Comparative assessment of Sensititre YeastOne and Micronaut-AM EUCAST for antifungal susceptibility testing in candidaemia isolates.

PURPOSE: Antifungal susceptibility testing (AFST) is essential to ensure appropriate antifungal therapy in candidaemia. This study compared two commercial colorimetric broth microdilution tests: Sensititre YeastOne (SYO; Thermo Scientific) and Micronaut-AM EUCAST AFST (M-AM; Bruker) for the AFST of Candida spp. MATERIAL AND METHODS: A total of 74 yeast strains, including C. albicans (n = 40) and non-albicans Candida species (NACS) (n = 34), were obtained from blood cultures of patients admitted to a tertiary care hospital in Belgium from 2017 to 2022. AFST by SYO and by M-AM were performed according to the manufacturers' protocols and interpreted using CLSI and EUCAST guidelines, respectively. Essential and categorical agreements (EA and CA), very major, major and minor discrepancies were calculated for amphotericin B, echinocandins and azoles considering SYO as the reference method. RESULTS: In total, 441 and 392 isolate-antifungal results were evaluable for EA and CA, respectively. SYO and M-AM, showed a high level of concordance for C. albicans strains, with an EA and CA ≥90 % for all tested antifungals. However, we noted significant discordances for NACS, the lowest EA were observed with micafungin (50 %) and voriconazole (58.8 %). These discrepancies were likely due to differences in the raw MIC values obtained by the two methods and the different interpretation breakpoints used by CLSI and EUCAST. CONCLUSION: Our study showed excellent agreement between SYO and M-AM for AFST of C. albicans, while the equivalency was lower for NACS. AFST method should be carefully selected, considering the results might impact the choice of antifungals for non-albicans candidaemia.

Epidemiology, management and outcome of candidaemia in patients with diabetes.

BACKGROUND: Candidaemia is the commonest fungal bloodstream infection in hospitalised patients. Diabetes is one of the risk factors for mortality from candidaemia. METHODS: We compared the epidemiology, clinical characteristics and management of candidaemia in patients with and without diabetes. RESULTS: Over a 10-year period, 200 episodes of Candida bloodstream infection were documented. Patients with diabetes were younger (58.7 vs 65.5 years), less likely to be suffering from cancer (21.8% vs 36%), and had significantly lower 30-day and 90-day crude mortality (17.2% vs 35.6% and 28.4% vs 48.6%, respectively). Candida glabrata was more common in patients with diabetes (39.3% vs 29.7%). Based on European Confederation of Medical Mycology (ECMM) quality indicators, the management of patients with and without diabetes was similar. DISCUSSION: Our study highlights the importance of epidemiological data in relation to candidaemia in patients with diabetes and the growing threat of invasive C. glabrata infection in this subset of patients.

Cost-utility analysis of caspofungin and fluconazole for primary treatment of invasive candidiasis and candidemia in Ethiopia.

BACKGROUND: Invasive candidiasis and/or candidemia (IC/C) is a common fungal infection leading to significant health and economic losses worldwide. Caspofungin was shown to be more effective than fluconazole in treating inpatients with IC/C. However, cost-effectiveness of caspofungin for treating IC/C in Ethiopia remains unknown. We aimed to assess the cost-utility of caspofungin compared to fluconazole-initiated therapies as primary treatment of IC/C in Ethiopia. METHODS: A Markov cohort model was developed to compare the cost-utility of caspofungin versus fluconazole antifungal agents as first-line treatment for adult inpatients with IC/C from the Ethiopian health system perspective. Treatment outcome was categorized as either a clinical success or failure, with clinical failure being switched to a different antifungal medication. Liposomal amphotericin B (L-AmB) was used as a rescue agent for patients who had failed caspofungin treatment, while caspofungin or L-AmB were used for patients who had failed fluconazole treatment. Primary outcomes were expected quality-adjusted life years (QALYs), costs (US$2021), and the incremental cost-utility ratio (ICUR). These QALYs and costs were discounted at 3% annually. Cost data was obtained from Addis Ababa hospitals while locally unavailable data were derived from the literature. Cost-effectiveness was assessed against the recommended threshold of 50% of Ethiopia's gross domestic product/capita (i.e.,US$476). Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of the findings. RESULTS: In the base-case analysis, treatment of IC/C with caspofungin as first-line treatment resulted in better health outcomes (12.86 QALYs) but higher costs (US$7,714) compared to fluconazole-initiated treatment followed by caspofungin (12.30 QALYs; US$3,217) or L-AmB (10.92 QALYs; US$2,781) as second-line treatment. Caspofungin as primary treatment for IC/C was not cost-effective when compared to fluconazole-initiated therapies. Fluconazole-initiated treatment followed by caspofungin was cost-effective for the treatment of IC/C compared to fluconazole with L-AmB as second-line treatment, at US$316/QALY gained. Our findings were sensitive to medication costs, drug effectiveness, infection recurrence, and infection-related mortality rates. At a cost-effectiveness threshold of US$476/QALY, treating IC/C patient with fluconazole-initiated treatment followed by caspofungin was more likely to be cost-effective in 67.2% of simulations. CONCLUSION: Our study showed that the use of caspofungin as primary treatment for IC/C in Ethiopia was not cost-effective when compared with fluconazole-initiated treatment alternatives. The findings supported the use of fluconazole-initiated therapy with caspofungin as a second-line treatment for patients with IC/C in Ethiopia.

