Empirical Antifungal Treatment Research Articles

EPICO 3.0. Empirical antifungal therapy in critically-ill hematology patients

BackgroundAlthough in the past decade the management of invasive fungal infections has improved, a number of controversies persist regarding empirical antifungal treatment in critically-ill hematology patients. AimsTo identify key clinical knowledge to elaborate a set of recommendations, with a high level of consensus, necessary for the approach to fungal infections in critically-ill hematology patients. MethodsA Spanish prospective questionnaire, which measures consensus through the Delphi technique, was anonymously answered and e-mailed by 30 multidisciplinary national experts, all specialists in fungal invasive infections from six scientific national societies; intensivists, anesthesiologists, microbiologists, pharmacologists and specialists in infectious diseases. They responded to 10 questions prepared by the coordination group after a thorough review of the literature published in the last few years. For a category to be selected, the level of agreement among the experts in each category must be equal to or greater than 70%. In a second round, 73 specialists attended a face-to-face meeting held after extracting the recommendations from the chosen topics, and validated the pre-selected recommendations and derived algorithm. ResultsAssess administering antifungal treatment to patients with high/medium risk factors and fever for over 4 days after onset of antibiotic therapy, and in the event of negative galactomannan or if no detection analysis has been performed and no relevant findings in the sinus and chest computed tomography (CT) have been detected, (1) in the case the patient did not receive prophylaxis, or was administered fluconazole, caspofungin treatment is recommended; (2) in the event the patient received prophylaxis with an azole with activity against filamentous fungi, the administration of liposomal amphotericin B is recommended and caspofungin as second choice therapy; (3) in the event that the prophylaxis received was an echinocandin, liposomal amphotericin B therapy is recommended and voriconazole as second choice. Assess administering antifungal treatment in patients with high/medium risk factors and fever for more than 4 days after onset of antibiotic therapy, and in the event of a positive galactomannan and/or sinus and chest CT suggests fungal infection caused by filamentous fungi, (1) in the event the patient did not receive antifungal prophylaxis or was administered fluconazole, the recommended treatment of choice is voriconazole or liposomal amphotericin B; (2) if the patient received prophylaxis with an azole with activity against filamentous fungi, the administration of liposomal amphotericin B with caspofungin is recommended and monotherapy with liposomal amphotericin B or the combination of voriconazole and anidulafungin are recommended as second choice therapies; (3) in the event an echinocandin was administered as prophylaxis, liposomal amphotericin B or voriconazole are the recommended treatments of choice. Consider the administration of antifungal treatment in patients with high/medium risk factors and fever for more than 4 days after onset of antibiotic therapy, and in the event of a negative galactomannan and the sinus and chest CT suggests fungal infection caused by filamentous fungi, (1) if the patient did not receive prophylaxis or was administered fluconazole, the recommended treatment of choice is liposomal amphotericin B or voriconazole; (2) in the case the patient received prophylaxis with an azole with activity against filamentous fungi, the administration of liposomal amphotericin B is recommended as first choice therapy and liposomal amphotericin B combined with caspofungin as second choice; (3) in the event an echinocandin was administered as prophylaxis, liposomal amphotericin B or voriconazole are the recommended treatments of choice. ConclusionsThe empirical antifungal approach in critically-ill hematology patients requires the application of the broad range of knowledge and skills described in our recommendations and algorithm. These recommendations, based on the DELPHI methodology, may help to identify potential patients, standardize their management and improve overall prognosis.

Critical review of current clinical practice guidelines for antifungal therapy in paediatric haematology and oncology.

The incidence of invasive fungal disease (IFD) is rising, but its treatment in paediatric haematology and oncology patients is not yet standardised. This review aimed to critically appraise and analyse the clinical practice guidelines (CPGs) that are available for paediatric IFD. Electronic searches of MEDLINE, MEDLINE in-Process & Other non-Indexed Citations, the Guidelines International Network (GIN), guideline.gov and Google were performed and combined fungal disease (Fung* OR antifung*OR Candida* OR Aspergill*) with prophylaxis or treatment (prophyl* OR therap* OR treatment). All guidelines were assessed using the AGREE II tool and recommendations relating to prophylaxis, empirical treatment and specific therapy were extracted. Nineteen guidelines met the inclusion criteria. The AGREE II scores for the rigour of development domain ranged from 11 to 92% with a median of 53% (interquartile range 32-69%). Fluconazole was recommended as antifungal prophylaxis in all nine of the included guidelines which recommended a specific drug. Liposomal amphotericin B was recommended in all five guidelines giving empirical therapy recommendations. Specific therapy recommendations were given for oral or genital candidiasis, invasive candida infection, invasive aspergillosis and other mould infections. In many areas, recommendations were clear about appropriate practice but further clarity was required, particularly relating to the decision to discontinue empirical antifungal treatment, the relative benefits of empiric and pre-emptive strategies and risk stratification. Future CPGs could consider working to published guideline production methodologies and sharing summaries of evidence appraisal to reduce duplication of effort, improving the quality and efficiency of CPGs in this area.

