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Efficacy of micafungin in invasive candidiasis caused by common Candida species with special emphasis on non- albicans Candida species
Abstract
The incidence of invasive candidiasis caused by non-albicans Candida (NAC) spp. is increasing. The aim of this analysis was to evaluate the efficacy of micafungin, caspofungin and liposomal amphotericin B in patients with invasive candidiasis and candidaemia caused by different Candida spp. This post hoc analysis used data obtained from two randomised phase III trials was conducted to evaluate the efficacy and safety of micafungin vs. caspofungin and micafungin vs. liposomal amphotericin B. Treatment success, clinical response, mycological response and mortality were evaluated in patients infected with C. albicans and NAC spp. Treatment success rates in patients with either C. albicans or NAC infections were similar. Outcomes were similar for micafungin, caspofungin and liposomal amphotericin B. Candida albicans was the most prevalent pathogen recovered (41.0%), followed by C. tropicalis (17.9%), C. parapsilosis (14.4%), C. glabrata (10.4%), multiple Candida spp. (7.3%) and C. krusei (3.2%). Age, primary diagnosis (i.e. candidaemia or invasive candidiasis), previous corticosteroid therapy and Acute Physiology and Chronic Health Evaluation II score were identified as potential predictors of treatment success and mortality. Micafungin, caspofungin and liposomal amphotericin B exhibit favourable treatment response rates that are comparable for patients infected with different Candida spp.
... The decreased susceptibility of non-albicans species to azoles and echinocandins has been reported [50][51][52]. The proportion of isolates with resistance to fluconazole was 9%, similar to the findings of previous studies that reported a low proportion of resistance in isolates from C. albicans, C. parapsilosis, and C. tropicalis, unlike global resistance in C. krusei and increasing resistance in C. glabrata [4,7,[53][54][55][56][57]. ...
... However, in the multivariate analysis, the diagnostic group (HR 1.72; p = 0.04) and ICU admission (HR 3.08; p =< 0.01) were the variables that maintained their association with statistical significance as risk factors for mortality in patients with fungemia. Septic shock and ICU admission have been widely described as a risk factors associated with mortality [10,14,15,33,50,58]; however, there is little information in the literature regarding the study of mortality according to the type of hematologic neoplasia [34]. ...
Fungemia in hematologic malignancies (HM) has high mortality. This is a retrospective cohort of adult patients with HM and fungemia between 2012 and 2019 in institutions of Bogotá, Colombia. The epidemiological, clinical, and microbiological characteristics are described, and risk factors related to mortality are analyzed. One hundred five patients with a mean age of 48 years (SD 19.0) were identified, 45% with acute leukemia and 37% with lymphomas. In 42%, the HM was relapsed/refractory, 82% ECOG > 3, and 35% received antifungal prophylaxis; 57% were in neutropenia, with an average duration of 21.8 days. In 86 (82%) patients, Candida spp. was identified, and other yeasts in 18%. The most frequent of the isolates were non-albicans Candida (61%), C. tropicalis (28%), C. parapsilosis (17%), and C. krusei (12%). The overall 30-day mortality was 50%. The survival probability at day 30 in patients with leukemia vs. lymphoma/multiple myeloma (MM0 group was 59% (95% CI 46–76) and 41% (95% CI 29–58), p = 0.03, respectively. Patients with lymphoma or MM (HR 1.72; 95% CI 0.58–2.03) and ICU admission (HR 3.08; 95% CI 1.12–3.74) were associated with mortality. In conclusion, in patients with HM, non-albicans Candida species are the most frequent, and high mortality was identified; moreover, lymphoma or MM and ICU admission were predictors of mortality.
... However, an increase in the number of fungal infections caused by non-albicans species, such as C. glabrata or C. krusei, showing natural resistance to fluconazole (Choi et al., 2009), is the reason for the application of echinocandins. Infections caused by C. glabrata are now the second most common cause of candidaemia in North America and Europe (Pappas et al., 2015), and result in increased mortality rates in patients with candidaemia (Cornely et al., 2014). The frequency of echinocandin resistance among Candida spp. ...
Purpose:
Candida spp. are ranked as one of the four major causative agents of fungal infections. The number of infections caused by Candida species resistant to fluconazole, which is applied as the first line drug in candidiasis treatment, increases every year. In such cases the application of echinocandin is necessary. Echinocandin susceptibility testing has become a routine laboratory practice in many countries due to the increasing frequency of clinical failures during treatment with these drugs.
Methods:
We performed anidulafungin, micafungin and caspofungin susceptibility testing according to the microdilution broth method on 240 Candida isolates collected in Polish hospitals.
Results:
We identified 12 isolates resistant to all echinocandins within 240 examined isolates. Moreover, 6 of the examined samples were identified as rare Candida species and among them we observed very high echinocandin MIC values.
Conclusion:
Our research proves that in Poland there is a problem of echinocandin resistance. Moreover, we identified two species of Candida which are rare causative agents of human infections, and there was no reported incidence of such infections in Poland until now.
... While most published studies were performed at large centers [3,4,11,21,31], our patients differ in risk factors. We report less Microbiological work-up closely followed current ESCMID recommendations including identification to species level and susceptibility testing. ...
