Candidemia in non-neutropenic critically ill patients: analysis of prognostic factors and assessment of systemic antifungal therapy

Objective: To determine the incidence and prognosis of candidemia in non-neutropenic critically ill patients, to define mortality-related factors, and to evaluate the results of systemic antifungal therapy. Design: A prospective multicenter survey in which medical and/or surgical intensive care units (ICUs) in 28 hospitals in Spain participated. Patients: All critically ill patients with positive blood cultures for Candida species admitted to the participating ICUs over a 15-month period were included. Interventions: Candidemia was defined as the presence of at least one positive blood culture containing Candida species. The follow-up period was defined as the time elapsed from the first positive blood culture for Candida species to discharge or death during hospitalization. Antifungal therapy was considered to be “early” when it was administered within 48 h of the date when the first positive blood culture was obtained and “late” when it was administered more than 48 h after the first positive blood culture. Measurements and main results: Candidemia was diagnosed in 46 patients (mean age 59 years), with an incidence of 1 critically ill patient per 500 ICU admissions. The species most frequently isolated were Candida albicans (60%) and C. parapsilosis (17%). Fluconazole alone was given to 27 patients, amphotericin B alone to 10, and sequential therapy to 6. Three patients did not receive antifungal therapy. The overall mortality was 56% and the attributable mortality 21.7%. In the univariate analysis, mortality was significantly associated with a higher Acute Physiology and Chronic Health Evaluation (APACHE) II score at the onset of candidemia (p=0.04) and with the time elapsed between the episode of candidemia and the start of antifungal therapy 48 h or more later (p<0.02). Patients with an APACHE II score lower than 21 at the onset of candidemia had a higher probability of survival than patients who were more seriously ill (p=0.04). Patients with “early” antifungal therapy (≤48 h between the onset of candidemia and the start of antifungal therapy) had a higher probability of survival compared with patients with late therapy (p=0.06). No significant differences were noted between the two groups on different antifungal therapy. Conclusions: The incidence of candidemia in ICU patients was very low. An APACHE II score >20 at the time of candidemia was associated with a higher mortality. Further studies with a large number of patients are needed to assess the effect of early antifungal therapy on the decrease in mortality associated with candidemia and to determine the appropriate dosage of fluconazole and duration of treatment. Received: 7 February 1996 Accepted: 28 September 1996     

The value of a risk model for early-onset candidemia

Bloodstream infections from Candida species are associated with an increased length of stay, increased hospital costs, and higher mortality when compared with bacterial bloodstream infections. Delayed or inappropriate therapy in candidemia leads to increased mortality, thus early recognition becomes paramount. With biomarkers showing promise, blood cultures still remain the gold standard but require 24 to 72 hours for growth. The reliance on epidemiologic risk factors for the initiation of empiric antifungal therapy therefore provides the best method for early appropriate therapy. Shorr and colleagues have devised a risk score to identify patients with early-onset candidemia as defined by positive blood cultures within 2 days of admission, thus allowing for the initiation of early appropriate antifungal therapy.     

Incidence,risk factors,and predictors of outcome of candidemia. Survey in 2 Italian university hospitals

In recent decades, Candida spp. emerged as the fourth most common cause of nosocomial bloodstream infections. The incidence of candidemia was 0.13 per 100 persons. Eighty-three cases (61%) of candidemia were due to Candida albicans and 53 (39%) to nonalbicans Candida spp. Twelve strains of Candida (9%) had shown in vitro resistance to fluconazole, 5 (4%) to itraconazole, 2 (1.5%) to voriconazole, 12 (9%) to 5-flucytosine, and 1 (0.7%) to amphotericin B. Multivariate logistic regression analysis of risk factors showed that length of hospitalization, presence of a central venous catheter, previous episodes of candidemia or bacteremia, parenteral nutrition, and chronic renal failure were variables independently associated with the development of candidemia. Multivariate logistic regression analysis of prognostic indicators showed that the independent variables associated with poor prognosis were inadequate initial therapy (P < .001) and high APACHE III score (P = .004). The inadequate initial therapy associated with mortality indicates the need for additional investigations to define high-risk patients for beneficial antifungal prophylaxis.     