Improved Radiographic Imaging of Invasive Fungal Disease: The Cornerstone to Antifungal Stewardship in the Hematology Units?

Empirical or fever-driven antifungal treatment strategies are widely recognized to result in overtreatment of patients and excessive cost. As a result, diagnostic-driven approaches for managing invasive fungal diseases (IFDs) in hematology units have been proposed that rely on early non-specific radiologic findings frequent testing with non-culture-based biomarkers (e.g., galactomannan, PCR) as a trigger for antifungal treatment. However, the performance of these non-culture-based biomarker tests varies significantly from one center to the next, and their sensitivity is reduced by prior antifungal therapy. Moreover, many clinicians do not have sufficient confidence in their negative predictive value to withhold antifungal treatment. An alternative strategy is to use existing (computer tomography pulmonary angiography) and developing technologies (immune-positron emission tomography with specific antibodies) to improve the sensitivity and specificity radiological for IFD. Currently available data suggest that these newer techniques may have similar or better diagnostic performance as biomarker tests with high negative predictive values. In this monograph, we review challenges and recent progress in radiological imaging of IFD in hematology patients, and discuss its potential implications for antifungal stewardship.

Invasive Aspergillosis in Hematological Patients.

Invasive aspergillosis (IA) is still one of the leading causes of morbidity and mortality in hematological patients, although its outcome has been improving. Prolonged and profound neutropenia in patients receiving intensive chemotherapy for acute leukemia and stem cell transplantation is a major risk factor for IA. Allogeneic stem cell transplant recipients with graft-versus-host disease and corticosteroid use are also at high risk. Management in a protective environment with high efficiency particular air (HEPA) filter is generally recommended to prevent aspergillosis in patients with prolonged and profound neutropenia. Antifungal prophylaxis against Aspergillus species should be considered in patients with past history of aspergillosis or colonization of Aspergillus species, at facilities with high incidence of IA and those without a protective environment. Early diagnosis and prompt antifungal treatment is important to improve outcome. Imaging studies such as computed tomography and biomarkers such as galactomannan antigen and β-D-glucan are useful for early diagnosis. Empirical antifungal treatment based on persistent or recurrent fever during neutropenia despite broad-spectrum antibiotic therapy is generally recommended in high-risk patients. Alternatively, a preemptive treatment strategy has recently been proposed in the context of progress in the early diagnosis of IA based on the results of imaging studies and biomarkers. Voriconazole is recommended for initial therapy for IA. Liposomal amphotericin B is considered as alternative initial therapy. Combination antifungal therapy of echinocandin with voriconazole or liposomal amphotericin B could be a choice for refractory cases.

Detection of Enterococcus spp. in bronchoalveolar lavage fluid of patients with high-risk neutropenia: May it be ignored?

We present a series of eight patients with hematological diseases predominantly including AML patients with longlasting neutropenia (Table 1). All patients are characterized by febrile neutropenia, the development of pulmonary infiltrates and comprehensive diagnostic evaluation including bronchoscopy. In all patients, Enterococcus spp. were isolated from bronchoalveolar lavage (BAL), while the majority of these samples contained at least 10,000 bacteria per ml of BAL fluid. Importantly, four out of five Enterococcus strains were characterized by resistance to vancomycin. Thus, half of all BAL specimens were tested positive concerning vancomycin-resistant enterococci (VRE). The consideration of additional BAL findings and the clinical course lead to the assumption that secondary infection with Enterococcus spp. represents the most frequent mechanism how Enterococci can contribute to pneumonia in these immunocompromised patients. In addition, primary infection with E. faecalis was supposed in one of the eight investigated patients. Nevertheless, potential effects of additional antibiotics used in these patients, e.g., empiric antifungal treatment, need to be discussed. Only a few reports on pulmonary infections that are caused by Enterococcus spp. have been published. In detail, in two large analyses of serious enterococcal infections only 4–5 % of patients had pleuropulmonary infections (Garrison et al. 1982; Patterson et al. 1995). This stands remarkably in contrast to our single-center observation of eight cases of nosocomial respiratory enterococcal infections during the last 2 years. We do not query the origin of pulmonary enterococci from resident oropharyngeal flora. In contrast, the relationship between resident Enterococcus spp. and their isolation from BAL has to be reconsidered, especially in such analyses demonstrating a high concentration of bacteria or indicating a potentially relevant resistance profile, e.g., VRE. Dear editor,

The expenditures related to the use of antifungal drugs in patients with hematological cancers: a cost analysis.