Candidemia epidemiology varies significantly by region; thus, local data are essential for evidence-based decision-making in prophylaxis and treatment. Current management strategies are derived from large randomized controlled trials mostly executed in large high-volume tertiary care centers. Results may not be entirely transferable to smaller hospitals. This study investigates epidemiology, diagnosis, and treatment standards in six hospitals in the Cologne metropolitan area (number of inhabitants approx. one million). We assessed adherence to the current guideline of the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and the Infectious Diseases Society of America (IDSA) using the EQUAL Candida Score of the European Confederation of Medical Mycology (ECMM). Data were documented by trained medical students as part of an integrated research and teaching concept at the University of Cologne. Between January 2014 and June 2017, 77 patients had candidemia, corresponding to an incidence of 0.2 cases/1000 admissions. While 55 patients were enrolled, 22 patients were excluded due to incompletely retrievable health records. Fluconazole monotherapy was the preferred first-line treatment in cases with Candida albicans infection (21/29). A central vascular catheter was present in 40 patients and was removed in 17 (43%) during treatment. Overall mortality at 30 days was 44%. Patients reached a mean EQUAL Candida Score of 9.9 (range 8–14), which was well below the maximum score of 22 for perfect guideline adherence. In summary, management of candidemia differed from current European recommendations. It remains unclear to what extent enhanced adherence would improve patient outcome. Larger prospective studies need to answer that question.
... The IDSA accepts fluconazole as first line treatment and as an alternative for these patients while only giving a weak recommendation with low-quality evidence. Based on the results of multiple RCT, candidemia (without metastatic complications) shall be treated 14 days from the first negative culture with systemic antifungal agents [36][37][38][39][40] . In general, this has been associated with few complications and relapses to date. ...
Candida species frequently cause blood stream infections and are reported to be the third to tenth most commonly isolated pathogens. Guidelines and standardized treatment algorithms provided by professional organisations aim to facilitate decision-making regarding diagnosis, management, and treatment of candidemia. In routine clinical practise, however, it may be challenging to comply with these guidelines. The reasons include lack of familiarity or feasibility to adherence, but also their length and complexity. There is no tool to measure guideline adherence currently. To provide such a tool, we reviewed the current guidelines provided by the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and by the Infectious Diseases Society of America (IDSA), and selected the strongest recommendations for management quality as the bases for our scoring tool. Factors incorporated were diagnostic (blood cultures, echocardiography, ophthalmoscopy, species identification) and follow-up procedures (repeat blood cultures until negative result) as well as key treatment parameters (echinocandin treatment, step down to fluconazole depending on susceptibility result, CVC removal). The EQUAL Candida Score weighs and aggregates factors recommended for the ideal management of candidemia and provides a tool for antifungal stewardship as well as for measuring guideline adherence.
... AUTHOR PLEASE ANSWER ALL QUERIES 1 ...
C. guilliermondii shows intrinsic reduced echinocandin susceptibility. It harbors two polymorphisms (L633M and T634A) at the Fks1p hot-spot 1 region. Our objective was to confirm that C. guilliermondii's reduced echinocandin susceptibility is due to those naturally occurring substitutions. We constructed a Saccharomyces cerevisiae mutant where a region of its FKS1 gene (including hot-spot 1) was replaced with that from C. guilliermondii . The chimeric mutants showed 32-fold echinocandin MIC values increase confirming the hypothesis.
... Other prognostic factors in ICU patients are APACHE II score, age, corticosteroid therapy and primary diagnosis (invasive candidiasis vs. candidaemia). 5 Early and reliable diagnosis, however, remains a challenge as blood culturesthe gold standard for diagnosis of IFIshow low sensitivity (<50%), and diagnosis based on radiological as well as clinical signs comes usually too late. 6,7 Nevertheless, rapid initiation of proper AF therapy is crucial to reduce mortality among critically ill patients. ...
... La instauración de un tratamiento antifúngico agresivo, según cultivos, más allá de la profilaxis con fluconazol, debe ser comenzado ante la sospecha clínica 10 . ...
La perforación asociada a infección intraabdominal difusa por Candida spp. es excepcional. Suele asociarse a pacientes inmunodeprimidos o con enfermedad tumoral avanzada. Presentamos 2 casos de perforación digestiva secundaria a candidiasis invasiva. En el primer caso, una mujer de 68 años con una perforación duodenal secundaria a Candida spp., se realiza laparotomía exploradora y reparación de la perforación duodenal. Sin embargo, la paciente requiere más de 2 intervenciones, observándose Candida spp. macroscópica diseminada por toda la cavidad abdominal. El segundo caso es el de un varón de 60 años que presenta un postoperatorio complicado de una hemicolectomía derecha, que se asocia con pancretitis, y con posterior diseminación fúngica abdominal secundaria a Candida parapsilopsis, con múltiples complicaciones infecciosas.
... [71][72][73][74][75] Micafungin, an equal alternative to CAS, is the only echinocandin approved for use in infants aged less than 3 months in European Union and Japan. 76 A population pharmacokinetics study of micafungin in neonates and young infants showed that a higher weight-based dose is required for infants compared with adults to achieve effective drug concentrations within the CNS. 77 According to an analysis of 9 clinical trials conducted, micafungin has a substantial efficacy with a reported treatment of invasive candidiasis reaching 73% in both premature and nonpremature groups. ...
