Mireia Puig-Asensio

Impact of therapeutic strategies on the prognosis of candidemia in the ICU.

Objectives:To determine the epidemiology of Candida bloodstream infections, variables influencing mortality, and antifungal resistance rates in ICUs in Spain. Design:Prospective, observational, multicenter population-based study. Setting:Medical and surgical ICUs in 29 hospitals distributed throughout five metropolitan areas of Spain. Patients:Adult patients (≥ 18 yr) with an episode of Candida bloodstream infection during admission to any surveillance area ICU from May 2010 to April 2011. Interventions:Candida isolates were sent to a reference laboratory for species identification by DNA sequencing and susceptibility testing using the methods and breakpoint criteria promulgated by the European Committee on Antimicrobial Susceptibility Testing. Prognostic factors associated with early (0–7 d) and late (8–30 d) mortality were analyzed using logistic regression modeling. Measurements and Main Results:We detected 773 cases of candidemia, 752 of which were included in the overall cohort. Among these, 168 (22.3%) occurred in adult ICU patients. The rank order of Candida isolates was as follows: Candida albicans (52%), Candida parapsilosis (23.7%), Candida glabrata (12.7%), Candida tropicalis (5.8%), Candida krusei (4%), and others (1.8%). Overall susceptibility to fluconazole was 79.2%. Cumulative mortality at 7 and 30 days after the first episode of candidemia was 16.5% and 47%, respectively. Multivariate analysis showed that early appropriate antifungal treatment and catheter removal (odds ratio, 0.27; 95% CI, 0.08–0.91), Acute Physiology and Chronic Health Evaluation II score (odds ratio, 1.11; 95% CI, 1.04–1.19), and abdominal source (odds ratio, 8.15; 95% CI, 1.75–37.93) were independently associated with early mortality. Determinants of late mortality were age (odds ratio, 1.04; 95% CI, 1.01–1.07), intubation (odds ratio, 7.24; 95% CI, 2.24–23.40), renal replacement therapy (odds ratio, 6.12; 95% CI, 2.24–16.73), and primary source (odds ratio, 2.51; 95% CI, 1.06–5.95). Conclusions:Candidemia in ICU patients is caused by non-albicans species in 48% of cases, C. parapsilosis being the most common among these. Overall mortality remains high and mainly related with host factors. Prompt adequate antifungal treatment and catheter removal could be critical to decrease early mortality.

Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study

BACKGROUND The best available treatment against carbapenemase-producing Enterobacteriaceae (CPE) is unknown. The objective of this study was to investigate the effect of appropriate therapy and of appropriate combination therapy on mortality of patients with bloodstream infections (BSIs) due to CPE. METHODS In this retrospective cohort study, we included patients with clinically significant monomicrobial BSIs due to CPE from the INCREMENT cohort, recruited from 26 tertiary hospitals in ten countries. Exclusion criteria were missing key data, death sooner than 24 h after the index date, therapy with an active antibiotic for at least 2 days when blood cultures were taken, and subsequent episodes in the same patient. We compared 30 day all-cause mortality between patients receiving appropriate (including an active drug against the blood isolate and started in the first 5 days after infection) or inappropriate therapy, and for patients receiving appropriate therapy, between those receiving active monotherapy (only one active drug) or combination therapy (more than one). We used a propensity score for receiving combination therapy and a validated mortality score (INCREMENT-CPE mortality score) to control for confounders in Cox regression analyses. We stratified analyses of combination therapy according to INCREMENT-CPE mortality score (0-7 [low mortality score] vs 8-15 [high mortality score]). INCREMENT is registered with ClinicalTrials.gov, number NCT01764490. FINDINGS Between Jan 1, 2004, and Dec 31, 2013, 480 patients with BSIs due to CPE were enrolled in the INCREMENT cohort, of whom we included 437 (91%) in this study. 343 (78%) patients received appropriate therapy compared with 94 (22%) who received inappropriate therapy. The most frequent organism was Klebsiella pneumoniae (375 [86%] of 437; 291 [85%] of 343 patients receiving appropriate therapy vs 84 [89%] of 94 receiving inappropriate therapy) and the most frequent carbapenemase was K pneumoniae carbapenemase (329 [75%]; 253 [74%] vs 76 [81%]). Appropriate therapy was associated with lower mortality than was inappropriate therapy (132 [38·5%] of 343 patients died vs 57 [60·6%] of 94; absolute difference 22·1% [95% CI 11·0-33·3]; adjusted hazard ratio [HR] 0·45 [95% CI 0·33-0·62]; p<0·0001). Among those receiving appropriate therapy, 135 (39%) received combination therapy and 208 (61%) received monotherapy. Overall mortality was not different between those receiving combination therapy or monotherapy (47 [35%] of 135 vs 85 [41%] of 208; adjusted HR 1·63 [95% CI 0·67-3·91]; p=0·28). However, combination therapy was associated with lower mortality than was monotherapy in the high-mortality-score stratum (30 [48%] of 63 vs 64 [62%] of 103; adjusted HR 0·56 [0·34-0·91]; p=0·02), but not in the low-mortality-score stratum (17 [24%] of 72 vs 21 [20%] of 105; adjusted odds ratio 1·21 [0·56-2·56]; p=0·62). INTERPRETATION Appropriate therapy was associated with a protective effect on mortality among patients with BSIs due to CPE. Combination therapy was associated with improved survival only in patients with a high mortality score. Patients with BSIs due to CPE should receive active therapy as soon as they are diagnosed, and monotherapy should be considered for those in the low-mortality-score stratum. FUNDING Spanish Network for Research in Infectious Diseases, European Development Regional Fund, Instituto de Salud Carlos III, and Innovative Medicines Initiative.