Anidulafungina para tratamento de pacientes com candidemia e outras formas de candidíase invasiva / Anidulafungin for the treatment of patients with candidemia and other forms of invasive candidiasis

CONTEXTO: A candidíase invasiva é uma condição grave, especialmente pelo aumento do grupo de pessoas sob condições de risco, como pessoas com imunossupressão e internação prolongada em unidade de terapia intensiva. No Brasil, a incidência estimada de candidemia é de 2,5 casos para cada 1.000 internações em hospitais terciários. Apesar dos avanços das terapias antifúngicas nas últimas décadas, a morbidade e mortalidade relacionadas à candidíase invasiva permanecem elevadas, especialmente quando o tratamento apropriado é retardado. Consensos de especialidades de sociedades científicas publicados têm sugerido o uso da anidulafungina como medicação antifúngica de primeira linha para o tratamento da candidíase invasiva, porém essa medicação está ausente da Relação Nacional de Medicamentos publicada em 2022 pelo Ministério da Saúde. Este relatório de recomendação visa auxiliar na tomada de decisão quanto à incorporação da anidulafungina para o tratamento da candidíase invasiva no âmbito do Sistema Único de Saúde (SUS). TECNOLOGIA: Anidulafungina. PERGUNTA DE PESQUISA: A anidulafungina é eficaz e segura, quando comparada a anfotericina B (desoxicolato ou formulações lipídicas) para o tratamento de pessoas com candidíase invasiva? EVIDÊNCIAS CLÍNICAS: A busca de evidências foi realizada nas bases de dados científicas: Medline (PUBMED), EMBASE, The Cochrane Library, Literatura Latino-americana e do Caribe em Ciências da Saúde (LILACS), Scopus e Web of Science. Foram encontrados 918 registros e ao final do processo de seleção de estudos, foram escolhidos dois artigos científicos, sendo duas revisões sistemáticas que comparam a anidulafungina e formulações de anfotericina B a partir de ensaios clínicos que incluíram essas drogas no tratamento de pessoas com candidíase invasiva. Há evidência moderada favorável ao uso da tecnologia anidulafungina para a eficácia absoluta / chance de ser a melhor droga (anidulafungina - 77,49% / 0,345, anfotericina B lipossomal - 72,98% / 0,070 e anfotericina B desoxicolato: 65,40% / 0,000). Não houve diferença significativa em relação a mortalidade. Nos eventos adversos, houve menor incidência de elevação de enzimas hepáticas sem necessidade de suspender a droga no tratamento com anidulafungina comparado aos tratamentos com formulações da anfotericina B. Não houve diferença em relação à elevação de enzimas hepáticas com necessidade de suspender a droga e descontinuação do tratamento por evento adverso. Ensaio clínico randomizado comparando outra droga da mesma classe com a anfotericina B mostrou que a micafungina foi tão eficaz e mais bem tolerada (menor incidência de disfunção renal e eventos adversos que levassem a descontinuação do tratamento) do que a anfotericina B lipossomal. Porém, salienta-se que não foram encontrados ensaios clínicos comparando diretamente a anidulafungina e formulações de anfotericina B em pessoas com candidíase invasiva. EVIDÊNCIAS ECONÔMICAS: Foi conduzido modelo de decisão com horizonte temporal de duas semanas. Considerou-se dois desfechos primários de efetividade: sobrevida e taxa de resposta do tratamento. Todos os pacientes foram acompanhados até o sucesso da terapia ou morte. A análise de custo-efetividade mostrou que anidulafungina é custoefetiva, dominando a alternativa do complexo lipídico de anfotericina B (CLAB) e apresentando uma melhor relação de custo-efetividade incremental (RCEI) quando comparada ao anfotericina B desoxicolato (ABD). Foi realizada análise de sensibilidade univariada determinística para a uma variação de 10% na taxa de resposta absoluta e na probabilidade da realização de diálise nos pacientes com nefrotoxicidade. Para este efeito adverso, também se variou taxa para 50% no uso do ABD. Nessas condições, o ABD passa a ser dominado pela anidulafungina no aumento da taxa de resposta, na diminuição do número de pacientes que necessitam diálise e no aumento da probabilidade da maior taxa de pacientes que desenvolvem nefrotoxicidade. As outras situações não mudam a melhor RCEI da anidulafungina. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: A análise de impacto orçamentário (AIO) foi realizada empregando-se o método da demanda aferida. Não se adotou um horizonte temporal, mas número de internações (por 1.000 internações). Em 5 anos, o custo adicional da anidulafungina em relação ao ABD seria de R$ 19.705,109,58. RECOMENDAÇÕES INTERNACIONAIS: Foi realizada busca por recomendações de uso do andidulafungina via International HTA Database (INAHTA) e em outras instituições e agências de ATS, tais como Health Technology Assessment International (HTAi); EUnetHTA, Canadian Agency for Drugs and Technologies in Health (CADTH) no Canadá, National Institute for Clinical Excellence (NICE) no Reino Unido, Agency for Healthcare Research and Quality (AHRQ) nos Estados Unidos. A recomendação identificada do National Health System (NHS) de Wales (Reino Unido), onde anidulafungina (Ecalta®) foi recomendada, em 2009, como uma opção para uso no NHS Wales dentro de sua indicação licenciada, para o tratamento de CI em pacientes adultos não neutropênicos (All Wales Medicine Strategy Group, 2022). MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram duas tecnologias para compor o esquema terapêutico da candidíase invasiva. CONSIDERAÇÕES FINAIS: Há evidência moderada favorável ao uso da tecnologia anidulafungina para a eficácia absoluta / chance de ser a melhor droga. Não houve diferença significativa em relação a mortalidade. Nos eventos adversos, houve menor incidência de elevação de enzimas hepáticas sem necessidade de suspender a droga no tratamento com anidulafungina comparado aos tratamentos com formulações da anfotericina B. Para a efetividade medida na taxa de resposta bem-sucedida (TRBS), o medicamento dominou as formulações CLAB e ABD. A análise de impacto orçamentário sugere uma economia de aproximadamente 148 milhões de reais em cinco anos, ao compará-la ao ABD. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Plenário presentes na 107ª Reunião Ordinária da Conitec, no dia 06 de abril de 2022, deliberaram por unanimidade que a matéria fosse disponibilizada em consulta pública com recomendação preliminar favorável à incorporação de anidulafungina para tratamento de pacientes com candidemia e outras formas de candidíase invasiva. Dentre as justificativas para a recomendação, considerou-se a tecnologia custoefetiva e que, de acordo com uma certeza de evidência baixa, resulta em redução de efeitos adversos diretamente relacionados a droga. Em uma metanálise em rede, a anidulafungina foi o antifúngico com a maior chance de ser a melhor droga no tratamento de pessoas com candidemia e outras formas de candidíase invasiva (grau de certeza da evidência baixo). A matéria foi disponibilizada em consulta pública. CONSULTA PÚBLICA: A Consulta Pública no 30/2022 foi realizada entre os dias 10/05/2022 a 30/05/2022. Foram recebidas 12 contribuições, sendo três pelo formulário para contribuições técnico-científicas e nove pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. As contribuições foram recebidas na consulta pública foram todas a favor da recomendação preliminar da Conitec que recomendava a recomendar a incorporação da anidulafungina, exceto uma que referiu não ter opinião formada. As argumentações destacaram os benefícios clínicos que o medicamento oferece com base em evidências já apresentadas na discussão inicial do tema e reitera que o medicamento se trata de opção terapêutica de primeira linha para a candidíase invasiva com espectro de cobertura bom contra infecções por Candida spp. Não foram adicionadas na CP referências que alterassem a análise das evidências científicas e econômicas apresentadas no relatório preliminar de recomendação. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do plenário presentes na 109ª reunião ordinária da Conitec, no dia 09 de junho de 2022, deliberaram, por unanimidade, recomendar a incorporação, no SUS, da anidalufungina para tratamento de pacientes com candidemia e outras formas de candidíase invasiva. Não foram adicionadas na consulta pública referências que alterassem a recomendação preliminar. Foi assinado o Registro de Deliberação nº 740/2022. DECISÃO: Incorporar, no âmbito do Sistema Único de Saúde - SUS, a anidulafungina para tratamento de pacientes com candidemia e outras formas de candidíase invasiva, conforme a Portaria nº 55, publicada no Diário Oficial da União nº 142, seção 1, página 130, em 28 de julho de 2022.