Fungal endocarditis (FE) remains an uncommon but life-threatening complication of invasive fungal infections. As data on neonatal FE are scant, we aimed to review all published experience regarding this serious infection.
Neonatal FE cases published in PubMed (1971-2013) as single cases or case series were identified using the terms "fungal endocarditis, neonates, cardiac vegetation". Data on predefined criteria including demographics, predisposing factors, mycology, sites of cardiac involvement, therapy and outcome were collected and analyzed.
The dataset comprised of 71 neonates with FE. Median birth weight was 940 g (IQR 609), median gestational age 27 wks (IQR 6) and median postnatal age at diagnosis 20 d (IQR 20). Ninety-two percent of the patients were premature. Right atrium was the most common vegetation site (63%). Seventy one percent of cases reported were associated with previous central venous catheters. Candida albicans was the most predominant fungal species (59%). Amphotericin B (AMB) monotherapy was used in 42.2% and fluconazole in 2.8%. AMB with flucytosine (25.3%) was the most frequent combined regimen. Surgical treatment was conducted in 28%. Overall mortality was 42.2%. Initiation with combined antifungal treatment was associated with lower mortality than monotherapy (24.2% vs 51.7%, respectively, p=0.036).
Neonatal FE most frequently occurs in very premature infants and is associated with central venous catheters. Candida albicans is the predominant fungus. Although outcome has been dismal, it may be improved with combined antifungal therapy.
... Other prognostic factors in ICU patients are APACHE II score, age, corticosteroid therapy and primary diagnosis (invasive candidiasis vs. candidaemia). 5 Early and reliable diagnosis, however, remains a challenge as blood culturesthe gold standard for diagnosis of IFIshow low sensitivity (<50%), and diagnosis based on radiological as well as clinical signs comes usually too late. 6,7 Nevertheless, rapid initiation of proper AF therapy is crucial to reduce mortality among critically ill patients. ...
The purpose of this study was to evaluate a preemptive approach with serum 1,3-beta-d-glucan (BDG) as a marker for treatment stratification of systemic antifungal (AF) therapy in patients with clinical suspected invasive fungal infections (IFI) at intensive care units (ICU), and the impact of surgical procedures. A total of 66 ICU patients with clinical suspected IFI were included in this retrospective analysis. Serum BDG testing was performed prior to initiation of AF treatment and in addition to routine diagnostic measures. Based on the BDG results the initial clinical decision whether or not to start systemic AF therapy was re-evaluated. Impact of surgical procedures on clinical utility of serum BDG was evaluated in a sub-group of 25 patients who had undergone surgical procedures prior to BDG evaluation. BDG test results led to discontinuation of AF therapy in 13 patients, and initiation of AF therapy in seven patients. In 46 patients the clinical decision was confirmed by BDG. The majority of suspected, probable and proven IFI cases (10/13, 77%) was predicted by the test. BDG testing turned out positive in 9/25 (36%) of patients that had undergone recent surgery and levels correlated with clinical findings. Serum BDG evaluation seems to be a promising tool to guide AF therapy in ICU patients even after recent surgical procedures.
Background
Invasive fungal diseases remain a major cause of morbidity and mortality in cancer patients undergoing intensive cytotoxic therapy. The choice of the most appropriate antifungal treatment (AFT) depends on the fungal species suspected or identified, the patient’s risk factors (e.g. length and depth of granulocytopenia) and the expected side effects.
Objectives
Since the last edition of recommendations for “Treatment of invasive fungal infections in cancer patients” of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) in 2013, treatment strategies were gradually moving away from solely empirical therapy of presumed or possible invasive fungal diseases (IFD) towards pre‐emptive therapy of probable IFD.
Methods
The guideline was prepared by German clinical experts for infections in cancer patients in a stepwise consensus process. Medline was systematically searched for English language publications from January 1975 up to September 2019 using the key terms such as “invasive fungal infection” and/or “invasive fungal disease” and at least one of the following: antifungal agents, cancer, hematological malignancy, antifungal therapy, neutropenia, granulocytopenia, mycoses, aspergillosis, candidosis, mucormycosis.
Results
AFT of IFDs in cancer patients may include not only antifungal agents but also non‐pharmacologic treatment. In addition, the armamentarium of antifungals for treatment of IFDs has been broadened (e.g. licensing of isavuconazole). Additional antifungals are currently under investigation or in clinical trials.
Conclusions
Here, updated recommendations for the treatment of proven or probable IFDs are given. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to key information.
Neonates and immunosuppressed/immunocompromised pediatric patients are at high risk of invasive fungal diseases. Appropriate antifungal selection and optimized dosing are imperative to the successful prevention and treatment of these life-threatening infections. Conventional amphotericin B was the mainstay of antifungal therapy for many decades, but dose-limiting nephrotoxicity and infusion-related adverse events impeded its use. Despite the development of several new antifungal classes and agents in the past 20 years, and their now routine use in at-risk pediatric populations, data to guide the optimal dosing of antifungals in children are limited. This paper reviews the spectra of activity for approved antifungal agents and summarizes the current literature specific to pediatric patients regarding pharmacokinetic/pharmacodynamic data, dosing, and therapeutic drug monitoring.