Initial Use of Echinocandins Does Not Negatively Influence Outcome in Candida parapsilosis Bloodstream Infection: A Propensity Score Analysis

BACKGROUND Concerns have arisen regarding the optimal antifungal regimen for Candida parapsilosis bloodstream infection (BSI) in view of its reduced susceptibility to echinocandins. METHODS The Prospective Population Study on Candidemia in Spain (CANDIPOP) is a prospective multicenter, population-based surveillance program on Candida BSI conducted through a 12-month period in 29 Spanish hospitals. Clinical isolates were identified by DNA sequencing, and antifungal susceptibility testing was performed by the European Committee on Antimicrobial Susceptibility Testing methodology. Predictors for clinical failure (all-cause mortality between days 3 to 30, or persistent candidemia for ≥72 hours after initiation of therapy) in episodes of C. parapsilosis species complex BSI were assessed by logistic regression analysis. We further analyzed the impact of echinocandin-based regimen as the initial antifungal therapy (within the first 72 hours) by using a propensity score approach. RESULTS Among 752 episodes of Candida BSI identified, 200 (26.6%) were due to C. parapsilosis species complex. We finally analyzed 194 episodes occurring in 190 patients. Clinical failure occurred in 58 of 177 (32.8%) of evaluable episodes. Orotracheal intubation (adjusted odds ratio [AOR], 2.81; P = .018) and septic shock (AOR, 2.91; P = .081) emerged as risk factors for clinical failure, whereas early central venous catheter removal was protective (AOR, 0.43; P = .040). Neither univariate nor multivariate analysis revealed that the initial use of an echinocandin-based regimen had any impact on the risk of clinical failure. Incorporation of the propensity score into the model did not change this finding. CONCLUSIONS The initial use of an echinocandin-based regimen does not seem to negatively influence outcome in C. parapsilosis BSI.

Epidemiology and outcome of candidaemia in patients with oncological and haematological malignancies: results from a population-based surveillance in Spain

A prospective, population-based surveillance on candidaemia was implemented in five metropolitan areas of Spain from May 2010 to April 2011. We aimed to describe the distribution and susceptibility pattern of Candida species, and to evaluate risk factors for mortality in patients with oncological (solid tumours) and haematological malignancies. Adults (≥ 16 years) with cancer were included in the present report. Impact of therapeutic strategies on 7- and 30-day mortality were analysed by logistic regression, adjusting for propensity score by inverse weighting probability of receiving early antifungal treatment and catheter removal. We included 238 (32.6%) patients (195 oncological, 43 haematological). Compared with oncological patients, haematological patients were more likely to have received chemotherapy (53.5% versus 17.4%, p < 0.001) or corticosteroids (41.9% versus 21%, p < 0.001), and have neutropenia (44.2% versus 1.5%, p < 0.001). Overall, 14.8% of patients developed breakthrough candidaemia. Non-albicans Candida species (71.1% versus 55.6%, p 0.056) and Candida tropicalis (22.2% versus 7.6%, p 0.011) were more frequent in haematological patients. Based on EUCAST breakpoints, 27.6% of Candida isolates were non-susceptible to fluconazole. Resistance to echinocandins was negligible. Mortality at 7 and 30 days was 12.2% and 31.5%, respectively, and did not differ significantly between the patient groups. Prompt antifungal therapy together with catheter removal (≤ 48 hours) was associated with lower mortality at 7 days (adjusted OR 0.05; 95% CI 0.01-0.42) and 30 days (adjusted OR 0.27; 95% CI 0.16-0.46). In conclusion, non-albicans species are emerging as the predominant isolates, particularly in haematological patients. Prompt, adequate antifungal treatment plus catheter removal may lead to a reduction in mortality.