Assessment of the In Vitro and In Vivo Antifungal Activity of NSC319726 against Candida auris.

Candida auris is an emerging yeast pathogen of candidemia with the ability to develop resistance to all current antifungal drug classes. Novel antifungal therapies against C. auris are warranted. NSC319726 is a thiosemicarbazone with an inhibitory effect on fungal ribosome biogenesis that has demonstrated some antifungal activity. In this study, we assessed the in vitro activity and in vivo efficacy of NSC319726 against C. auris. NSC319726 was active in vitro against 22 C. auris isolates from different clades, with MICs ranging from 0.125 to 0.25 mg/liter. Despite complete visual growth inhibition, the effect was described as fungistatic in time-kill curves. Interactions with fluconazole, amphotericin B, and micafungin, as tested by the checkerboard dilution method, were described as indifferent. NSC319726 demonstrated significant effects in rescuing G. mellonella larvae infected with two distinct C. auris isolates, compared to the untreated group. In conclusion, NSC319726 demonstrated in vitro activity against C. auris and in vivo efficacy in an invertebrate model of infection. Its potential role as a novel antifungal therapy in humans should be further investigated. IMPORTANCE Candida auris is emerging as a major public health threat because of its ability to cause nosocomial outbreaks of severe invasive candidiasis. Management of C. auris infection is difficult because of its frequent multidrug-resistant profile for currently licensed antifungals. Here, we show that the thiosemicarbazone NSC319726 was active in vitro against a large collection of C. auris isolates from different clades. Moreover, the drug was well tolerated and effective for the treatment of C. auris infection in an invertebrate model of Galleria mellonella. We conclude that NSC319726 might represent an interesting drug candidate for the treatment of C. auris infection.

Modifiable healthcare factors affecting 28-day survival in bloodstream infection: a prospective cohort study.

BACKGROUND: Bloodstream infection is common in the UK and has significant mortality depending on the pathogen involved, site of infection and other patient factors. Healthcare staffing and ward activity may also impact on outcomes in a range of conditions, however there is little specific National Health Service (NHS) data on the impact for patients with bloodstream infection. Bloodstream Infections - Focus on Outcomes is a multicentre cohort study with the primary aim of identifying modifiable risk factors for 28-day mortality in patients with bloodstream infection due to one of six key pathogens. METHODS: Adults under the care of five NHS Trusts in England and Wales between November 2010 and May 2012 were included. Multivariable Cox regression was used to quantify the association between modifiable risk factors, including staffing levels and timing of appropriate therapy, and 28-day mortality, after adjusting for non-modifiable risk factors such as patient demographics and long-term comorbidities. RESULTS: A total of 1676 patients were included in the analysis population. Overall, 348/1676 (20.8%) died within 28 days. Modifiable factors associated with 28-day mortality were ward speciality, ward activity (admissions and discharges), movement within ward speciality, movement from critical care, and time to receipt of appropriate antimicrobial therapy in the first 7 days. For each additional admission or discharge per 10 beds, the hazard increased by 4% (95% CI 1 to 6%) in medical wards and 11% (95% CI 4 to 19%) in critical care. Patients who had moved wards within speciality or who had moved out of a critical care ward had a reduction in hazard of mortality. In the first 7 days, hazard of death increased with increasing time to receipt of appropriate antimicrobial therapy. CONCLUSION: This study underlines the importance of appropriate antimicrobials within the first 7 days, and the potential for ward activity and ward movements to impact on survival in bloodstream infection.

Candidaemia in the elderly: Epidemiology, management and adherence to the European Confederation of Medical Mycology quality indicators.

BACKGROUND: Candidaemia in the elderly has not been extensively investigated. OBJECTIVES: We compared the management of candidaemia in the elderly patients (age ≥65 years) and the very elderly subgroup of patients (age ≥75 years) with those belonging to the younger group (age <65 years) using the European Confederation of Medical Mycology (ECMM) Quality (EQUAL) standard. PATIENTS & METHODS: Over a 10-year period (April 2011-March 2020), patients with candida bloodstream infection were identified. Data pertaining to demographics, clinical risk factors, antifungal treatment, central venous catheter and investigations such as echocardiogram and fundoscopy were obtained from electronic sources and medical case notes. RESULTS: A total of 174 episodes of candidaemia were recorded, comprising of 74 episodes in younger patients and 100 in the elderly, of whom 56 were in the very elderly patients. Of the 177 Candida species recovered, 79 were Candida albicans. EQUAL scores were analysed for 148 patients. The mean score was significantly lower in the elderly (10.4) and the very elderly (9.7) patients compared to the patients in the younger age group (12.19) (P < .01). In particular, this was due to lower blood culture volume drawn (P < .01) and, in the very elderly group, significantly lower scores for the quality indicators pertaining to echocardiogram and fundoscopy (P = .03). The overall mean EQUAL score was 11.16 (median 11; interquartile range 8-14). The 30-day survival was 68% and was similar between all groups. CONCLUSIONS: Areas of improvement were identified in the management of candidaemia in the elderly patients.