Echinocandins are used for treatment of invasive candidiasis, but data on their use in children are limited. We sought to describe the epidemiology of echinocandin use in hospitalized children in the United States.
We performed a retrospective cohort study of children <18 years of age hospitalized between January 2005 and December 2015 and exposed to ≥1 day of a systemic antifungal agent using the Pediatric Health Information System (PHIS) database. Univariate analyses compared recipients of two echinocandin agents, caspofungin and micafungin. Crude prescribing rates of each antifungal group were calculated across hospitals and per year. The rate of antifungal agent prescribing over time was assessed using two-level mixed-effects negative binomial regression, accounting for variability in prescribing by hospital over time. From 2005 to 2015, fluconazole was prescribed most often (n = 148,859, 74.3%), followed by mould-active triazoles (n = 36,131, 18.0%), amphotericin products (n = 29,008, 14.5%), and echinocandins (n = 28,371, 14.2%). The crude rate of systemic antifungal prescribing decreased across all PHIS hospitals from 36.3 to 33.8 per 1000 admissions during the study period, but echinocandin prescribing increased from 2.2 to 7.2 per 1000 admissions. A mixed effects regression model revealed that echinocandin prescribing increased by 15.1% per year (95% CI 11.2–19.2). Echinocandin administration increased from 6.1% to 21.0% of admissions during which a systemic antifungal agent was given. In conclusion, echinocandin use has increased significantly over time, accounting for an increasing proportion of systemic antifungal prescribing in children.
Background:
Echinocandins are recommended for the treatment of suspected or confirmed invasive candidiasis (IC) in adults. Less is known about the use of echinocandins for the management of IC in children. The aim of this study was to investigate the overall efficacy and safety of echinocandin class in neonatal and pediatric patients with IC.
Methods:
PubMed, Cochrane Central, Scopus and Clinical trial registries were searched up to July 27, 2017. Eligible studies were randomized trials (RCTs) that evaluated the efficacy and safety of any echinocandin versus agents of other antifungal classes for the treatment of IC in pediatric patients. The primary outcome was treatment success with resolution of symptoms and signs, and absence of IC. In the meta-analysis a random effects model was used, and the odds ratio (OR) and 95% confidence intervals (CI) were calculated.
Results:
Four randomized clinical trials (324 patients), 2 confirmed IC (micafungin vs. liposomal amphotericin B and caspofungin vs. liposomal amphotericin B) and 2 empirical therapy trials (caspofungin vs. deoxycholate amphotericin B and caspofungin vs. liposomal amphotericin B) were included. There was no significant difference between echinocandins and comparator in terms of treatment success (OR=1.61, 95% CI 0.74-3.50) and incidence of treatment-related adverse events (OR=0.70, 95% CI 0.39-1.26). However, fewer children treated with echinocandins discontinued treatment due to adverse events than amphotericin B formulations (OR=0.26, 95% CI 0.08-0.82, p=0.02).
Conclusions:
In the treatment of IC in children echinocandins show non-inferior efficacy compared to amphotericin B formulations with fewer discontinuations than in comparator arm.
Fungal infections represent a major and increasing threat to public health resulting in a growing demand for new drugs. The genus Hypericum is a rich source of bioactive secondary metabolite, including antimicrobials and the exploration of uninvestigated species holds the potential for the discovery of novel molecules for the pharma- ceutical market. Here the chemical composition, phytochemical relationships and the antifungal potential of seven of neglected Andean Hypericum species has been investigated. Through liquid chromatography and mass spectrometry analysis, 34 phenolic compounds have been identified and quantified. Quercetin derivatives, ca- techin and epicatechin, procyanidin B2 and chlorogenic acid derivatives represented the most abundant com- pounds in all extracts. The antifungal activity was evaluated against a panel of clinical isolates of pathogenic fungi. Four of the tested extracts were active against C. albicans (MIC50 < 353.25 μg/ml) and five against C. parapsilosis (MIC50 < 1000 μg/ml). Noteworthy was the activity of H. garciae, that was subjected to a com- prehensive investigation against a broad panel of Candida spp. clinical strains. H. garciae extracts showed higher activity than fluconazole against C. intermedia and C. parapsilosis. The methanolic extract was active against all of the tested species with MIC50 values as low as 4 μl/ml and 5 μl/ml against C. lusitaniae and C. albicans respec- tively and 64 μl/ml against C. glabrata. The chloroformic extract displayed a higher activity than fluconazole against C. tropicalis. The presented data represent an advancement in the knowledge of the chemistry and an- tifungal potential of Hypericum species and offer interesting suggestions for deeper studies in the field of che- motaxonomy and drug discovery.