ObjectiveThe aim of this study is to analyze the expenditures related to the use of antifungal drugs in patients with hematological malignancies.MethodsIn this retrospective study, the expenditures related to use of antifungal drugs for treatment of invasive fungal infections in patients with hematological malignancies between November 2010 and November 2012 were analyzed. Expenditures of antifungal drugs were calculated by converting the price billed to the Republic of Turkey Social Security Institution per patient using the US dollar ($) exchange rate.ResultsWe retrospectively analyzed the expenditures related to the use of antifungal drugs in 282 febrile episodes of 126 neutropenic patients. Voriconazole (VOR), caspofungin, and liposomal amphotericin B (L-AmB) were administered as a first-line antifungal therapy to treat 72 febrile episodes of 65 neutropenic patients, 45 febrile episodes of 37 neutropenic patients, and 34 febrile episodes of 32 neutropenic patients, respectively. The expenditures related to the use of antifungal drugs per febrile neutropenic episode were $3,857.85 for VOR; $15,783.34 for caspofungin, and $21,561.02 for L-AmB, respectively. The expenditure related to the use of posaconazole (POS) was $32,167.39 per patient for primary or secondary prophylaxis.ConclusionImproving conditions in the patient’s room, choosing pre-emptive antifungal treatment instead of empirical antifungal treatment, switching to tablet form of VOR after initiation of its intravenous form, secondary prophylaxis with VOR against invasive aspergillosis, primary prophylaxis with POS in high-risk patients, and choosing less L-AmB as being an alternative to other antifungal drugs, may reduce expenditures related to the use of antifungal drugs in the treatment of invasive fungal infections during febrile neutropenic episodes of patients with hematological malignancies.

Combination of Candida biomarkers in patients receiving empirical antifungal therapy in a Spanish tertiary hospital: a potential role in reducing the duration of treatment.

Initiation of empirical antifungal therapy for invasive candidiasis (IC) is usually based on clinical suspicion. Serological biomarkers have not yet been studied as a means of ruling out IC. We evaluated the potential role of two combined biomarkers in stopping unnecessary antifungals in patients at risk of IC in the ICU and in other wards. This was a prospective observational study including adults starting empirical antifungal treatment for suspected IC, at Gregorio Marañón Hospital, Madrid (Spain). Patients were stratified according to admission department (ICU or other wards) and final diagnosis (no IC or proven or probable IC). Type of candidiasis (candidaemia or deep-seated candidiasis) was also considered. The Candida albicans germ tube antibody (CAGTA) test and the β-d-glucan (BDG) test were performed on serum samples collected by venepuncture on days 0, 3 and 5 after starting empirical antifungal therapy. Sixty-three ICU patients and 37 non-ICU patients were included. High-risk gastrointestinal surgery and sepsis in non-surgical patients were the main indications for empirical treatment (30% each). Patients had no IC (58%), proven IC (30%) or probable IC (12%). Overall, sensitivity and negative predictive value of the combination of both the CAGTA test and the BDG test were 97% for the entire population. The best performance was observed in ICU patients (sensitivity and negative predictive value of 100%). Among patients without IC, all biomarkers were negative in 31 patients. Serial determination of CAGTA/BDG during empirical antifungal therapy has a high sensitivity and negative predictive value. If properly confirmed, this strategy could be used to discontinue antifungal treatment in at least 31% of patients as a complementary tool in antifungal stewardship programmes.

Posaconazole for primary antifungal prophylaxis in patients with acute myeloid leukaemia or myelodysplastic syndrome during remission induction chemotherapy: a single-centre retrospective study in Korea and clinical considerations.

Posaconazole was introduced as the primary antifungal prophylaxis (PAP) in acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) patients during remission induction chemotherapy. Data on breakthrough invasive fungal infections (IFIs) from various centres are essential, as there are several considerations in treating IFIs in the posaconazole era. The aim of this study was to evaluate the effectiveness of posaconazole PAP and identify characteristics of IFIs at a single centre in Korea. We retrospectively reviewed consecutive patients with AML/MDS undergoing remission induction chemotherapy between December 2010 and November 2013. Of the 424 patients, 140 received posaconazole and 284 received fluconazole prophylaxis. The incidence of breakthrough proven/probable IFIs (15.5% vs. 2.9%, P < 0.001) and empirical antifungal treatment (EAFT) (45.8% vs. 12.9%, P < 0.001) decreased in the posaconazole group compared to the fluconazole group. In the posaconazole PAP group, two cases of breakthrough mucormycosis were noted among 13 proven/probable/possible IFI cases (15.4%). Overall and IFI-related mortality was 12.1% and 1.9% respectively. Fungus-free survival was significantly higher in the posaconazole group (74.7% vs. 87.1%, P = 0.028). Breakthrough IFIs and EAFT decreased significantly after posaconazole PAP. The benefit in fungus-free survival was noted with posaconazole PAP. Clinicians should be vigilant to identify non-Aspergillus IFIs with active diagnostic effort.