How can we optimise antifungal use in a solid organ transplant centre? Local epidemiology and antifungal stewardship implementation: A single-centre study.

PURPOSE: We aimed to implement and to assess the impact of the antifungal stewardship programme (AFSp) on prescription appropriateness of antifungals, management and outcomes of candidaemia patients, and antifungal consumption and costs at our solid organ transplant (SOT) institute. METHODS: Local epidemiology of invasive fungal infections (IFIs) from 2009 to 2017 was analysed in order to prepare an effective AFSp, implemented in January 2018. It included suspension of empirical antifungal prescriptions after 72 hours (antifungal time-out), automated alert and infectious disease (ID) consult for empirical prescriptions and for every patient with IFI, and indication for step-down to oral fluconazole when possible. We used process measures and results measures to assess the effects of the implemented programme. RESULTS: The ASFp led to significant improvements in selection of the appropriate antifungal (40.5% in pre-AFS vs 78.6% in post-AFS), correct dosing (51.2% vs 79.8%), correct length of treatment (55.9% vs 75%) and better management of patients with candidaemia. Analysis of prescribed empirical antifungal revealed that defined daily doses (DDDs) per 100 patient days decreased by 36.7% in 2018 compared to the average of pre-AFSp period, with important savings in costs. CONCLUSION: This AFSp led to a better use of antifungal drugs in terms of appropriateness and consumption, with stable clinical and microbiological outcomes in patients with IFI.

Epidemiological Trends of Fungemia in Greece with a Focus on Candidemia during the Recent Financial Crisis: a 10-Year Survey in a Tertiary Care Academic Hospital and Review of Literature.

Updated information on the epidemiology of candidemia, particularly during severe socioeconomic events, is important for proper management of these infections. A systematic literature review on candidemia in Greece and a retrospective surveillance study were conducted in a tertiary university hospital during the years of the recent financial crisis (2009 to 2018) in order to assess changes in incidence rates, patient characteristics, species distribution, antifungal susceptibilities, and drug consumption. The average annual incidence of 429 candidemic episodes was 2.03/10,000 bed days, with 9.88 in adult intensive care units (ICUs), 1.74 in surgical wards, and 1.81 in internal medicine wards, where a significant increase was observed (1.15, 1.85, and 2.23/10,000 bed days in 2009 to 2011, 2012 to 2014, and 2015 to 2018, respectively; P = 0.004). Candida albicans was the most common species (41%), followed by Candida parapsilosis species complex [SC] (37%), Candida glabrata SC (11%), Candida tropicalis (7%), Candida krusei (1%), and other rare Candida spp. (3%). Mixed infections were found in 20/429 (4.7%) cases, while 33 (7%) cases were due to non-Candida spp. Overall, 44/311 (14%) isolates were resistant/non-wild type (WT) to the nine antifungals tested, with 23/113 (20%) C. parapsilosis SC and 2/34 (6%) C. glabrata SC isolates being resistant to fluconazole (1 panechinocandin and 2 panazole resistant). All isolates were susceptible/WT to amphotericin B and flucytosine. While the overall consumption of antifungals diminished (P = 0.02), with a mean of 17.93 defined daily doses (DDD)/100 bed days, increased micafungin use was correlated with the rise in C. parapsilosis SC (P = 0.04). A significant increase of candidemia in internal medicine wards and of C. parapsilosis SC infections was found during the years of financial crisis. Although resistance rates remain low (<14%), fluconazole-resistant C. parapsilosis SC and multidrug-resistant C. glabrata SC isolates are of major concern.

Changes in the utilization patterns of antifungal agents, medical cost and clinical outcomes of candidemia from the health-care benefit expansion to include newer antifungal agents.