Risk Factors for Fluconazole-Resistant Candidemia

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.Bloodstream infections (BSIs) due to Candida species are a serious complication in hospitalized patients. Candidemia is associated with a high mortality rate and has obvious effects on resource use (11). Over the past few decades, the incidence of candidemia has increased markedly (2, 3). Moreover, the increment of candidemia caused by Candida species other than Candida albicans is a common finding in recent series (3, 12). These species include C. glabrata and C. krusei, which tend to be more resistant to fluconazole and therefore present a particular challenge for clinical management.Diverse studies highlight the importance of early and appropriate empirical therapy in invasive Candida infection (14, 21). Fluconazole is currently considered the initial therapy for most adult patients with candidemia (20). As the selection of empirical therapy is driven in large part by the likely epidemiology, there is a need to identify patients at risk of candidemia caused by species resistant to fluconazole in order to begin with adequate empirical antifungal therapy.In order to provide guidance to clinicians to initiate empirical treatment for candidemia, prior studies have addressed risk factors for candidemia caused by non-albicans Candida spp. (1, 9, 10, 23) or by potentially fluconazole-resistant organisms (Candida glabrata and Candida krusei) (16, 23, 28) but have not taken into consideration in vitro resistance to fluconazole. In these studies, prior fluconazole exposure was an independent risk factor for candidemia caused by non-albicans Candida species (1) or by potentially fluconazole-resistant species (23), whereas other studies did not find this association (16, 28).Therefore, to the best of our knowledge, the risk factors for microbiologically proven fluconazole-resistant Candida spp. BSIs have not been comprehensively studied. We conducted the prospective single-center study described here to identify the variables associated with the diagnosis of fluconazole-resistant candidemia. Our working hypothesis was that fluconazole administration is an independent risk factor only in the emergence of BSIs caused by fluconazole-resistant Candida.     

A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality

Purpose

Candida is the most common cause of severe yeast infections worldwide, especially in critically ill patients. In this setting, septic shock attributable to Candida is characterized by high mortality rates. The aim of this multicenter study was to investigate the determinants of outcome in critically ill patients with septic shock due to candidemia.

Methods

This was a retrospective study in which patients with septic shock attributable to Candida who were treated during the 3-year study period at one or more of the five participating teaching hospitals in Italy and Spain were eligible for enrolment. Patient characteristics, infection-related variables, and therapy-related features were reviewed. Multiple logistic regression analysis was performed to identify the risk factors significantly associated with 30-day mortality.

Results

A total of 216 patients (mean age 63.4 ± 18.5 years; 58.3 % males) were included in the study. Of these, 163 (75 %) were admitted to the intensive care unit. Overall 30-day mortality was 54 %. Significantly higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores, dysfunctional organs, and inadequate antifungal therapy were compared in nonsurvivors and survivors. No differences in survivors versus nonsurvivors were found in terms of the time from positive blood culture to initiation of adequate antifungal therapy. Multivariate logistic regression identified inadequate source control, inadequate antifungal therapy, and 1-point increments in the APACHE II score as independent variables associated with a higher 30-day mortality rate.     

Relationship of fluconazole prophylaxis with fungal microbiology in hospitalized intra-abdominal surgery patients: a descriptive cohort study

Introduction

Historically, Candida albicans has represented the most common cause of candidemia. However, the proportion of bloodstream infections due to non-albicans Candida species has increased. Because of the risk for candidemia in intra-abdominal surgical patients, some experts advocate the use of fluconazole prophylaxis. The impact of this practice on the distribution of Candida species isolated in breakthrough fungal infections in this population is unknown. We examined the association of fluconazole prophylaxis with the distribution of Candida species in intra-abdominal surgery patients.

Methods

We retrospectively identified cases with a positive blood culture (BCx) for Candida among hospitalized adult intra-abdominal surgery patients between July 2005 and October 2012. Distribution of Candida species isolated represented our primary endpoint. Qualifying surgical cases were determined based on a review of discharge International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Patients receiving low-dose fluconazole prior to the positive BCx with a known indication for prophylaxis including neutropenia, ICU exposure or history of organ transplantation were classified as prophylaxis. Appropriateness of fungal treatment was determined by the timing and selection of antifungal agent based on fungal isolate.

Results

Among 10,839 intra-abdominal surgery patients, 227 had candidemia. The most common Candida species isolated was C. albicans (n = 90, 39.6%) followed by C. glabrata (n = 81, 35.7%) and C. parapsilosis (n = 38, 16.7%). Non-albicans Candida accounted for 57.7% of isolates among the 194 non-prophylaxis patients and 75.8% among the 33 prophylaxis patients (P = 0.001). C. glabrata, the most common non-C. albicans species, was more prevalent than C. albicans in persons given prophylaxis, but not in those without prophylaxis. A total of 63% of those with candidemia were treated inappropriately based on the timing and selection of antifungal administration.