PIN55 - Economic Analysis of Empiric Versus Diagnostic-Driven Strategies for Immunocompromised Patients With Suspected Aspergillus Invasive Fungal Infections In China

PIN55 EcoNomIc ANAlysIs of EmPIrIc VErsus DIAgNostIc-DrIVEN strAtEgIEs for ImmuNocomPromIsED PAtIENts WIth susPEctED AsPErgIllus INVAsIVE fuNgAl INfEctIoNs IN chINA Qin L.1, Chen Y.2, Lesher B.1, Liu Q.3, Charbonneau C.4, Earnshaw S.R.5, McDade C.5, Mao N.6, Gao X.1 1Pharmerit International, Bethesda, MD, USA, 2Pfizer Investment Co. Ltd., Beijing, China, 3Southern Medical UniversityNanfang Hospital, Guangzhou, China, 4Pfizer Inc, Paris, France, 5RTI Health Solutions, Research Triangle Park, NC, USA, 6China Pharmaceutical University, Nanjing, China OBJECTIVES: To examine the clinical and economic impact of diagnostic-driven (DD) versus empiric treatment strategies in neutropenic patients with suspected Aspergillus invasive fungal infections (IFIs) in Beijing, Chengdu, and Guangzhou, China. METHODS: A decision-analytic model was used to estimate total costs and survival associated with a DD and empiric treatment strategy for managing suspected IFIs in adult patients with neutropenia due to hematological malignancy or autologous/allogeneic stem cell transplant. In the DD strategy, IFI was identified via serum galactomannan (GM) enzyme-linked immunosorbent assay (ELISA) so that early initiation of targeted treatment could be administered. IFI incidence (10.9%), portion of actual IFIs diagnosed via empiric treatment (30%), overall mortality (10.7%), and IFI-related mortality (28.6%) were obtained from the literature. Survival rates were generated based on the proportion of patients with identified and appropriately treated IFIs. Empiric and DD treatment patterns and resource use were based on clinical opinion (3-5 clinicians from top hospitals per city). Medical costs (in 2014 Chinese Yuan [¥]) included antifungal drugs, treatment-related adverse events, and other medical resource costs. Cityspecific costing sources were used wherever possible. RESULTS: Medical costs were lower for the DD versus the empiric strategy in Beijing (¥4,118 vs ¥5,245), Chengdu, (¥5,463 vs ¥6,389), and Guangzhou (¥9,762 vs ¥10,351). Fewer patients received antifungal treatment using the DD strategy (6.7% versus 11.4%), and survival rates were similar. One-way sensitivity analysis showed results were most sensitive to changes in GM test sensitivity followed by IFI incidence. Probabilistic sensitivity analysis showed that treating via a DD strategy was dominant 99% of the time. CONCLUSIONS: These results suggest that in China, a DD strategy to identify IFIs in immunocompromised patients with persistent fever in order to better target antifungal treatment compared to an empiric antifungal treatment strategy may be cost-saving, while maintaining a similar overall survival rate.