OBJECTIVES: In 2014, South Korea expanded its national health insurance coverage to include newer antifungal agents, such as echinocandins. This study aimed to investigate the effects of policy change on the prescription patterns of antifungals, medical costs and clinical outcomes of candidemia. METHODS: This retrospective cohort enrolled hospitalized patients with candidemia at three tertiary care hospitals in South Korea from January 2012 to December 2015. The utilization of antifungal agents, medical costs, length of hospital stay (LOS), and mortality before and after the health-care benefit expansion were compared, and the factors associated with all-cause 28-day mortality during the study period were analyzed. RESULTS: A total of 769 candidemia cases were identified. The incidence of candidemia did not significantly vary during the study period (P = 0.253). The proportion of echinocandins, as the initial antifungal agent, and medical costs associated with candidemia significantly increased since the change in insurance coverage (P < 0.001). There was no significant difference in LOS and mortality associated with candidemia before and after the health-care benefit expansion (P = 0.696 and 0.931, respectively). Multivariate logistic regression analysis showed that initial treatment with caspofungin was associated with decreased mortality (adjusted odds ratio: 0.784; 95% confidence interval: 0.681-0.902; reference: fluconazole). CONCLUSIONS: Although the utilization of newer antifungal agents and medical cost for candidemia has significantly increased since the health-care benefit expansion, there has been no change in the outcome of candidemia. However, the further increased use of newer antifungals may improve the outcome of candidemia in this country.

The impact of age on risk assessment, therapeutic practice and outcome in candidemia.

BACKGROUND: In Norway, the epidemiological situation of candidemia is followed closely. We have previously demonstrated the highest incidence of candidemia in elderly >65 years of age. However, knowledge of other aspects of this infection is lacking. OBJECTIVE: The aim of this nationwide, retrospective study was to examine risk factors, therapeutic practice and outcome in adult candidemia patients according to age. METHODS: We retrieved data from medical records from patients who developed candidemia in Norway between 1 January 2008 and 31 December 2012. Data were analyzed according to age, younger patients being between 18 and 65 years, elderly being ≥65 years of age. RESULTS: From 771 eligible patients, 738 patients (95.7%) were included (58% men, mean age 65.2 years, 58.1% being ≥65 years). Exposure to health-care related risk factors for candidemia were significantly more common in the younger patients (neutropenia, central venous catheter, mechanical ventilation and chemotherapy) who received empirical treatment more often than the elderly (29.8% vs. 21.7%, p = .01). More elderly did not received any antifungal therapy (27.3% vs 16.8%, p < 0001) and had higher mortality compared to younger patients (45.5% vs 23.9%, p < .0001). In the study population, mortality was higher with age (per 10-years increase, OR 1.43;1.28-1.59, p < 0.0001), in patients not receiving targeted therapy (OR 2.5; CI 1.82-3.36, p < .0001) or any therapy at all (OR 4.64; 3.23-6.68, p < .0001). CONCLUSIONS: Risk factors for candidemia, treatment and outcome differed significantly according to age. Given the increasing numbers of elderly, scrutiny on our clinical practice is warranted.

The epidemiology and management of candidemia in Northern Ireland during 2002-2011, including a 12-month enhanced case review.

In Northern Ireland there are concerns about candidaemia, with rates higher than those reported in England and Wales. Our aim was to explore the epidemiology of candidaemia during a 10 year period and the clinical management upon suspicion of cases during a one year enhanced investigation in Northern Ireland.Candidaemia reports to the Public Health Agency were validated during 2002-2011 and used to examine incidence and antifungal sensitivity trends (during 2007-2011). A clinical proforma was used to collate information for all patients with candidaemia in 2011.The majority (96%) of isolates were captured through voluntary laboratory reporting. There was a year-on-year increase in candidaemia from 2002-2011, from 80 to 131 episodes (incidence rate ratio 1.09 95% CI 1.05-1.13). Rates were highest in males under 1 year and over 75 years. 83/98 (85%) of case notes were available from candidaemia patients during 2011. The most prevalent risk factors were patients on total parenteral nutrition (26 people, 31.3%), surgery in the two months prior to the candidaemia (25 people, 30.1%), significant steroid use in the previous 3 months (24 people, 28.9%) and active neoplastic disease (23 people, 27.7%),This study confirmed an increase in candidaemia rates over time, with the observed incidence in 2011 higher than England and Wales. We identified areas for improvement around the clinical management of candidaemia. We recommend raising the awareness of guidelines for fundoscopy, echocardiography and central venous catheter removal.

Effectiveness of an antifungal stewardship programme at a London teaching hospital 2010-16.

