de fungemia, incluindo 25 neonatos com hemocultura negativa; e grupo com fungemia definida, incluindo 11 neonatos com Candida comprovada por cultura. Os organismos em crescimento foram: {Klebsiella spp 14/54; E. coli 12/54; Staphylococcus spp 12/54 (Staph coagulase negativa 9/54; Staph aureus 3/54); pseudomonous aerouginosa 3/54 e Proteus spp 2/54}, além de 11/54 Candida. A concentração de (1,3)-β-D-glucano no soro foi significativamente inferior no grupo sem fungemia em comparação ao grupo com fungemia definida. O melhor valor de corte da (1,3)-β-D-glucano foi 99 pg/mL com sensibilidade, especificidade, valor preditivo positivo, valor preditivo negativo e precisão de 63,6%, 95,1%, 77,8%, 90,7% e 88,5%, respectivamente. Conclusão: O ensaio de (1,3)-β-D-glucano possui sensibilidade limitada com especificidade e valor preditivo negativo excelentes que possibilitam seu uso e ajudam na exclusão de infecção fúngica invasiva neonatal. O diagnóstico preciso e as decisões oterapêuticas devem ter como base a combinação di ensaio de (1,3)-β-D-glucano com outros achados clínicos, radiológicos e microbiológicos.

Evaluación del rendimiento de 1, 3-β -d-glucano como apoyo diagnóstico de infecciones invasoras por Candida spp. en pacientes críticos adultos / The 1,3-β -d-glucan in critical adult patients as diagnostic tool for invasive Candida spp. infection, performance evaluation

Resumen Introducción: La enfermedad fúngica invasora (EFI) se reconoce como causa importante de morbi-mortalidad en pacientes críticos. La mayoría de estas infecciones son provocadas por Candida spp. para cuyo diagnóstico existen importantes limitaciones. Objetivo: Realizar una evaluación inicial de la utilidad de la medición del 1,3-β-D- glucano (BDG) como herramienta diagnóstica de apoyo de las infecciones invasoras por Candida spp. en pacientes críticos. Pacientes y Método: Estudio prospectivo de pacientes mayores de 18 años hospitalizados en unidades de pacientes críticos por más de cinco días, con fiebre sin foco claro y dos o más factores de riesgo para EFI por Candida spp. Se obtuvieron muestras para BDG en dos días consecutivos. Los resultados se confrontaron con el diagnóstico definitivo de candidemia/candidiasis invasora (C/CI) demostrado según cultivos. Resultados: El valor promedio de BDG en los pacientes con diagnóstico de C/CI fue 224,3 ± 213,7 pg/ml y en aquellos sin C/CI 63,8 ± 76,7 pg/ml (p: 0,02). La sensibilidad y especificidad de BDG para diagnóstico de C/CI fue 60 y 92%, respectivamente. El valor predictor positivo fue 60% y el valor predictor negativo de 92%. Conclusión: BDG puede considerarse como un examen de apoyo en el diagnóstico de C/CI en pacientes críticos con factores de riesgo.

Background: Invasive fungal infections are important causes of morbimortality in critical patients. Most of these infections are caused by Candida spp. which diagnosis has important limitations. Aim: Initial evaluation of the utility of 1,3-β-D-glucan (BDG) as a diagnostic tool for invasive candida infections in critical patients. Patients and Methods: Adult patients over 18 years old, hospitalized in intensive care units for more than five days, with fever > 38 °C of unclear origin and two or more risk factors for invasive Candida spp. infection were included. Samples for BDG were obtained on two consecutive days. The results were compared with definitive diagnosis of candidemia/invasive candidiasis (C/IC) confirmed by cultures. Results: Median value of BDG in patients with C/IC was 224.3 ± 213.7 pg/ml and in patients without C/IC was 63.8 ± 76.7 pg/ml (p: 0.02). Sensitivity and specificity for the diagnosis of C/IC were 60 and 92%, respectively. Positive predictive value was 60% and negative predictive value was 92%. Conclusion: BDG could be considered as a complementary diagnostic tool for the diagnosis of C/IC in critical patients with risk factors.