Candida biomarkers in patients with candidaemia and bacteraemia

Microbiological strategies are necessary to help clinicians discontinue empirical antifungal therapy in patients with suspected invasive candidiasis. Culture methods and biomarkers each show low sensitivity. We analysed the value of combining different biomarkers as a decision-making tool for discontinuing empirical antifungal treatment. We studied stored serum samples from 31 patients with candidaemia (Candida albicans 40%, Candida tropicalis 20%, Candida parapsilosis 18%, Candida glabrata 12% and other 10%) and 50 patients with bacteraemia at Gregorio Marañón Hospital, Madrid, Spain. C. albicans germ tube antibody (CAGTA), mannan antigens (MN), antimannan antibodies (AMN) and (1→3)-β-d-glucan (BDG) were assayed using the manufacturer's and alternative cut-offs to improve the accuracy of the tests. The sensitivity of the biomarkers when used alone was low (58%-84%), but specificity was high (65.8%-92.0%). The best combinations were CAGTA and BDG using cut-offs of 1/80 and 80 pg/mL, respectively (sensitivity 96.8% and specificity 84%), and CAGTA and MN using cut-offs of 1/80 and 75 pg/mL, respectively (sensitivity 93.5% and specificity 86.0%). The sensitivity of both combinations was 100% for C. albicans, C. tropicalis and C. parapsilosis, but only combinations including BDG detected Candida krusei. The negative predictive values (NPVs) of both combinations were, respectively, 97.7% and 95.6% (prevalence of candidaemia, 23.6%). For a prevalence of candidaemia of 5% and 10%, the NPV reached 99.8% and 99.6%. The combinations of CAGTA and BDG or CAGTA and MN had a very high NPV at the alternative cut-offs and could be used in antifungal stewardship programmes as a decision-making tool for discontinuing unnecessary empirical therapy in patients with suspected candidaemia.

G415(P) Cytomegalovirus infection presenting as recurrent fever in a child receiving standard chemotherapy for acute lymphoblastic leukaemia

<h3>Introduction</h3> Infection presenting with fever is a common cause for hospital admission of immunocompromised children. Initial management is aimed at the treatment and identification of bacterial and fungal infection. Cytomegalovirus (CMV) is well recognised as causing increased morbidity and mortality in immunocompromised children who have undergone stem cell transplants but less so in children receiving standard chemotherapy in acute lymphoblastic leukaemia. <h3>Case description</h3> Our patient is a 7 year old girl receiving standard chemotherapy for acute lymphoblastic leukaemia. Post induction she was admitted with significant fever but no other clinical signs or symptoms. She was not neutropenic, CRP was unremarkable and cultures negative. A chest X-ray showed right middle lobe changes and CT chest showed consolidation and atelectasis but no ground glass appearance or nodules. Candida PCR and beta-D-glucan test were negative. She received a course of empiric antibiotics, including macrolides, and antifungal treatment. Her fever settled. Following cessation of treatment she was readmitted with fever and a dry cough and intravenous antibiotic and antifungal therapy was recommenced. Repeat investigative workup was unremarkable. She settled. A further brief admission with fever settled without intervention following which she was readmitted for the fourth time with fever and cough. She became unwell, developing an oxygen requirement with respiratory signs on chest auscultation. Blood viral PCRs were sent. CMV PCR was significantly elevated at 142,000 copies/ml. BAL fluid was CMV positive and negative for fungi. Intravenous foscarnet was added to the treatment regime. She improved with this and empirical antifungal treatment. <h3>Results and conclusion</h3> This patient presented with recurrent fevers resulting in prolonged admissions impacting on quality of life and interruption of treatment. No other positive pathogens for the fever were identified apart from CMV. A literature review confirms that CMV is an opportunistic infection that can cause serious, sometimes life-threatening, illness even during conventional anticancer infection due to profound immunosuppression. This is less recognised in clinical practice. We would highlight the importance of considering CMV infection in cases of recurrent and prolonged fever in these children.

Preventing invasive candida infections. Where could we do better?

Invasive candidiasis is associated with high mortality rates, ranging from 35% to 60%, in the range reported for septic shock. The epidemiology and pathogenesis of invasive candidiasis differ according to the patient's immune status; the majority of cases in immunocompromised hosts are candidaemia, whereas non-candidaemic systemic candidiasis accounts for the majority of cases in critically ill patients. In contrast to candidaemia, non-candidaemic systemic candidiasis is difficult to prove, especially in critically ill patients. Up to 80% of these patients are colonized, but only 5-30% develop invasive infection. The differentiation of colonization and proven infection is challenging, and evolution from the former to the latter requires seven to 10 days. This continuum from colonization of mucosal surfaces to local invasion and then invasive infection makes it difficult to identify those critically ill patients likely to benefit most from antifungal prophylaxis or early empirical antifungal treatment. Early empirical treatment of non-candidaemic systemic candidiasis currently relies on the positive predictive value of risk assessment strategies, such as the colonization index, candida score, and predictive rules based on combinations of risk factors such as candida colonization, broad-spectrum antibiotics, and abdominal surgery. Although guidelines recently scored these strategies as being supported by limited evidence, they are widely used at bedside and have substantially decreased the incidence of invasive candidiasis.

Candida in the respiratory tract secretions of critically ill patients and the impact of antifungal treatment: a randomized placebo controlled pilot trial (CANTREAT study).