Conclusions

Selection pressure from fluconazole prophylaxis in at-risk surgical patients may be associated with a drift toward fluconazole-resistant species in subsequent candidemia. Tools are needed to guide appropriate treatment through the prompt recognition and characterization of candidemia.

     

Fatal candidemia caused by azole-resistant Candida tropicalis in patients with hematological malignancies

Candida tropicalis is one of the most important Candida species causative of candidemia that is isolated from the blood of patients with hematological malignancies. Candidemia caused by C. tropicalis is known to be highly virulent in neutropenic patients. C. tropicalis has been shown to be favorably sensitive to azole agents in general. Here we discuss 5 cases of candidemia caused by C. tropicalis in patients with hematological malignancies in our unit, and we note that 4 isolates were resistant to azole agents, including fluconazole, itraconazole, and voriconazole. In addition, 2 patients developed breakthrough candidemia caused by C. tropicalis while receiving prophylaxis with azole agents. Interestingly, 2 of the 4 patients with azole-resistant C. tropicalis isolates had never received any antifungal drugs. We also examined the susceptibilities of C. tropicalis to antifungal agents, using 39 non-blood isolates detected from 2003 to 2009. Around 40 % of the isolates were resistant to azole agents, and all of them were highly sensitive to amphotericin B and micafungin. The resistance to azoles was not associated with previous exposure to those agents. In our unit, 2 of the 4 cases of candidemia caused by azole-resistant C. tropicalis resulted in a poor prognosis. These findings suggested that empirical therapeutic strategies for candidemia should be modified based on the local antifungal resistance pattern.     

Impact of first-line antifungal agents on the outcomes and costs of candidemia

Candida species are the leading causes of invasive fungal infection among hospitalized patients and are responsible for major economic burdens. The goals of this study were to estimate the costs directly associated with the treatment of candidemia and factors associated with increased costs, as well as the impact of first-line antifungal agents on the outcomes and costs. A retrospective study was conducted in a sample of 199 patients from four university-affiliated tertiary care hospitals in Korea over 1 year. Only costs attributable to the treatment of candidemia were estimated by reviewing resource utilization during treatment. Risk factors for increased costs, treatment outcome, and hospital length of stay (LOS) were analyzed. Approximately 65% of the patients were treated with fluconazole, and 28% were treated with conventional amphotericin B. The overall treatment success rate was 52.8%, and the 30-day mortality rate was 47.9%. Hematologic malignancy, need for mechanical ventilation, and treatment failure of first-line antifungal agents were independent risk factors for mortality. The mean total cost for the treatment of candidemia was $4,743 per patient. Intensive care unit stay at candidemia onset and antifungal switch to second-line agents were independent risk factors for increased costs. The LOS was also significantly longer in patients who switched antifungal agents to second-line drugs. Antifungal switch to second-line agents for any reasons was the only modifiable risk factor of increased costs and LOS. Choosing an appropriate first-line antifungal agent is crucial for better outcomes and reduced hospital costs of candidemia.     

Propensity Score Analysis of the Role of Initial Antifungal Therapy in the Outcome of Candida glabrata Bloodstream Infections

Candida glabrata isolates have reduced in vitro susceptibility to azoles, which raises concerns about the clinical effectiveness of fluconazole for treating bloodstream infection (BSI) by this Candida species. We aimed to evaluate whether the choice of initial antifungal treatment (fluconazole versus echinocandins or liposomal amphotericin B [L-AmB]-based regimens) has an impact on the outcome of C. glabrata BSI. We analyzed data from a prospective, multicenter, population-based surveillance program on candidemia conducted in 5 metropolitan areas of Spain (May 2010 to April 2011). Adult patients with an episode of C. glabrata BSI were included. The main outcomes were 14-day mortality and treatment failure (14-day mortality and/or persistent C. glabrata BSI for ≥48 h despite antifungal initiation). The impact of using fluconazole as initial antifungal treatment on the patients'' prognosis was assessed by logistic regression analysis with the addition of a propensity score approach. A total of 94 patients with C. glabrata BSI were identified. Of these, 34 had received fluconazole and 35 had received an echinocandin/L-AmB-based regimen. Patients in the echinocandin/L-AmB group had poorer baseline clinical status than did those in the fluconazole group. Patients in the fluconazole group were more frequently (55.9% versus 28.6%) and much earlier (median time, 3 versus 7 days) switched to another antifungal regimen. Overall, 14-day mortality was 13% (9/69) and treatment failure 34.8% (24/69), with no significant differences between the groups. On multivariate analysis, after adjusting for baseline characteristics by propensity score, fluconazole use was not associated with an unfavorable evolution (adjusted odds ratio [OR] for 14-day mortality, 1.16, with 95% confidence interval [CI] of 0.22 to 6.17; adjusted OR for treatment failure, 0.83, with 95% CI of 0.27 to 2.61). In conclusion, initial fluconazole treatment was not associated with a poorer outcome than that obtained with echinocandins/L-AmB regimens in patients with C. glabrata BSI. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01236261","term_id":"NCT01236261"}}NCT01236261.)     