Pediatric infective endocarditis (PIE) is an infection of the endocardial surface of a child’s heart. Children with abnormal hearts from congenital heart disease are at higher risk for PIE. This chapter describes the epidemiology, etiology, diagnosis, treatment and prevention of PIE – focusing on children with congenital heart defects. In the future, the incidence of PIE will likely continue to increase and the etiologic agents will likely become more difficult to treat as antimicrobial resistance increases. Research is needed in the areas of primary prevention of PIE, improved diagnostic methods for PIE and effective therapies for PIE caused by multidrug resistant pathogens. In the interim, health care providers need to be cognizant of PIE in children with CHD because early diagnosis and therapy can decrease morbidity and mortality.
Fungal endocarditis remains a rare disease occurring mostly in patients with predisposing host conditions. Regarding its poor prognosis because of severe complications, there is an urgent need for properly established treatment guidelines and prophylaxis for patients at risk. In this review we provide up-to-date information on treatment recommendations, and discuss recent case reports on fungal endocarditis and challenges in prophylaxis and treatment.
Over the last year, an increase in cases caused by non-albicans species of Candida and other fungi like Fusarium solani, Lodderomyces elongisporus and Exophiala dermatitidis was reported. They were treated individually in case-by-case approaches, lacking randomized controlled trials and, mostly, treatment recommendations.
The scarcity of fungal endocarditis demands a high index of suspicion and knowledge of the group of at-risk patients. Diagnosis aggressively pursued by echocardiography and multiple blood cultures or surgical specimens has the potential to improve outcome. Candida endocarditis should be treated immediately, including surgical treatment in combination with liposomal amphotericin B or caspofungin with optional addition of flucytosine. Aspergillus endocarditis requires rapid surgery and voriconazole.
This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases.When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.
Candida spp. are the fourth leading cause of bloodstream infections, and non-albicans species are increasing in importance. Micafungin is a new echinocandin antifungal agent with excellent in vitro activity against Candida spp. Pediatric, neonatal, and adult patients with new or refractory candidemia were enrolled into this open-label, noncomparative, international study. The initial dose of micafungin was 50 mg/d (1 mg/kg for patients <40 kg) for infections due to C. albicans and 100 mg/d (2 mg/kg for patients <40 kg) for infections due to other species. Dose escalation was allowed. Maximum length of therapy was 42 days. A total of 126 patients were evaluable (received at least five doses of micafungin). Success (complete or partial response) was seen in 83.3% patients overall. Success rates for treatment of infections caused by the most common Candida spp. were as follows: C. albicans 85.1%, C. glabrata 93.8%, C. parapsilosis 86.4%, and C. tropicalis 83.3%. Serious adverse events related to micafungin were uncommon. Micafungin shows promise as a safe and effective agent for the treatment of newly diagnosed and refractory cases of candidemia. Large-scale, randomized, controlled trials are warranted
The echinocandin class of antifungal agents is considered to be the first-line treatment of bloodstream infections (BSI) due
to Candida glabrata. Recent reports of BSI due to strains of C. glabrata resistant to both fluconazole and the echinocandins are of concern and prompted us to review the experience of two large
surveillance programs, the SENTRY Antimicrobial Surveillance Program for the years 2006 through 2010 and the Centers for Disease
Control and Prevention population-based surveillance conducted in 2008 to 2010. The in vitro susceptibilities of 1,669 BSI isolates of C. glabrata to fluconazole, voriconazole, anidulafungin, caspofungin, and micafungin were determined by CLSI broth microdilution methods.
Fluconazole MICs of ≥64 μg/ml were considered resistant. Strains for which anidulafungin and caspofungin MICs were ≥0.5 μg/ml
and for which micafungin MICs were ≥0.25 μg/ml were considered resistant. A total of 162 isolates (9.7%) were resistant to
fluconazole, of which 98.8% were nonsusceptible to voriconazole (MIC > 0.5 μg/ml) and 9.3%, 9.3%, and 8.0% were resistant
to anidulafungin, caspofungin, and micafungin, respectively. There were 18 fluconazole-resistant isolates that were resistant
to one or more of the echinocandins (11.1% of all fluconazole-resistant isolates), all of which contained an acquired mutation
in fks1 or fks2. By comparison, there were no echinocandin-resistant strains detected among 110 fluconazole-resistant isolates of C. glabrata tested in 2001 to 2004. These data document the broad emergence of coresistance over time to both azoles and echinocandins
in clinical isolates of C. glabrata.
Invasive candidiasis (IC) is an important healthcare-related infection, with increasing incidence and a crude mortality exceeding 50%. Numerous treatment options are available yet comparative studies have not identified optimal therapy.
We conducted an individual patient-level quantitative review of randomized trials for treatment of IC and to assess the impact of host-, organism-, and treatment-related factors on mortality and clinical cure. Studies were identified by searching computerized databases and queries of experts in the field for randomized trials comparing the effect of ≥2 antifungals for treatment of IC. Univariate and multivariable analyses were performed to determine factors associated with patient outcomes.
Data from 1915 patients were obtained from 7 trials. Overall mortality among patients in the entire data set was 31.4%, and the rate of treatment success was 67.4%. Logistic regression analysis for the aggregate data set identified increasing age (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.00-1.02; P = .02), the Acute Physiology and Chronic Health Evaluation II score (OR, 1.11; 95% CI, 1.08-1.14; P = .0001), use of immunosuppressive therapy (OR, 1.69; 95% CI, 1.18-2.44; P = .001), and infection with Candida tropicalis (OR, 1.64; 95% CI, 1.11-2.39; P = .01) as predictors of mortality. Conversely, removal of a central venous catheter (CVC) (OR, 0.50; 95% CI, .35-.72; P = .0001) and treatment with an echinocandin antifungal (OR, 0.65; 95% CI, .45-.94; P = .02) were associated with decreased mortality. Similar findings were observed for the clinical success end point.
