Ana Díaz-Martín

Epidemiology, Species Distribution, Antifungal Susceptibility, and Outcome of Candidemia across Five Sites in Italy and Spain

ABSTRACT Candidemia has become an important bloodstream infection that is frequently associated with high rates of mortality and morbidity, and its growing incidence is related to complex medical and surgical procedures. We conducted a multicenter study in five tertiary care teaching hospitals in Italy and Spain and evaluated the epidemiology, species distribution, antifungal susceptibilities, and outcomes of candidemia episodes. In the period of 2008 to 2010, 995 episodes of candidemia were identified in these hospitals. The overall incidence of candidemia was 1.55 cases per 1,000 admissions and remained stable during the 3-year analysis. Candida albicans was the leading agent of infection (58.4%), followed by Candida parapsilosis complex (19.5%), Candida tropicalis (9.3%), and Candida glabrata (8.3%). The majority of the candidemia episodes were found in the internal medicine department (49.6%), followed by the surgical ward, the intensive care unit (ICU), and the hemato-oncology ward. Out of 955 patients who were eligible for evaluation, 381 (39.9%) died within 30 days from the onset of candidemia. Important differences in the 30-day mortality rates were noted between institutions: the lowest mortality rate was in the Barcelona hospital, and the highest rate was in the Udine hospital (33.6% versus 51%, respectively; P = 0.0005). Overall, 5.1% of the 955 isolates tested were resistant or susceptible dose dependent (SDD) to fluconazole, with minor differences between the hospitals in Italy and Spain (5.7% versus 3.5%, respectively; P = 0.2). Higher MICs for caspofungin were found, especially with C. parapsilosis complex (MIC90, 1 μg/ml). Amphotericin B had the lowest MICs. This report shows that candidemia is a significant source of morbidity in Europe, causing a substantial burden of disease and mortality.

Risk Factors for Fluconazole-Resistant Candidemia

ABSTRACT Previous studies have sought to determine the risk factors associated with candidemia caused by non-albicans Candida spp. or with potentially fluconazole-resistant Candida spp. (C. glabrata and C. krusei). Non-albicans Candida strains are a heterogeneous group that includes species with different levels of virulence, and only a limited number of C. glabrata isolates are resistant to fluconazole. We set out to identify the risk factors associated with microbiologically proven fluconazole-resistant candidemia. A prospective study including adult patients with candidemia was performed. Data were collected on patient demographics; underlying diseases; exposure to corticosteroids, antibiotics, or fluconazole; and invasive procedures. Risk factors associated either with non-albicans Candida spp. or potentially fluconazole-resistant Candida spp. (C. glabrata or C. krusei) or with Candida spp. with microbiologically confirmed fluconazole resistance were assessed using logistic regressions. We included 226 candidemia episodes. Non-albicans Candida isolates accounted for 53.1% of the fungal isolates, but only 18.2% of the cases were caused by potentially fluconazole-resistant organisms. Thirty isolates exhibited microbiologically confirmed fluconazole resistance. The multivariate analysis revealed that independent predictors associated with fluconazole-resistant Candida spp. were neutropenia (odds ratio [OR] = 4.94; 95% confidence interval [CI] = 1.50 to 16.20; P = 0.008), chronic renal disease (OR = 4.82; 95% CI = 1.47 to 15.88; P = 0.01), and previous fluconazole exposure (OR = 5.09; 95% CI = 1.66 to 15.6; P = 0.004). Independently significant variables associated with non-albicans Candida bloodstream infection or with potentially fluconazole-resistant Candida spp. did not include previous fluconazole exposure. We concluded that prior fluconazole treatment is an independent risk factor only for candidemia caused by microbiologically confirmed fluconazole resistant species. Our findings may be of value for selecting empirical antifungal therapy.

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.