Daptomycin plus fosfomycin versus daptomycin monotherapy in treating MRSA: protocol of a multicentre, randomised, phase III trial

Introduction Despite the availability of new antibiotics such as daptomycin, methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia continues to be associated with high clinical failure rates. Combination therapy has been proposed as an alternative to improve outcomes but there is a lack of clinical studies. The study aims to demonstrate that combination of daptomycin plus fosfomycin achieves higher clinical success rates in the treatment of MRSA bacteraemia than daptomycin alone. Methods and analysis A multicentre open-label, randomised phase III study. Adult patients hospitalised with MRSA bacteraemia will be randomly assigned (1:1) to group 1: daptomycin 10 mg/kg/24 h intravenous; or group 2: daptomycin 10 mg/kg/24 h intravenous plus fosfomycin 2 gr/6 g intravenous. The main outcome will be treatment response at week 6 after stopping therapy (test-of-cure (TOC) visit). This is a composite variable with two values: Treatment success: resolution of clinical signs and symptoms (clinical success) and negative blood cultures (microbiological success) at the TOC visit. Treatment failure: if any of the following conditions apply: (1) lack of clinical improvement at 72 h or more after starting therapy; (2) persistent bacteraemia (positive blood cultures on day 7); (3) therapy is discontinued early due to adverse effects or for some other reason based on clinical judgement; (4) relapse of MRSA bacteraemia before the TOC visit; (5) death for any reason before the TOC visit. Assuming a 60% cure rate with daptomycin and a 20% difference in cure rates between the two groups, 103 patients will be needed for each group (α:0.05, ß: 0.2). Statistical analysis will be based on intention to treat, as well as per protocol and safety analysis. Ethics and dissemination The protocol was approved by the Spanish Medicines and Healthcare Products Regulatory Agency (AEMPS). The sponsor commits itself to publishing the data in first quartile peer-review journals within 12 months of the completion of the study. Trial registration number NCT01898338.

Candida tropicalis bloodstream infection: Incidence, risk factors and outcome in a population-based surveillance☆

OBJECTIVE To assess the current clinical features and determinants of outcome of Candida tropicalis bloodstream infection (BSI). METHODS A population-based surveillance on Candida BSI was conducted from May 2010 to April 2011 in 29 Spanish hospitals. Antifungal susceptibility testing (EUCAST methodology) was centrally performed. The characteristics and outcome of C. tropicalis BSI episodes were compared with those due to other species. RESULTS Fifty-nine out of 752 episodes (7.8%) were due to C. tropicalis (annual incidence: 0.62 cases per 100,000 population). Resistance to fluconazole and voriconazole was found in 23.2% and 26.8% of isolates. Breakthrough BSI occurred in 10.5% of episodes. Risk factors for C. tropicalis BSI were age (odds ratio [OR]: 1.01; P-value = 0.05), underlying leukaemia (OR: 4.77; P-value = 0.001) and chronic lung disease (OR: 2.62; P-value = 0.002). There were no differences in clinical failure (persistent BSI for ≥72 h after initiation of therapy and/or 30-day all-cause mortality) between C. tropicalis (39.6%) and non-C. tropicalis groups (45.6%). The appropriateness of antifungal therapy or the fluconazole MIC values had no significant impact on outcome, whereas early central venous catheter removal exerted a protective effect. CONCLUSIONS C. tropicalis BSI was associated with advanced age, haematological malignancy and respiratory comorbidity. We found no correlation between the unexpectedly high resistance rate to azoles observed and outcome.

A simple prediction score for estimating the risk of candidaemia caused by fluconazole non-susceptible strains

We aimed to develop a simple prediction score to identify fluconazole non-susceptible (Flu-NS) candidaemia using simple clinical criteria. A derivation cohort was extracted from the CANDIPOP study, a prospective, multicentre, population-based surveillance programme on candidaemia conducted in 29 hospitals in Spain from April 2010 to May 2011. The score was validated with an external, multicentre cohort of adults with candidaemia in six tertiary hospitals in three countries. The prediction score was based on three variables selected by a logistic regression model together with the severity of disease. In total, 617 and 297 cases of candidaemia were included in the derivation and validation cohorts, respectively; of these, 134 (21.7%) and 57 (19.2%) were caused by Flu-NS strains. Factors independently associated with Flu-NS were transplant recipient status (adjusted odds ratio (AOR) 2.13; 95% CI 1.01-4.55; p 0.047), hospitalization in a unit with a high prevalence (≥ 15%) of Flu-NS strains (7.53; 4.68-12.10; p < 0.001), and previous azole therapy for at least 3 days (2.04; 1.16-3.62; p 0.014). The area under the receiver operating characteristics curve (AUC) was 0.76 (0.72-0.81), and using 2 points as the Flu-NS prediction score cut-off gave a sensitivity of 82.1%, a specificity of 65.6%, and a negative predictive value of 93%. The AUC in the validation cohort was 0.72 (95% CI 0.65-0.79). Hence, the Flu-NS prediction score helped to exclude Flu-NS Candida strains. This could improve the selection of empirical treatments for candidaemia in the future.