Incidencia y etiología de la candidiasis invasiva en la Unidad de Cuidados Intensivos de Niños del Centro Hospitalario Pereira Rossell / Incidence and etiology of invasive candidiasis in the Pediatric Intensive Care Unit of of the Pereira Rossell Hospital Center

Introducción: en los últimos años ha aumentado la incidencia de candidiasis invasiva (CI) a nivel mundial. En nuestro país no se disponen de estudios epidemiológicos sobre CI. El objetivo fue determinar incidencia de CI en la Unidad de Cuidados Intensivos de Niños del Centro Hospitalario Pereira Rossell. Metodología: estudio descriptivo retrospectivo. Se incluyeron los niños con CI hospitalizados entre 1/1/2009-1/6/2014. A partir de los cultivos micológicos se identificaron las historias clínicas de los pacientes que desarrollaron CI. Se definió CI al aislamiento de Candida en algún sitio estéril. Se calcularon la densidad de incidencia y de prevalencia. Se registró motivo de ingreso y presencia de factores de riesgo para CI. Resultados: se identificaron 6 casos de CI, incidencia de 1,86 c/1000 ingresos. Los aislamientos se realizaron en hemocultivos (n=3) y líquido peritoneal (n=3). Las especies de Candida aisladas fueron C. albicans (n=3), C. parapsilosis (n=2) y C. tropicalis (n=1). Los factores de riesgo para CI presentes fueron dispositivos invasivos (n=6), antibióticos de amplio espectro (n=6), alimentación parenteral (n=5), cirugía abdominal(n=4). Todos los aislamientos fueron sensibles a los azoles. En 1 de las 6 CI se inició tratamiento empírico previo al aislamiento. Fallecieron 4 de los 6 pacientes. Discusión: la incidencia fue similar a otra experiencia realizada en cuidados intensivos pediátricos. Los pacientes que desarrollaron CI presentaron asociación de factores de riesgo. Los aislamientos fueron sensibles a fluconazol. Caracterizar a estos niños permitirá iniciar en forma oportuna el tratamiento antifúngico. Se destaca la importancia de desarrollar la vigilancia continua sobre las especies de Candida y su patrón de sensibilidad a los antifúngicos.

Introduction: invasive infections by Candida strains have increased around the world in the last years. There are no epidemiological studies on invasive candidiasis (IC) in Uruguay. The study aimed to find out the incidence of IC in the Pediatric Intensive Care Unit (PICU) at the Pereira Rossell Hospital Center (CHPR). Method: a retrospective and descriptive study was conducted. Children hospitalized in PICU of the CHPR between 1/1/2009 and 1/6/2014 were included in the study. The medical records of patients who developed IC were identified based on mycological cultures. Invasive candidiasis was defined as the isolation of the fungus in a sterile site. Incidence and prevalence density were calculated. Cause for hospitalization and risk factors for IC were recorded. Results: six cases of IC were identified and the incidence was of 1.86/1000 hospitalized children in PICU. Isolation of Candida was done in blood cultures (n=3) and peritoneal fluid (n=3). The species of Candida isolated were C. albicans (n=3), C.parapsilosis (n=2) and C. tropicalis (n=1). Risk factors for IC were identified in the 6 cases. Use of invasive prosthesis and a wide spectrum antibiotics were identified in the 6 cases, as well as parenteral nutrition (n=5) and abdominal surgery (n=4). All isolations of Candida were sensitive to fluconazole. Antifungal empiric treatment was started in one case prior to the isolation of Candida. Four out of six children died. Discussion: the incidence of IC found was similar to that in another study in a PICU. Children who developed IC presented several risk factors for IC. The 6 isolations of Candida were sensitive to fluconazole. Analyzing the clinical features of these children will allow the identification of patients with high risk of IC and to timely initiate antifungal treatment. It is necessary to maintain a continuous surveillance on Candida species and their sensitivity pattern to antifungal medication.

Tuberculosis and fungal co-infection present in a previously healthy patient / Coinfección de tuberculosis y candidiasis pulmonar en paciente previamente sana

Background: The coexistance among fungal pathogens and tuberculosis pulmonary is a clinical condition that generally occurs in immunosuppressive patients, however, immunocompetent patients may have this condition less frequently. Objective: We report the case of an immunocompetent patient diagnosed with coinfection Mycobacterium tuberculosis and Candida albicans. Case Description: A female patient, who is a 22-years old, with fever and a new onset of hemoptysis. Clinical findings and diagnosis: PDiminished vesicular breath sounds in the apical region and basal crackling rales in the left lung base were found in the physical examination. Microbiological tests include: chest radiography and CAT scan pictograms in high resolution, Ziehl-Neelsen stain, growth medium for fungus and mycobacteria through Sabouraudís agar method with D-glucose. Medical examinations showed Candida albicans fungus and Mycobacterium tuberculosis present in the patient. Treatment and Outcome: Patient was treated with anti-tuberculosis and anti-fungal medications, which produced good responses. Clinical relevance: Pulmonary tuberculosis and fungal co-infection are not common in immunocompetent patients. However, we can suspect that there is a presence of these diseases by detecting new onset of hemoptysis in patients.