Epidemiology and outcomes of candidemia in 3648 patients: data from the Prospective Antifungal Therapy (PATH Alliance®) registry, 2004–2008

This analysis describes the epidemiology and outcomes of candidemia in patients enrolled in the Prospective Antifungal Therapy Alliance (PATH Alliance®) registry from 2004 to 2008. Overall, 4067 Candida isolates were identified from 3648 patients. The most common Candida spp. were C. albicans (42.1%), C. glabrata (26.7%), C. parapsilosis (15.9%), C. tropicalis (8.7%), and C. krusei (3.4%). The proportion of candidemia caused by non-albicans Candida spp. (57.9%) was higher than that caused by C. albicans (42.1%). Infections with C. albicans were most common in neonatal intensive care unit (54.8%). In total, 3342 patients received antifungal therapy; fluconazole (66.0%) and echinocandins (50.5%) were most frequently administered. The 90-day survival rate for all patients was 61.3%. Among the most common Candida spp., the highest 90-day survival rate was observed for C. parapsilosis (70.0%) and the lowest for C. krusei (53.6%). In conclusion, this study expands the current knowledge of the epidemiology and outcomes of candidemia.     

Risk factors and outcomes of candidemia caused by Candida parapsilosis complex in a medical center in northern Taiwan

To investigate the risk factors and outcomes associated with Candida parapsilosis candidemia, a retrospective study was conducted at a tertiary medical center in northern Taiwan. Patients with C. parapsilosis candidemia and corresponding controls with C. albicans candidemia were chosen and their demographics, comorbidities, risk factors, and clinical outcomes were reviewed. Antifungal susceptibility tests were performed using the Sensititre YeastOne colorimetric system. Matrix-assisted laser desorption ionization–time of flight mass spectrometry was used to classify the genomic species. Of the 270 candidemias found in 253 patients, C. albicans was the most common Candida species isolated (43.0%), followed by C. parapsilosis (22.6%), C. tropicalis (17.4%), and C. glabrata (10.0%). The 30-day mortality of C. parapsilosis candidemia was significantly lower than that of C. albicans candidemia (21.7% vs. 53.9%, P < 0.001). C. parapsilosis was positively associated with antifungal agent exposure [OR 7.261 (95% CI, 1.603–32.879), P = 0.010], but negatively associated with Candida colonization [OR 0.303 (95% CI, 0.123–0.745), P = 0.009], and immunosuppressant use [OR 0.264 (95% CI, 0.099–0.705), P = 0.008]. In-hospital mortality was associated with the Sequential Organ Failure Assessment Score [OR 1.255 (95% CI, 1.002–1.573), P = 0.048]. The clinical outcomes did not differ across genomic species and in the minimum inhibitory concentrations of fluconazole.     

Epidemiology and outcome of multiple-species candidemia at a tertiary care center between 2004 and 2007

The incidence of multiple-species candidemia (MSC) among cases of candidemia ranges between 2.8% and 8.0%. We sought to study the epidemiology and outcome of MSC at a tertiary care center. A retrospective analysis of MSC episodes occurring between 2004 and 2007 was performed. MSC was defined as ≥2 different Candida spp. growing concomitantly within the same blood culture bottle or within 72 h of each other. Information on demographics, comorbidities, antifungal use, and survival was collected. Forty MSC patients with 81 Candida isolates were identified. Non-albicans Candida spp. (54 of 81 isolates, 66.7%) were more frequently identified. The most common combinations observed were Candida albicans/Candida glabrata (15 of 40 patients, 37.5%), C. albicans/Candida parapsilosis (8, 20.0%), and C. glabrata/Candida krusei (5, 12.5%). The overall crude 4- and 12- week mortality, excluding patients lost to follow-up, was 41.9% and 66.7%, respectively. In this contemporary sampling of patients with MSC, the combination of C. albicans/C. glabrata was most frequently observed and mortality was high.     