Fungemia due to rare opportunistic yeasts: data from a population-based surveillance in Spain

Abstract Fungemia due to rare yeasts constitutes an emerging but poorly investigated condition. Data on risk factors, clinical features, therapy, and outcome of episodes of fungemia due to rare (non‐Candida, non‐Cryptococcus) yeasts were analyzed in a population‐based surveillance program conducted in 29 Spanish hospitals between May 2010 and April 2011. Species identification (DNA sequencing) and antifungal susceptibility testing (EUCAST and CLSI methods) were centrally performed. Fourteen out of 767 episodes of fungemia (1.8%) were due to rare yeasts: Trichosporon asahii, Magnusiomyces capitatus (three cases each), Rhodotorula mucilaginosa, Wickerhamomyces anomalus (two cases each), and Pichia kudriavzevii, Cyberlindnera fabianii, Kodamaea ohmeri, and Lodderomyces elongisporus (one case each). Misidentification by local laboratories was observed in two isolates. Breakthrough fungemia occurred in two episodes due to M. capitatus. MIC values for echinocandins were generally high (particularly for M. capitatus, T. asahii, and R. mucilaginosa isolates [≥2 mg/l]), whereas T. asahii isolates showed MICs ≥1 mg/l to amphotericin B. Patients with fungemia due to rare yeasts were more likely to have hematological malignancies (28.6% vs. 7.8%; P‐value = .021), chronic lung disease (50.0% vs. 22.3%; P‐value = .023), and prior immunosuppression (57.1% vs. 22.2%; P‐value = .005) compared to those with candidemia. The rate of clinical failure (persistent fungemia and/or 30‐day mortality) was 46.2% and did not significantly differ from that observed in episodes of candidemia. In conclusion, non‐Candida, non‐Cryptococcus yeasts are uncommon causes of fungemia, with immunosuppression and chronic lung disease as predisposing factors. Outcome does not appear to be worse than that of candidemia.

Empirical and targeted therapy of candidemia with fluconazole versus echinocandins: a propensity score–derived analysis of a population-based, multicentre prospective cohort

We compared the clinical efficacy of fluconazole and echinocandins in the treatment of candidemia in real practice. The CANDIPOP study is a prospective, population-based cohort study on candidemia carried out between May 2010 and April 2011 in 29 Spanish hospitals. Using strict inclusion criteria, we separately compared the impact of empirical and targeted therapy with fluconazole or echinocandins on 30-day mortality. Cox regression, including a propensity score (PS) for receiving echinocandins, stratified analysis on the PS quartiles and PS-based matched analyses, were performed. The empirical and targeted therapy cohorts comprised 316 and 421 cases, respectively; 30-day mortality was 18.7% with fluconazole and 33.9% with echinocandins (p 0.02) in the empirical therapy group and 19.8% with fluconazole and 27.7% with echinocandins (p 0.06) in the targeted therapy group. Multivariate Cox regression analysis including PS showed that empirical therapy with fluconazole was associated with better prognosis (adjusted hazard ratio 0.38; 95% confidence interval 0.17-0.81; p 0.01); no differences were found within each PS quartile or in cases matched according to PS. Targeted therapy with fluconazole did not show a significant association with mortality in the Cox regression analysis (adjusted hazard ratio 0.77; 95% confidence interval 0.41-1.46; p 0.63), in the PS quartiles or in PS-matched cases. The results were similar among patients with severe sepsis and septic shock. Empirical or targeted treatment with fluconazole was not associated with increased 30-day mortality compared to echinocandins among adults with candidemia.

No evidence of increased ocular involvement in candidemic patients initially treated with echinocandins

Candins are commonly used as initial therapy in patients with candidemia and are known to diffuse poorly into ocular tissue. The aim of our multicenter study was to assess whether eye involvement was more common in patients initially treated with echinocandins. We performed a post hoc analysis of a prospective, multicenter, population-based candidemic surveillance program implemented in Spain during 2010-2011 (CANDIPOP project). Eye involvement was detected in 13 of 168 patients with candidemia (7.7%) who underwent ophthalmoscopy. Two patients had endophthalmitis, while the remaining patients had chorioretinitis. The frequency of ocular candidiasis was similar in patients receiving initial therapy with candins (3/56; 5.4%) or with other regimens (10/112; 8.9%). At multivariate analysis, risk conditions for eye involvement were dialysis after candidemia (OR, 19.4; 95% CI, 1.7-218.4) and involvement of organs other than the eye (OR, 5.4; 95% CI, 1.1-25.7). In conclusion, eye involvement was not found to be more frequent in patients receiving initial therapy with echinocandins than in patients receiving other drugs.