Two treatment-related factors were associated with improved survival and greater clinical success: use of an echinocandin and removal of the CVC.
Candida is an important cause of bloodstream infections (BSI), causing significant mortality and morbidity in health care settings. From January 2008 to December 2010 all consecutive patients who developed candidemia at San Martino University Hospital, Italy were enrolled in the study. A total of 348 episodes of candidaemia were identified during the study period (January 2008–December 2010), with an incidence of 1,73 episodes/1000 admissions. Globally, albicans and non-albicans species caused around 50% of the cases each. Non-albicans included Candida parapsilosis (28.4%), Candida glabrata (9.5%), Candida tropicalis (6.6%), and Candida krusei (2.6%). Out of 324 evaluable patients, 141 (43.5%) died within 30 days from the onset of candidemia. C. parapsilosis candidemia was associated with the lowest mortality rate (36.2%). In contrast, patients with C. krusei BSI had the highest mortality rate (55.5%) in this cohort. Regarding the crude mortality in the different units, patients in Internal Medicine wards had the highest mortality rate (54.1%), followed by patients in ICU and Hemato-Oncology wards (47.6%).
This report shows that candidemia is a significant source of morbidity in Italy, with a substantial burden of disease, mortality, and likely high associated costs. Although our high rates of candidemia may be related to high rates of BSI in general in Italian public hospitals, reasons for these high rates are not clear and warrant further study. Determining factors associated with these high rates may lead to identifying measures that can help to prevent disease.
Echinocandins represent the newest class of antifungal agents. Currently, three echinocandins, anidulafungin, caspofungin and micafungin are licensed for clinical use in various indications. They act as inhibitors of β-(1,3)-glucan synthesis in the fungal cell wall and have a favorable pharmacological profile. They have a broad spectrum of activity against all Candida species. Higher MIC's have been observed against C. parapsilosis and C. guilliermondii. Data from clinical trials for invasive Candida infections / candidaemia suggest that the clinical outcome of patients treated with either drug may be very similar. A comparison has been done between caspofungin and micafungin but for anidulafungin a comparative trial with another echinocandin is still lacking. All three drugs are highly effective if not superior to treatment with either fluconazole or Amphotericin B, particularly in well-defined clinical settings such as invasive Candida infections, Candida oesophagitis and candidaemia. Differences between the three echinocandins with regard to the route of metabolism, requirement for a loading dose, dose adjustment in patients with moderate to severe hepatic disease and different dosing schedules for different types of Candida infections have to be considered. Relevant drug-drug interactions of Caspofungin and Micafungin are minimal. Anidulafungin has no significant drug interactions at all. However, echinocandins are available only for intravenous use. All three agents have an excellent safety profile.
Patients with candidemia frequently have a central venous catheter (CVC) in place, and its early removal is considered the standard of care.
We performed a subgroup analysis of 2 phase III, multicenter, double-blind, randomized, controlled trials of candidemia to examine the effects of early CVC removal (within 24 or 48 h after treatment initiation) on the outcomes of 842 patients with candidemia. Inclusion criteria were candidemia, age >16 years, CVC at diagnosis, and receipt of 1 dose of the study drug. Six outcomes were evaluated: treatment success, rates of persistent and recurrent candidemia, time to mycological eradication, and survival at 28 and 42 days. Univariate and multivariate analyses were performed, controlling for potential confounders.
In univariate analysis, early CVC removal did not improve time to mycological eradication or rates of persistent or recurrent candidemia but was associated with better treatment success and survival. These benefits were lost in multivariate analysis, which failed to show any beneficial effect of early CVC removal on all 6 outcomes and identified Acute Physiology and Chronic Health Evaluation II score, older age, and persistent neutropenia as the most significant variables. Our findings were consistent across all outcomes and time points (removal within 24 or 48 h and survival at 28 and 42 days). The median time to eradication of candidemia was similar between the 2 study groups.
In this cohort of 842 adults with candidemia followed up prospectively, early CVC removal was not associated with any clinical benefit. These findings suggest an evidence-based re-evaluation of current treatment recommendations.
This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases. When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.