Background: The need for antifungal stewardship is gaining recognition with increasing incidence of invasive fungal infection (IFI) and antifungal resistance alongside the high cost of antifungal drugs. Following an audit showing suboptimal practice we initiated an antifungal stewardship programme and prospectively evaluated its impact on clinical and financial outcomes. Patients and methods: From October 2010 to September 2016, adult inpatients receiving amphotericin B, echinocandins, intravenous fluconazole, flucytosine or voriconazole were reviewed weekly by an infectious diseases consultant and antimicrobial pharmacist. Demographics, diagnosis by European Organization for Research and Treatment of Cancer (EORTC) criteria, drug, indication, advice, acceptance and in-hospital mortality were recorded. Antifungal consumption and expenditure, and candidaemia species and susceptibility data were extracted from pharmacy and microbiology databases. Results: A total of 432 patients were reviewed, most commonly receiving AmBisome® (35%) or intravenous fluconazole (29%). Empirical treatment was often unnecessary, with 82% having no evidence of IFI. Advice was given in 64% of reviews (most commonly de-escalating or stopping treatment) and was followed in 84%. Annual antifungal expenditure initially reduced by 30% (£0.98 million to £0.73 million), then increased to 20% above baseline over a 5 year period; this was a significantly lower rise compared with national figures, which showed a doubling of expenditure over the same period. Inpatient mortality, Candida species distribution and rates of resistance were not adversely affected by the intervention. Conclusions: Provision of specialist input to optimize antifungal prescribing resulted in significant cost savings without compromising on microbiological or clinical outcomes. Our model is readily implementable by hospitals with high numbers of at-risk patients and antifungal expenditure.

Desirability of outcome ranking (DOOR) for comparing diagnostic tools and early therapeutic choices in patients with suspected candidemia.

Desirability of outcome ranking (DOOR) has been developed for assessing desirability of outcome in interventional studies. However, its possible use in observational studies of the diagnosis and early treatment of infectious diseases has not been explored so far, and it might introduce interesting features in specific scenarios. This was a post hoc analysis of a prospective observational study in intensive care unit patients with sepsis and at risk of candidemia. The probabilities that a randomly selected patient would have a more, less, and equally cost-effective early therapeutic choice following a BDG-based diagnostic strategy rather than the empirical administration of antifungals to all patients were calculated using DOOR methods. The probability of a more cost-effective therapeutic choice following the BDG-based rather than the empirical strategy was 67.81% (95% CI 67.32-68.30), whereas the probabilities of a less and equally cost-effective early therapeutic choice were 19.68% (95% CI 19.27-20.10) and 12.50% (95% CI 12.16-12.85), respectively. The application of DOOR methods to observational studies focused on diagnosis and early treatment is a novel field that could merit further investigation.

Assessment of the anti-biofilm effect of micafungin in an animal model of catheter-related candidemia.

In cases where catheter-related candidemia (CRC) must be managed without catheter withdrawal, antifungal lock therapy using highly active anti-biofilm (HAAB) agents is combined with systemic treatment. However, the activity of HAAB agents has never been studied in in vivo models using bioluminescence. We assessed the efficacy of micafungin using a bioluminescent Candida albicans SKCA23-ACTgLuc strain in an animal model of CRC. We divided 33 female Wistar rats into five groups: sham (A), infected nontreated (B), treated with lock therapy (0.16 mg/ml) (C), systemically treated only (1 mg/kg) (D), and systemically treated+lock (E). Catheters were colonized 24 h before insertion into the femoral vein (day 0). Treatment started on day 1 and lasted 7 days, followed by 7 days of surveillance. Bioluminescence assays were carried out on days 1, 3, 5, and 14, together with daily monitoring of clinical variables. Postmortem microbiological cultures from the catheter and several tissue samples were also obtained. Overall, 28 rats (84.8%) completed the study. Group B animals showed significant weight loss at days 2, 4, and 5 compared with groups C and D (P < .05). In group B, no animals survived after day 7, 75% had CRC, and bioluminescence remained constant 5 days after catheter implantation. Positive catheter culture rates in groups C, D, and E were, respectively, 83.3%, 62.5%, and 25.0% (P = .15). Micafungin proved to be a HAAB agent when administered both systemically and in lock therapy in an animal model of CRC, although the bioluminescence signal persists after treatment. This persistence should be further analyzed.

Economic evaluation of micafungin versus liposomal amphotericin B (LAmB) for treating patients with candidaemia and invasive candidiasis (IC) in Turkey.

Micafungin was reported to be non-inferior to liposomal amphotericin B (LAmB) in treating patients with candidaemia and invasive candidiasis (IC). The current study aimed to evaluate the economic impact of using micafungin versus LAmB for treatment of candidaemia and IC in Turkey. A decision analytic model, which depicted economic consequences upon administration of micafungin or LAmB for treating patients with candidaemia and IC in the Turkish hospitals, was constructed. Patients were switched to an alternative antifungal agent if initial treatment failed due to mycological persistence. All patients were followed up until treatment success or death. Outcome probabilities were obtained from published literature and cost inputs were derived from the latest Turkish resources. Expert panels were used to estimate data that were not available in the literature. Cost per patient treated for each intervention was then calculated. Sensitivity analyses including Monte Carlo simulation were performed. For treatment of candidaemia and IC, micafungin (€4809) was associated with higher total cost than LAmB (€4467), with an additional cost of €341 per treated patient. Cost of initial antifungal treatment was the major cost driver for both comparators. The model outcome was robust over a wide variation in input variables except for drug acquisition cost and duration of initial antifungal treatment with micafungin or LAmB. LAmB is cost-saving relative to micafungin for the treatment of candidaemia and IC from the Turkish hospital perspective, with variation in drug acquisition cost of the critical factor affecting the model outcome.