An approach to develop clinical prediction rule for candidemia in critically ill patients: A retrospective observational study

PurposeEarly detection of candidemia in critically ill patients is important for preemptive antifungal treatment. Our study aimed to identify the independent risk factors for the development of a new candidemia prediction score.MethodsThis single-centre retrospective observational study evaluated 2479 intensive care unit (ICU) cases from January 2016 to December 2018. A total of 76 identified candidemia cases and 76 matched control cases were analyzed. The patients' demographic characteristics and illness severity were analyzed, and possible risk factors for candidemia were investigated.ResultsMultivariate logistic regression analysis identified renal replacement therapy (RRT) (odds ratio [OR]: 52.83; 95% confidence interval [CI]: 7.82–356.92; P < 0.0001), multifocal Candida colonization (OR: 23.55; 95% CI: 4.23–131.05; P < 0.0001), parenteral nutrition (PN) (OR: 63.67; 95% CI: 4.56–889.77; P = 0.002), and acute kidney injury (AKI) (OR: 7.67; 95% CI: 1.24–47.30; P = 0.028) as independent risk factors. A new prediction score with a cut-off value of 5.0 (80.3% sensitivity and 77.3% specificity) was formulated from the logit model equation.ConclusionsRenal replacement therapy, AKI, PN, and multifocal Candida colonization were the independent risk factors for the new candidemia prediction score with high discriminatory performance and predictive accuracy.     

Cost-effectiveness of micafungin as an alternative to fluconazole empiric treatment of suspected ICU-acquired candidemia among patients with sepsis: a model simulation

Introduction  

Recent epidemiologic literature indicates that candidal species resistant to azoles are becoming more prevalent in the face of increasing incidence of hospitalizations with candidemia. Echinocandins, a new class of antifungal agents, are effective against resistant candidal species. As delaying appropriate antifungal coverage leads to increased mortality, we evaluated the cost-effectiveness of 100 mg daily empiric micafungin (MIC) vs. 400 mg daily fluconazole (FLU) for suspected intensive care unit-acquired candidemia (ICU-AC) among septic patients.     

Association of fluconazole pharmacodynamics with mortality in patients with candidemia

Recent studies of nonneutropenic patients with candidemia or candidiasis suggest that fluconazole pharmacodynamic parameters correlate with clinical outcomes; however, additional data of correlation to mortality in patients with candidemia would be valuable. We assessed the impact of MICs for Candida, fluconazole pharmacodynamics, and patient characteristics on all-cause mortality with use of a prospective cohort of 96 hospitalized patients with candidemia. Among 84 patients for whom Candida isolates were available for testing, the most frequent Candida species isolated were Candida albicans (44%), followed by Candida parapsilosis (20.2%), and Candida glabrata (20.2%). Fluconazole resistance (MIC of ≥64 μg/ml) was present in 7 (8.3%) to 10 (11.9%) of 84 isolates, depending on the MIC endpoint determination method (50% or 80% inhibition read at 24 or 48 h). Overall mortality occurred in 27 (28.1%) of 96 patients, and nonsurvivors were more likely to have fluconazole-resistant isolates (25% versus 6.7%; P = 0.02). Multivariable analysis demonstrated an association between fluconazole resistance and mortality, but it did not reach statistical significance (odds ratio, 5.3; 95% confidence interval, 0.8 to 33.4; P = 0.08). By pharmacodynamic analysis, a fluconazole area under the concentration-time curve/MIC of <11.5 or MIC of ≥64 was associated with increased patient mortality (P ≤ 0.09). These data support previous findings of an antifungal exposure-response relationship to mortality in patients with candidemia. In addition, similar MICs were obtained using a 24- or 48-h MIC endpoint determination, thus providing the opportunity to assess earlier the impact of isolate susceptibility on therapy.     