Candida spp. are frequently recovered from endotracheal secretions in critically ill patients suspected of having ventilator-associated pneumonia. Observational studies reported an association with worse clinical outcomes but the effect of antifungal therapy in these patients remains unclear. We designed this pilot study to assess the feasibility of a larger trial and to evaluate inflammatory profiles and clinical outcomes in these patients. We conducted a double-blind, placebo-controlled, multicenter pilot randomized trial of antifungal therapy in critically ill patients with a clinical suspicion of ventilator-associated pneumonia with positive airway secretion specimens for Candida spp. We also included an observational group without Candida spp. in their airway secretions. We measured recruitment rate, inflammatory and innate immune function profiles over time, and clinical outcomes. We recruited 60 patients into the randomized trial and 29 patients into the observational study. Markers of inflammation and all clinical outcomes were comparable between placebo and antifungal treatment group at baseline and over time. At baseline, plasma TNF-α levels were higher in patients with VAP and Candida compared to the observational group (mean ± SD) (21.8 ± 23.1 versus 12.4 ± 9.3 pg/ml, p = 0.02) and these patients had lower innate immune function as evidenced by reduced whole blood ex vivo LPS-induced TNF-α production capacity (854.8 ± 855.2 versus 1,559.4 ± 1,290.6 pg/ml, p = 0.01). This study does not provide evidence to support a larger trial examining the efficacy of empiric antifungal treatment in patients with a clinical suspicion of ventilator-associated pneumonia and Candida in the endotracheal secretions. The presence of Candida in the lung may be associated with persistent inflammation and immunosuppression.

EPICO 2.0 project. Development of educational therapeutic recommendations using the DELPHI technique on invasive candidiasis in critically ill adult patients in special situations

BackgroundAlthough there has been an improved management of invasive candidiasis in the last decade, still controversial issues remain, especially in different therapeutic critical care scenarios. AimsWe sought to identify the core clinical knowledge and to achieve high agreement recommendations required to care for critically ill adult patients with invasive candidiasis for antifungal treatment in special situations and different scenarios. MethodsSecond prospective Spanish survey reaching consensus by the DELPHI technique, conducted anonymously by electronic e-mail in the first phase to 23 national multidisciplinary experts in invasive fungal infections from five national scientific societies including intensivists, anesthesiologists, microbiologists, pharmacologists and infectious disease specialists, answering 30 questions prepared by a coordination group after a strict review of literature in the last five years. The educational objectives spanned four categories, including peritoneal candidiasis, immunocompromised patients, special situations, and organ failures. The agreement among panelists in each item should be higher than 75% to be selected. In a second phase, after extracting recommendations from the selected items, a meeting was held with more than 60 specialists in a second round invited to validate the preselected recommendations. Measurements and main resultsIn the first phase, 15 recommendations were preselected (peritoneal candidiasis (3), immunocompromised patients (6), special situations (3), and organ failures (3)). After the second round the following 13 were validated: Peritoneal candidiasis (3): Source control and early adequate antifungal treatment is mandatory; empirical antifungal treatment is recommended in secondary nosocomial peritonitis with Candida spp. colonization risk factors and in tertiary peritonitis. Immunocompromised patients (5): consider hepatotoxicity and interactions before starting antifungal treatment with azoles in transplanted patients; treat candidemia in neutropenic adult patients with antifungal drugs at least 14 days after the first blood culture negative and until normalization of neutrophils is achieved. Caspofungin, if needed, is the echinocandin with most scientific evidence to treat candidemia in neutropenic adult patients; caspofungin is also the first choice drug to treat febrile candidemia; in neutropenic patients with candidemia remove catheter. Special situations (2): in moderate hepatocellular failure, patients with invasive candidiasis use echinocandins (preferably low doses of anidulafungin and caspofungin) and try to avoid azoles; in case of possible interactions review all the drugs involved and preferably use anidulafungin. Organ failures (3): echinocandins are the safest antifungal drugs; reconsider the use of azoles in patients under renal replacement therapy; all of the echinocandins to treat patients under continuous renal replacement therapy are accepted and do not require dosage adjustment. ConclusionsTreatment of invasive candidiasis in ICU patients requires a broad range of knowledge and skills as summarized in our recommendations. These recommendations may help to optimize the therapeutic management of these patients in special situations and different scenarios and improve their outcome based on the DELPHI methodology.