Rapid species identification of Candida directly from blood culture broths by Sepsityper-MALDI-TOF mass spectrometry: impact on antifungal therapy.

Rapid identification of Candida species facilitates pathogen-directed therapy with either fluconazole or an echinocandin. METHOD: We applied Sepsityper matrix-assisted laser desorption ionisation time of flight mass spectrometry (MALDI-TOF-MS) technology on positive blood culture broths for rapid species identification. RESULTS: Of the 74 patients with candidaemia, 25 had the species identified on the day of the positive blood culture directly from the broth (rapid identification group) while the remaining 49 had the species identified from culture (conventional identification group). Three (13.6%) out of 22 treated patients in the rapid identification group received echinocandin compared to 20/45 (44.4%) in the conventional identification group. The appropriateness of therapy was 90.9% in the rapid identification group and 62.2% in the conventional identification group (p = 0.01). Cost savings were more than £10,000 in the first three days of treatment. CONCLUSION: Sepsityper-MALDI-TOF-MS is a useful tool in supporting antifungal stewardship programmes.

Candidemia in children: Epidemiology, prevention and management.

Candidemia is the leading cause of invasive fungal infections in hospitalised children. The highest rates of candidemia have been recorded in neonates and infants <1 year of age. Candidemia is more frequent in neonates and young infants than in adults, and is associated with better clinical outcomes, but higher inpatient costs. Over the last 10 years, a declining trend has been noted in the incidence of paediatric candidemia in the US and elsewhere due to the hospital-wide implementation of central-line insertion and maintenance bundles that emphasise full sterile barrier precautions, chlorhexidine skin preparation during line insertion, meticulous site and tubing care, and daily discussion of catheter necessity. Additional interventions aiming at reducing gut-associated candidemia are required in immunocompromised and critically ill children.

Use of T2MR in invasive candidiasis with and without candidemia.

The mortality associated with invasive candidiasis remains unacceptably high. The T2 magnetic resonance (T2MR) assay is a novel US FDA-approved molecular diagnostic assay for the diagnosis of candidemia that can rapidly detect the five most commonly isolated Candida spp. In clinical trials, T2MR has exhibited good clinical sensitivity and specificity. Potential benefits from the adoption of T2MR technology in the diagnostic and therapeutic algorithms for invasive candidiasis can arise from timely diagnosis of disease, increased case detection, tailored therapy and decrease in empiric antifungal treatment. As everyday clinical experience with the assay is evolving, we discuss the utility of T2MR in invasive candidiasis with and without candidemia based on the currently available evidence regarding its performance.

Overcoming the Resistance Hurdle: Pharmacokinetic-Pharmacodynamic Target Attainment Analyses for Rezafungin (CD101) against Candida albicans and Candida glabrata.

Rezafungin (CD101) is a novel echinocandin antifungal agent with activity against Aspergillus and Candida species, including azole- and echinocandin-resistant isolates. The objective of these analyses was to conduct pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analyses to evaluate single and once-weekly rezafungin dosing to provide dose selection support for future clinical studies. Using a previously developed rezafungin population PK model, Monte Carlo simulations were conducted utilizing the following three intravenous rezafungin regimens: (i) a single 400 mg dose, (ii) 400 mg for week 1 followed by 200 mg weekly for 5 weeks, and (iii) 400 mg weekly for 6 weeks. Percent probabilities of achieving the nonclinical PK-PD targets associated with net fungal stasis and 1-log10 CFU reductions from baseline for Candida albicans and Candida glabrata were calculated for each rezafungin regimen. At the MIC90 for C. albicans and C. glabrata, a single 400 mg dose of rezafungin achieved probabilities of PK-PD target attainment of ≥90% through week 3 of therapy for all PK-PD targets evaluated. When evaluating the multiple-dose (i.e., weekly) regimens under these conditions, percent probabilities of PK-PD target attainment of 100% were achieved through week 6. Moreover, high (>90%) probabilities of PK-PD target attainment were achieved through week 6 following administration of the weekly regimens at or above the MIC100 values for C. albicans and C. glabrata based on contemporary in vitro surveillance data. These analyses support the use of single and once-weekly rezafungin regimens for the treatment of patients with candidemia and/or candidiasis due to C. albicans or C. glabrata.