Impact on hospital mortality of catheter removal and adequate antifungal therapy in Candida spp. bloodstream infections

OBJECTIVES We set out to identify the prognostic factors in adult patients with Candida spp. bloodstream infection, assessing the impact on in-hospital mortality of catheter removal and adequacy of antifungal therapy. METHODS Patients with positive blood culture for Candida spp. and a central venous catheter in place at the time of candidaemia were included. Data collected included demographics, underlying diseases, severity of illness, clinical presentation, catheter withdrawal and adequacy of empirical therapy. RESULTS We included 188 patients (mortality 36.7%). The mortality rate was 34.9% (23/66) in patients with early adequate antifungal treatment and 18.9% (7/37) in patients with early adequate antifungal therapy and catheter withdrawal in the first 48 h. The APACHE (Acute Physiology and Chronic Health Evaluation) II score on the day of candidaemia [adjusted hazard ratio (aHR) 1.12; 95% CI 1.06-1.17; P < 0.001] was associated with death whereas early adequate therapy (aHR 0.4; 95% CI 0.23-0.83; P = 0.012) and catheter withdrawal (aHR 0.34; 95% CI 0.16-0.70; P = 0.03) were protective factors. In primary candidaemia, mortality was 28% (14/50) in patients with adequate therapy and decreased to 17.7% (6/34) in patients with both interventions in the first 48 h. Catheter removal was a protective factor and adequacy of antifungal therapy in the first 48 h showed a strong tendency to protection against death (aHR 0.46; 95% CI 0.19-1.08; P = 0.07). In secondary non-catheter-related candidaemia, only early adequate therapy was a protective factor for mortality. CONCLUSIONS Delay in catheter withdrawal and in administration of adequate antifungal therapy was associated with increased mortality in candidaemic patients. Catheter management did not influence the prognosis of secondary non-catheter-related candidaemia.

Determinants of outcome in patients with bacteraemic pneumococcal pneumonia: Importance of early adequate treatment

Abstract We set out to determine the factors influencing mortality in 125 adult patients with bacteraemic pneumococcal community-acquired pneumonia (CAP), assessing the impact on outcomes of early adequate therapy in particular. Presumed prognostic factors with p < 0.1 in the unadjusted model were subjected to multivariate Cox regression analysis, with in-hospital and 90-day mortalities as the dependent variables. A time period of >4 h from admission to start of adequate antibiotic treatment (adjusted hazard ratio (aHR) 2.62, 95% confidence interval (CI) 1.06–6.45; p =0.037) and severe sepsis or septic shock (aHR 5.06, 95% CI 1.63–15.71; p = 0.005) were independently associated with in-hospital mortality. Variables associated with 90-day mortality were Charlson comorbidity index (aHR 1.17, 95% CI 1.02–1.34; p = 0.018), severe sepsis or septic shock (aHR 3.03, 95% CI 1.22–7.51; p = 0.016) and delay of adequate antibiotic therapy >4 h (aHR 2.21, 95% CI 1.01–4.86; p = 0.048). The use of combination therapy was not included in these models but was a protective factor for delayed adequate therapy (aHR 0.53, 95% CI 0.29–0.95; p = 0.033). Administration of adequate antimicrobial therapy within 4 h of arrival is a critical determinant of survival in patients with bacteraemic pneumococcal CAP.

Antibiotic prescription patterns in the empiric therapy of severe sepsis: combination of antimicrobials with different mechanisms of action reduces mortality