A randomized trial was conducted to compare the efficacy and safety of fluconazole versus that of amphotericin B in the treatment of candidemia in non-neutropenic adults. Enrollment was stratified by disease severity (APACHE II score). Patients were randomized (1:1) to receive amphotericin B 0.6 mg/kg/day (cumulative dose 8 mg/kg) or fluconazole 800 mg intravenous loading dose, then 400 mg daily for four weeks (intravenous for at least 10 days). Patients were monitored for six months. A total of 106 patients were enrolled. A protocol amendment implemented midway through the trial required patients to be removed from the study and treated with amphotericin B if species identification indicated candidemia due to Candida glabrata or Candida krusei. Baseline characteristics were similar for the two groups; 103 patients (fluconazole, 50; amphotericin B, 53) met the major enrollment criteria. The intention-to-treat analysis indicated successful therapy in 50% of fluconazole recipients compared to 58% of the amphotericin B group (p = 0.39; one-sided 95% CI, -8 to 24%). The efficacy analysis included 84 patients (fluconazole, 42; amphotericin B, 42); successful outcomes were observed in 57% and 62% of cases in the fluconazole and amphotericin B groups, respectively (p = 0.66: one-sided 95% CI, -12 to 22%). The mortality at day 14 for the fluconazole group was 26% and for the amphotericin B group 21% (p = 0.52; chi-square test) and remained similar throughout the course of follow-up, Drug-related adverse events were more frequent with amphotericin B than with fluconazole and prompted switching of therapy for two (4%) and zero cases, respectively. Fluconazole and amphotericin B were associated with similar clinical response rates and survival in the treatment of candidemia among non-neutropenic patients; however, drug-related adverse events were more frequent with amphotericin B.
We conducted a prospective, randomized, double-blind study comparing amphotericin B colloidal dispersion (ABCD) with amphotericin
B in the empirical treatment of fever and neutropenia. Patients with neutropenia and unresolved fever after ⩾3 days of empirical
antibiotic therapy were stratified by age and concomitant use of cyclosporine or tacrolimus. Patients were then randomized
to receive therapy with ABCD (4 mg/[kg·d]) or amphotericin B (0.8 mg/[kg·d]) for ⩽14 days. A total of 213 patients were enrolled,
of whom 196 were evaluable for efficacy. Fifty percent of ABCD-treated patients and 43.2% of amphotericin B—treated patients
had a therapeutic response (P = .31). Renal dysfunction was less likely to develop and occurred later in ABCD recipients than in amphotericin B recipients
(P < .001 for both parameters). Infusion-related hypoxia and chills were more common in ABCD recipients than in amphotericin
B recipients (P = .013 and P = .018, respectively). ABCD appeared comparable in efficacy with amphotericin B, and renal dysfunction associated with ABCD
was significantly less than that associated with amphotericin B. However, infusion-related events were more common with ABCD
treatment than with amphotericin B treatment.
In a surveillance study of candidemia in cancer patients that was conducted by the European Organization for Research and
Treatment of Cancer, 249 episodes were noted; Candida albicans was isolated in 70% (63) of the 90 cases involving patients with solid tumors (tumor patients) and in 36% (58) of the 159
involving those with hematologic disease (hematology patients). Neutropenia in tumor patients and acute leukemia and antifungal
prophylaxis in hematology patients were significantly associated with non-albicans candidemia in a multivariate analysis. Overall 30-day mortality was 39% (97 of 249). In a univariate analysis, Candida glabrata was associated with the highest mortality rate (odds ratio, 2.66). Two multivariate analyses showed that mortality was associated
with older age and severity of the underlying disease. Among hematology patients, additional factors associated with mortality
were allogeneic bone marrow transplantation, septic shock, and lack of antifungal prophylaxis.
Candida species are the fourth most frequent cause of nosocomial bloodstream infections, and 25%–50% occur in critical care
units. During an 18-month prospective study period, all patients admitted for ⩾72 hours to the surgical (SICUs) or neonatal
intensive care units (NICUs) at each of the participant institutions were followed daily. Among 4,276 patients admitted to
the seven SICUs in six centers, there were 42 nosocomial bloodstream infections due to Candida species (9.8/1,000 admissions; 0.99/1,000 patient-days). Of 2,847 babies admitted to the six NICUs, 35 acquired a nosocomial
bloodstream infection due to Candida species (12.3/1,000 admissions; 0.64/1,000 patient-days). The following were the most
commonly isolated Candida species causing bloodstream infections in the SICU: Candida albicans, 48%; Candida glabrata, 24%; Candida tropicalis, 19%; Candida parapsilosis, 7%; Candida species not otherwise specified, 2%. In the NICU the distribution was as follows: C. albicans, 63%; C. glabrata, 6%; C. parapsilosis, 29%; other, 3%. Of the patients, 30%–50% developed incidental stool colonization, 23% of SICU patients developed incidental
urine colonization, and one-third of SICU health care workers' hands were positive for Candida species.