Effects of Empiric Antifungal Therapy for Septic Shock on Time to Appropriate Therapy for Candida Infection: A Pilot Study

Purpose

Inappropriate initial therapy for Candida-related septic shock is common and associated with a high mortality rate. This before-after pilot study was conducted to determine the feasibility of using empiric therapy for reducing the time to appropriate antifungal therapy in patients with Candida-related septic shock.

Methods

Patients aged 18–99 years with septic shock presenting to Barnes-Jewish Hospital, St. Louis, Missouri, in 2012–2013 were assigned to 1 of 2 groups. Patients presenting between January 1, 2012, and December 31, 2012, were managed according to local standard of care for patients with septic shock, to include antifungal therapy at the discretion of the treating physician (standard therapy group). Patients presenting between January 1, 2013, and December 31, 2013, received empiric antifungal therapy (primarily micafungin 100 mg/d or fluconazole 800 mg on day 1, followed by 400 mg/d), facilitated by a clinical pharmacist in the medical intensive care unit, until microbiologic cultures were available to determine the cause of septic shock (empiric therapy group). The primary outcome was time to appropriate therapy after shock onset.

Findings

A total of 28 patients were enrolled (mean age, 56.3 [15.1] years [range, 30–92 years]; 16 [57.1%] men). The time to appropriate therapy after shock onset was statistically shorter with empiric therapy (n = 13) compared with standard therapy (n = 15) (10.6 [15.8] vs 40.5 [26.0] hours; P = 0.001). Patients receiving empiric therapy were more likely to have received appropriate therapy within 12 hours (69.2% vs 6.7%; P = 0.001) and within 24 hours (76.9% vs 40.0%; P = NS) of shock onset. In an analysis to determine the number of septic shock patients needed to be treated with empiric antifungal therapy for 1 patient with Candida-related septic shock to receive appropriate treatment, 256 patients without Candida infection received a total of 687 doses of empiric antifungal therapy (mean, 2.7 doses per patient) compared with 136 patients who received 382 doses of standard antifungal therapy (mean, 2.8 doses per patient); the number needed to treat was 19.6.

Implications

The present pilot study demonstrated that the use of empiric antifungal therapy for Candida-related septic shock was associated with a statistically shorter time to administration of appropriate treatment. ClinicalTrials.gov identifier.     

The SOFA score could predict the severity and prognosis of infective endocarditis

IntroductionAlthough infectious endocarditis (IE) is a potentially severe infectious disease, there are no prognostic tools for in-hospital mortality for IE patients. This is the first report documenting that the Sequential Organ Failure Assessment (SOFA) score could evaluate the severity and outcome among IE patients.Patients and methodsFrom 2007 to 2018, we reviewed all patients who were diagnosed as having IE at our institue. Patients diagnosed as definite IE according to the modified Duke criteria or by surgical procedure were included in this study.ResultsA total of 66 IE patients were enrolled in this study. They were 45 males (68%) and the median age was 70 years. As for prognostic factors for in-hospital death among IE patients, SOFA score ≥6, CCI ≥3, surgical procedure, heart failure, immunological phenomena and detection of S. aureus as a causative pathogen were identified as prognostic factors by univariate analysis. Of these 6 factors, SOFA score ≥6 (OR 7.6, 95%CI 1.3–46.6, p = 0.029), heart failure (OR 9.7, 95%CI 1.1–86.1, p = 0.042), surgery (OR 0.1, 95%CI 0–0.8, p = 0.037) and immunological phenomena (OR 0.1, 95%CI 0–0.9, p = 0.042) were independent prognostic factors for in-hospital mortality among IE by logistic regression analysis.ConclusionThe SOFA score could be a good prognostic tool to use for IE patients. Also, SOFA score ≥6, surgery, immunological phenomena and heart failure were independent prognostic factors for in-hospital mortality among IE patients.     

Could risk assessment for non-albicans Candida improve empiric treatment for invasive candidiasis?

The changing epidemiology of invasive candidiasis, along with concerns for the emergence of drug resistance, necessitates the identification of patients at increased risk of non-albicans Candida (NAC) to optimize selection of antifungal therapy. The major findings of a study regarding the demographic characteristics, costs, and outcomes of nonneutropenic patients with candidemia due to NAC are discussed. Given available treatment options, such risk assessment is most relevant to initial empiric therapy in stable patients without neutropenia who might be candidates for initial therapy with an azole (eg, fluconazole). The study's investigators reinforce the need for timely antifungal therapy for patients with candidemia.     