Factors predicting prolonged empirical antifungal treatment in critically ill patients

ObjectiveTo determine the incidence, risk factors, and impact on outcome of prolonged empirical antifungal treatment in ICU patients.MethodsRetrospective observational study performed during a one-year period. Patients who stayed in the ICU >48 h, and received empirical antifungal treatment were included. Patients with confirmed invasive fungal disease were excluded. Prolonged antifungal treatment was defined as percentage of days in the ICU with antifungals > median percentage in the whole cohort of patients.ResultsAmong the 560 patients hospitalized for >48 h, 153 (27%) patients received empirical antifungal treatment and were included in this study. Fluconazole was the most frequently used antifungal (46% of study patients). Median length of ICU stay was 19 days (IQR 8, 34), median duration of antifungal treatment was 8 days (IQR 3, 16), and median percentage of days in the ICU with antifungals was 48% (IQR 25, 80). Seventy-seven patients (50%) received prolonged empirical antifungal treatment. Chemotherapy (OR [95% CI] 2.6 [1.07-6.69], p = 0.034), and suspected infection at ICU admission (3.1 [1.05-9.48], p = 0.041) were independently associated with prolonged empirical antifungal treatment.Duration of mechanical ventilation and ICU stay were significantly shorter in patients with prolonged empirical antifungal treatment compared with those with no prolonged empirical antifungal treatment. However, ICU mortality was similar in the two groups (46 versus 52%, p = 0.62).ConclusionEmpirical antifungal treatment was prescribed in a large proportion of study patients. Chemotherapy, and suspicion of infection at ICU admission are independently associated with prolonged empirical antifungal treatment.

Association of clinical and demographic factors in invasive candidiasis caused by fluconazole-resistant Candida species: a study in 15 hospitals, Medellín, Colombia 2010–2011

Candida is the most important agent of fungal infections. Several risk factors have been described associated with invasive infection by fluconazole-resistant Candida spp. A prospective cross-sectional study with case–control analysis was conducted. Case group patients with fluconazole-resistant Candida isolate were included; control group were patients with fluconazole-susceptible Candida spp. A multivariate logistic regression model was performed. Three hundred isolates of Candida spp. were analyzed. Most frequent species were Candida albicans/Candida dubliniensis (48.3%) and Candida tropicalis (22.3%). Posaconazole susceptibility was 93.7%; voriconazole, 84%; and fluconazole, 78.7%. Susceptibility to anidulafungin and caspofungin was 92.7% and 92.3%, respectively. Neutropenia (adjusted odds ratio [aOR] 6.5, 95% confidence interval [CI] 1.0–43.1), antifungal exposure (aOR 5.1, 95% CI 2.3–11.2), and antituberculosis therapy (aOR 7.7, 95% CI 1.4–43.2) were associated to fluconazole resistance. Susceptibility results are useful to guide the selection of empiric antifungal treatment and the design of local therapeutic guidelines. Previous antifungal exposure suggests possible resistance to fluconazole, pointing towards the selection of a different class of antifungal agents.

Micafungin as antifungal prophylaxis in recipients of allogeneic hematopoietic stem cell transplantation: results of different dosage levels in clinical practice

Micafungin has been approved for the prophylaxis of Candida infections in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report a single-center experience of three different dose levels regarding efficacy, toxicity, and colonization with Candida ssp. in clinical practice. In total, 150 consecutive adult patients who underwent allo-HSCT received micafungin at a dosage of 50, 100, or 150mg once daily for primary antifungal prophylaxis. Of those patients receiving more than sixd of micafungin prophylaxis, 12/46 (26%), 6/44 (14%), and 9/46 (20%) were switched to empiric antifungal treatment. The frequency of invasive fungal infections (IFIs) according to EORTC criteria did not differ significantly (7/46; 15% vs. 5/44; 11% vs. 5/46; 11%) across the different dosage groups. In the 50-mg group, there was one case of candidemia with C.parapsilosis after 12d of micafungin prophylaxis. In all three groups, micafungin prophylaxis was well tolerated without any case of toxicity-related treatment discontinuation. Renal function was not significantly altered, while increase of bilirubin was mainly due to concomitant ATG application. The incidence of IFIs is similar irrespective of the micafungin dosage while there was a trend toward more frequent change to empiric antifungal treatment as well as oropharyngeal colonization with candida in the lowest dosage group.

An Observational Study on Early Empiric versus Culture-Directed Antifungal Therapy in Critically Ill with Intra-Abdominal Sepsis.