Antecedentes: La coexistencia entre los hongos patógenos y la tuberculosis pulmonar es una condición clínica que se produce generalmente en pacientes inmunosuprimidos, sin embargo, los pacientes inmunocompetentes puede tener esta condición con menor frecuencia. Objetivo: Presentamos el caso de un paciente inmunocompetente con diagnóstico de una coinfección de tuberculosis Mycobacterium tuberculosis y Candida albicans. Caso clínico: Paciente femenina de 22 años con cuadro abrupto de tos, fiebre y hemoptisis sin antecedentes de enfermedad. Hallazgos clínicos y métodos diagnósticos: Al examen respiratorio se halló disminución del murmullo vesicular en la región apical y estertores crepitantes basales en el pulmón izquierdo. Se realizó estudios microbiológicos de muestras tomadas por expectoración y por fibrobroncoscopia en el que se incluyó la tinción de Ziehl-Neelsen, cultivo para micobacteria y hongos en medio Agar Dextrosa Sabouraud y filamentización en suero obteniéndose positividad para Mycobacterium tuberculosis y Candida albicans. Tratamiento y resultado: Se le realizó manejo con antifímicos de primera categoría y antimicóticos con buena respuesta clínica. Relevancia clínica: La coinfección fúngica y tuberculosis pulmonar no es frecuente en pacientes inmunocompetentes, debe sospecharse en episodios abruptos de hemoptisis.

Tuberculosis ineection might increase the risk f invasive candidiasis in an immmunocompetent patient / Tuberculose pode aumentar o risco de candidíase invasiva em paciente imunocompetente

Deep Candida infections commonly occur in immunosuppressed patients. A rare case of a multiple deep organ infection with Candida albicans and spinal tuberculosis was reported in a healthy young man. The 19-year-old man complained of month-long fever and lower back pain. He also had a history of scalded mouth syndrome. Coinfection with Mycobacterium tuberculosis and Candida albicans was diagnosed using the culture of aspirates from different regions. Symptoms improved considerably after antifungal and antituberculous therapy. This case illustrates that infection with tuberculosis might impair the host's immune system and increase the risk of invasive candidiasis in an immunocompetent patient.

As infecções profundas por Candida ocorrem geralmente em pacientes imunossuprimidos. Relatamos caso raro de infecções profundas em múltiplos órgãos por Candida albicans e neuro tuberculose em homem jovem saudável. Um jovem de 19 anos de idade queixou-se de febre e lombalgia há um mês. Relatava ainda histórico de síndrome da boca escaldada. Foi diagnosticada co-infecção por Mycobacterium tuberculosis e Candida albicans em cultura do aspirado de diferentes regiões do organismo. Os sintomas melhoraram significativamente após a terapia antifúngica e antituberculosa. Este caso é apresentado para mostrar que a tuberculose pode prejudicar o sistema imune do hospedeiro e aumentar o risco de candidíase invasiva em paciente imunocompetente.

A non-controlled, multicenter open-label study to evaluate the safety, tolerability and efficacy of caspofungin in the treatment of invasive candidiasis and esophageal candidiasis / 中国感染与化疗杂志

Objective This study was designed to evaluate the safety ,tolerability and efficacy of intravenous caspofungin for treatment of invasive candidiasis and esophageal candidiasis in Chinese adults .Methods This was a non-controlled ,multicenter ,candidiasis .All the 63 patients were included in the safety set (SS) and the full analysis set (FAS) .In the SS ,19 SAEs occurred in 14 patients .All these SAEs were unrelated to caspofungin .There were 73 caspofungin-related non-serious AEs in 31 patients (49 .2% ) .Five patients (7 .9% ) had both clinical AEs and laboratory abnormalities .Eight patients (12 .7% ) had clinical AEs (mainly rashes) ,and 27 patients (42 .9% ) had laboratory abnormalities ,mainly increases in liver enzymes alanine transaminase and aspartate transaminase and reduction in blood potassium .About 91 .7% of the clinical AEs were mild to moderate .Treatment was discontinued in 1 patient (1 .6% ,1/63) due to AEs .The overall efficacy was 58 .1% (36/62) in the FAS and 70 .0% (35/70) in the per-protocol set (PPS) .In the FAS ,the therapeutic efficacy was 57 .6% (34/59) for invasive candidiasis and 66 .7% (2/3) for esophageal candidiasis .In the PPS , the therapeutic efficacy was 68 .8% (33/48 ) for invasive candidiasis and 100% (3/3 ) for esophageal candidiasis .Conclusions The AEs of caspofungin were mostly mild to moderate in the treatment of invasive candidiasis and esophageal candidiasis in Chinese adults .Only one patient terminated therapy due to drug-related AE .Caspofungin is safe and effective for the treatment of invasive candidiasis and esophageal candidiasis in Chinese adults .