IntroductionAlthough early institution of adequate antimicrobial therapy is lifesaving in sepsis patients, optimal antimicrobial strategy has not been established. Moreover, the benefit of combination therapy over monotherapy remains to be determined. Our aims are to describe patterns of empiric antimicrobial therapy in severe sepsis, assessing the impact of combination therapy, including antimicrobials with different mechanisms of action, on mortality.MethodsThis is a Spanish national multicenter study, analyzing all patients admitted to ICUs who received antibiotics within the first 6 hours of diagnosis of severe sepsis or septic shock. Antibiotic-prescription patterns in community-acquired infections and nosocomial infections were analyzed separately and compared. We compared the impact on mortality of empiric antibiotic treatment, including antibiotics with different mechanisms of action, termed different-class combination therapy (DCCT), with that of monotherapy and any other combination therapy possibilities (non-DCCT).ResultsWe included 1,372 patients, 1,022 (74.5%) of whom had community-acquired sepsis and 350 (25.5%) of whom had nosocomial sepsis. The most frequently prescribed antibiotic agents were β-lactams (902, 65.7%) and carbapenems (345, 25.1%). DCCT was administered to 388 patients (28.3%), whereas non-DCCT was administered to 984 (71.7%). The mortality rate was significantly lower in patients administered DCCTs than in those who were administered non-DCCTs (34% versus 40%; P = 0.042). The variables independently associated with mortality were age, male sex, APACHE II score, and community origin of the infection. DCCT was a protective factor against in-hospital mortality (odds ratio (OR), 0.699; 95% confidence interval (CI), 0.522 to 0.936; P = 0.016), as was urologic focus of infection (OR, 0.241; 95% CI, 0.102 to 0.569; P = 0.001).Conclusionsβ-Lactams, including carbapenems, are the most frequently prescribed antibiotics in empiric therapy in patients with severe sepsis and septic shock. Administering a combination of antimicrobials with different mechanisms of action is associated with decreased mortality.

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.

Optimum treatment strategies for carbapenem-resistant Acinetobacter baumannii bacteremia

Carbapenem-resistant Acinetobacter baumannii (CRAB) constitutes an increasing problem worldwide. CRAB bacteremia is associated with a high fatality rate and its optimal treatment has not been established. Early institution of appropriate therapy is shown to improve survival of patients with CRAB bloodstream infection. Regrettably, treatment options are limited. Little information exists about the efficacy of sulbactam for the treatment of CRAB bacteremia. Colistin and tigecycline possess good in vitro activity and represent in many cases the only therapeutic options although clinical data are scarce. The need for a loading dose of colistin has been recently demonstrated to rapidly achieve therapeutic levels. The use of combination therapy is also a matter of debate but current evidence do not support its routine use.

Genetic variants of the MBL2 gene are associated with mortality in pneumococcal sepsis

Studies evaluating associations between polymorphisms of innate immunity genes and prognosis of infectious diseases have yielded conflicting results. Our aim was to assess the impact on mortality of different genotypic variants of the innate immunity in patients with pneumococcal sepsis. All adults admitted to the hospital with diagnosis of sepsis caused by Streptococcus pneumoniae were enrolled and single-nucleotide polymorphisms (SNP) in mannose-binding lectin 2 (MBL2), toll-like receptor (TLR) 2, TLR4, and Fcγ receptor IIa genes were genotyped. Underlying diseases, severity of illness, and antibiotic management were also recorded. We included 117 patients: 98 pneumonias (83.6%), 17 meningitis (14.5%), and 2 patients (1.9%) with primary pneumococcal bacteremia. Allelic variants of the MBL2 gene (individuals heterozygous or homozygous for one of the 3 allelic variants B, C, and D: AO/OO) were present in 37 patients (32%), T399I polymorphism in TLR4 in 19 (16.2%), TLR4 D299G/T399I in 11 (9.4%), TLR2 R753Q in 3 (2.5%), and FcγRIIa-R/R131 in 26 patients (23%). Factors associated independently with in-hospital mortality were SNP MBL2 AO/OO (adjusted hazard ratios [aHR] 3.2, 95% confidence interval [CI] 1.01-9.8) and septic shock (aHR 15.3, 95% CI 3.5-36.5), whereas first adequate antibiotic dose ≤ 4 h was a protective factor (aHR 0.2, 95% CI 0.06-0.8). SNP MBL2 AO/OO (aHR 2.2, 95% CI 1.1-8.1) remained as a variable independently associated with 90-day mortality. In conclusion, variant alleles in the MBL2 gene are independently associated with in-hospital and medium-term mortalities in patients admitted to the hospital with pneumococcal sepsis.

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.