Objective. To compare early empiric antifungal treatment with culture-directed treatment in critically ill patients with intra-abdominal sepsis. Methods. A prospective observational cohort study was conducted between August 2010 and July 2011, on SICU patients admitted after surgery for gastrointestinal perforation, bowel obstruction or ischemia, malignancy and anastomotic leakages. Patients who received antifungal treatment within two days of sepsis onset were compared to patients who received culture-directed antifungal treatment in terms of mortality rate and clinical improvement. Patients' demographics, comorbidities, severity-of-illness scores, and laboratory results were systematically collected and analysed. Results. Thirty-three patients received early empiric and 19 received culture-directed therapy. Of these, 30 from the early empiric group and 18 from culture-directed group were evaluable and analysed. Both groups had similar baseline characteristics and illness severity. Patients on empiric antifungal use had significantly lower 30-day mortality (P = 0.03) as well as shorter median time to clinical improvement (P = 0.025). Early empiric antifungal therapy was independently associated with survival beyond 30 days (OR 0.131, 95% CI: 0.018 to 0.966; P = 0.046). Conclusion. Early empiric antifungal therapy in surgical patients with intra-abdominal sepsis was associated with reduced mortality and warrants further evaluation in randomised controlled trials.

Effect of Statin Use on Outcomes of Adults with Candidemia

BackgroundStatins have immunomodulatory properties and hinder Candida growth. However, it is unknown whether they may improve prognosis in patients with candidemia. We sought to determine the effect of prior statin use on the clinical outcomes of patients suffering candidemia.Methods and FindingsMulticenter cohort study of hospitalized adults with candidemia between 2005 and 2011 in six hospitals in Spain, Brazil and Argentina. Of 326 candidemias, 44 (13.5%) occurred in statin users and 282 (86.5%) in statin non-users. The median value of APACHE II at candidemia diagnosis was similar between groups (18 vs. 16; p=.36). Candida albicans was the most commonly isolated species, followed by C. parapsilosis, C. tropicalis, C. glabrata, and C. krusei. There were no differences regarding appropriate empirical antifungal treatment. Statin users had a lower early (5 d) case-fatality rate than non-users (4.5 vs. 17%; p=.031). This effect was not observed with other cardiovascular drugs (aspirin, beta blockers and ACE inhibitors). Independent factor related to early case-fatality rate was APACHE II score (AOR, 1.08; 95% CI, 1.03–1.14; p=.002). An appropriate empirical antifungal therapy (AOR, 0.11; 95% CI, 0.04–0.26; p=<.001) and prior statin use were independently associated with lower early case-fatality (AOR, 0.17; 95% CI, 0.03–0.93; p=.041). Fourteen days (14d) and overall (30d) case-fatality rates were similar between groups (27% vs. 29%; p=0.77 and 40% vs. 44%; p=.66).ConclusionsThe use of statins might have a beneficial effect on outcomes of patients with candidemia. This hypothesis deserves further evaluation in randomized trials.

A research agenda on the management of intra-abdominal candidiasis: results from a consensus of multinational experts

intra-abdominal candidiasis (IAC) may include Candida involvement of peritoneum or intra-abdominal abscess and is burdened by high morbidity and mortality rates in surgical patients. Unfortunately, international guidelines do not specifically address this particular clinical setting due to heterogeneity of definitions and scant direct evidence. In order to cover this unmet clinical need, the Italian Society of Intensive Care and the International Society of Chemotherapy endorsed a project aimed at producing practice recommendations for the management of immune-competent adult patients with IAC. A multidisciplinary expert panel of 22 members (surgeons, infectious disease and intensive care physicians) was convened and assisted by a methodologist between April 2012 and May 2013. Evidence supporting each statement was graded according to the European Society of Clinical Microbiology and Infection Diseases (ESCMID) grading system. Only a few of the numerous recommendations can be summarized in the Abstract. Direct microscopy examination for yeast detection from purulent and necrotic intra-abdominal specimens during surgery or by percutaneous aspiration is recommended in all patients with nonappendicular abdominal infections including secondary and tertiary peritonitis. Samples obtained from drainage tubes are not valuable except for evaluation of colonization. Prophylactic usage of fluconazole should be adopted in patients with recent abdominal surgery and recurrent gastrointestinal perforation or anastomotic leakage. Empirical antifungal treatment with echinocandins or lipid formulations of amphotericin B should be strongly considered in critically ill patients or those with previous exposure to azoles and suspected intra-abdominal infection with at least one specific risk factor for Candida infection. In patients with nonspecific risk factors, a positive mannan/antimannan or (1→3)-β-D-glucan (BDG) or polymerase chain reaction (PCR) test result should be present to start empirical therapy. Fluconazole can be adopted for the empirical and targeted therapy of non-critically ill patients without previous exposure to azoles unless they are known to be colonized with a Candida strain with reduced susceptibility to azoles. Treatment can be simplified by stepping down to an azole (fluconazole or voriconazole) after at least 5-7 days of treatment with echinocandins or lipid formulations of amphotericin B, if the species is susceptible and the patient has clinically improved. Specific recommendations were elaborated on IAC management based on the best direct and indirect evidence and on the expertise of a multinational panel.