Effect of Antifungal Therapy Timing on Mortality in Cancer Patients with Candidemia

Prior studies have shown that delays in treatment are associated with increased mortality in patients with candidemia. The purpose of this study was to measure three separate time periods comprising the diagnosis and treatment of candidemia and to determine which one(s) is associated with hospital mortality. Patients with blood cultures positive for Candida spp. were identified. Subjects were excluded if no antifungal therapy was given or if there was preexisting antifungal therapy. Collected data included the time from blood culture collection to positivity (incubation period), the time from blood culture positivity to provider notification (provider notification period), and the time from provider notification to the first dose of antifungal given (antifungal initiation period). These times were assessed as predictors of inpatient mortality. A repeat analysis was done with adjustments for age, sex, race, underlying cancer, catheter removal, APACHE III score, acute renal failure, neutropenia, and non-Candida albicans species. A total of 106 episodes of candidemia were analyzed. The median incubation time was 32.1 h and was associated with mortality (univariate hazard ratio per hour, 1.025; P = 0.001). The median provider notification and antifungal initiation periods were 0.3 and 7.5 h, respectively, and were not associated with mortality. Adjusted analysis yielded similar results. For cancer patients with candidemia, the incubation period accounts for a significant amount of time, compared with the provider notification and antifungal initiation times, and is associated with in-hospital mortality. Strategies to shorten the incubation time, such as utilizing rapid molecularly based diagnostic methods, may help reduce in-hospital mortality.Candidemia has been reported to be the fourth most common hospital-associated bloodstream infection in the United States (48). Estimates of its attributable mortality are substantial (14, 47). Among cancer patients, candidemia also contributes to overall mortality. According to one study, candidemia was thought to play either a primary or a secondary role in about two-thirds of all deaths in infected cancer patients (46).For the general patient with candidemia, reported predictors of mortality include, but are not limited to, age, duration of hospitalization, severity-of-illness score, acute renal failure, intensive care unit (ICU) stay, retention of a central venous catheter, mechanical ventilation, non-Candida albicans Candida species, and persistence of the candidemia (5, 11, 21, 28). These variables are also risk factors in the cancer patient population, with some additional predictors: neutropenia, hematologic malignancy, visceral dissemination, poor performance status, and stage of disease (2, 29, 43).In addition to all of these associations, two studies that were performed on general patients with candidemia have demonstrated that a delay in antifungal therapy is associated with an increase in mortality (13, 27). In both of these studies, delays were analyzed by measuring the time from blood culture collection to the initiation of antifungal therapy. However, during this overall time interval, several different events occur: the collected blood culture incubates until it becomes positive; the positive result is conveyed to the health care provider, who interprets its clinical significance; the health care provider decides whether to prescribe therapy, and if so, the drug has to be administered to the patient. Although the overall time interval has been demonstrated to be associated with mortality, it is not clear if a delay in one, two, or all of these components leads to the observed increased mortality, since no prior studies have examined these events separately. In addition, no prior studies have examined antifungal delay specifically for the cancer patient population. In this study, we sought to measure the duration of each event occurring from blood culture collection to the initiation of antifungal therapy in episodes of candidemia in cancer patients and to see which, if any, of these events were associated with mortality.     

Clinical significance of Candida colonization of intravascular catheters in the absence of documented candidemia

In order to assess the significance of Candida colonization of intravascular catheters (IVC) in patients without documented candidemia, we retrospectively reviewed all Candida-positive IVC tip cultures over a 4-year period. Cases were defined as those with a culture yielding ≥15 colony-forming units of Candida spp. that either did not have blood cultures (BC) taken or had concomitant BC negative for Candida. Patients were followed up until death or 8 months after discharge. Risk factors for poor outcome following IVC removal (death, candidemia, or Candida-related complication) were analyzed. We analyzed a total of 40 patients. Overall mortality was 40.0%, with no death directly attributed to Candida infection. Twenty-two patients received antifungal therapy at the time of IVC removal. Only 1 patient developed a metastatic complication (chorioretinitis) attributable to transient candidemia (2.5% of the global cohort and 3.7% among those with concomitant BC). There were no cases of subsequent candidemia. In the multivariate analysis, the use of antifungal therapy did not show any impact on the risk of poor outcome. The risk of invasive disease in patients with isolated IVC colonization by Candida seems to be low. Nevertheless, the initiation of systemic antifungal therapy should be carefully considered in such context.