Infections due to Candida species are the most common of the fungal infections. Candida species produce a broad range of infections, ranging from nonlife-threatening mucocutaneous illnesses to invasive process that may involve virtually any organ. Such a broad range of infections requires an equally broad range of diagnostic and therapeutic strategies. This document summarizes current knowledge about treatment of multiple forms of candidiasis and is the guideline of the Infectious Diseases Society of America (IDSA) for the treatment of candidiasis. Throughout this document, treatment recommendations are scored according to the standard scoring scheme used in other IDSA guidelines to illustrate the strength of the underlying data. The document covers 4 major topical areas. The role of the microbiology laboratory. To a greater extent than for other fungi, treatment of candidiasis can now be guided by in vitro susceptibility testing. The guidelines review the available information supporting current testing procedures and interpretive breakpoints and place these data into clinical context. Susceptibility testing is most helpful in dealing with infection due to non-albicans species of Candida. In this setting, especially if the patient has been treated previously with an azole antifungal agent, the possibility of microbiological resistance must be considered. Treatment of invasive candidiasis. In addition to acute hematogenous candidiasis, the guidelines review strategies for treatment of 15 other forms of invasive candidiasis. Extensive data from randomized trials are really available only for therapy of acute hematogenous candidiasis in the nonneutropenic adult. Choice of therapy for other forms of candidiasis is based on case series and anecdotal reports. In general, both amphotericin B and the azoles have a role to play in treatment. Choice of therapy is guided by weighing the greater activity of amphotericin B for some non-albicans species (e.g., Candida krusei) against the lesser toxicity and ease of administration of the azole antifungal agents. Flucytosine has activity against many isolates of Candida but is not often used. Treatment of mucocutaneous candidiasis. Therapy for mucosal infections is dominated by the azole antifungal agents. These drugs may be used topically or systemically and have been proven safe and efficacious. A significant problem with mucosal disease is the propensity for a small proportion of patients to suffer repeated relapses. In some situations, the explanation for such a relapse is obvious (e.g., relapsing oropharyngeal candidiasis in an individual with advanced and uncontrolled HIV infection), but in other patients the cause is cryptic (e.g., relapsing vaginitis in a healthy woman). Rational strategies for these situations are discussed in the guidelines and must consider the possibility of induction of resistance over time. Prevention of invasive candidiasis. Prophylactic strategies are useful if the risk of a target disease is sharply elevated in a readily identified group of patients. Selected patient groups undergoing therapy that produces prolonged neutropenia (e.g., some bone-marrow transplant recipients) or who receive a solid-organ transplant (e.g., some liver transplant recipients) have a sufficient risk of invasive candidiasis to warrant prophylaxis.
In this double-blind study to compare safety of 2 lipid formulations of amphotericin B, neutropenic patients with unresolved
fever after 3 days of antibacterial therapy were randomized (1 : 1 : 1) to receive amphotericin B lipid complex (ABLC) at
a dose of 5 mg/kg/d (n = 78), liposomal amphotericin B (L Amph) at a dose of 3 mg/kg/d (n = 85), or L Amph at a dose of 5 mg/kg/d (n = 81). L Amph (3 mg/kg/d and 5 mg/kg/d) had lower rates of fever (23.5% and 19.8% vs. 57.7% on day 1; P < .001), chills/rigors (18.8% and 23.5% vs. 79.5% on day 1; P < .001), nephrotoxicity (14.1% and 14.8% vs. 42.3%; P < .01), and toxicity-related discontinuations of therapy (12.9% and 12.3% vs. 32.1%; P = .004). After day 1, infusional reactions were less frequent with ABLC, but chills/rigors were still higher (21.0% and 24.3%
vs. 50.7%; P < .001). Therapeutic success was similar in all 3 groups.
A randomized, blinded, multicenter trial was conducted to compare fluconazole (800 mg per day) plus placebo with fluconazole
plus amphotericin B (AmB) deoxycholate (0.7 mg/kg per day, with the placebo/AmB component given only for the first 5–6 days)
as therapy for candidemia due to species other than Candida krusei in adults without neutropenia. A total of 219 patients met criteria for a modified intent-to-treat analysis. The groups were
similar except that those who were treated with fluconazole plus placebo had a higher mean (± standard error) Acute Physiology
and Chronic Health Evaluation II score (16.8 ± 0.6 vs. 15.0 ± 0.7; P = .039). Success rates on study day 30 by Kaplan-Meier time-to-failure analysis were 57% for fluconazole plus placebo and
69% for fluconazole plus AmB (P = .08). Overall success rates were 56% (60 of 107 patients) and 69% (77 of 112 patients; P = .043), respectively; the bloodstream infection failed to clear in 17% and 6% of subjects, respectively (P = .02). In nonneutropenic subjects, the combination of fluconazole plus AmB was not antagonistic compared with fluconazole
alone, and the combination trended toward improved success and more-rapid clearance from the bloodstream.
We conducted a prospective, multicenter observational study of adults (n = 1447) and children (n = 144) with candidemia at tertiary care centers in the United States in parallel with a candidemia treatment trial that included
nonneutropenic adults. Candida albicans was the most common bloodstream isolate recovered from adults and children (45% vs. 49%) and was associated with high mortality
(47% among adults vs. 29% among children). Three-month survival was better among children than among adults (76% vs. 54%;
P < .001). Most children received amphotericin B as initial therapy, whereas most adults received fluconazole. In adults, Candida parapsilosis fungemia was associated with lower mortality than was non-parapsilosis candidemia (24% vs. 46%; P < .001). Mortality was similar among subjects with Candida glabrata or non-glabrata candidemia; mortality was also similar among subjects with C. glabrata candidemia who received fluconazole rather than other antifungal therapy. Subjects in the observational cohort had higher
Acute Physiology and Chronic Health Evaluation II scores than did participants in the clinical trial (18.6 vs. 16.1), which
suggests that the former subjects are more often excluded from therapeutic trials.
We reexamined the attributable mortality of nosocomial candidemia 15 years after a retrospective cohort study performed at
our hospital demonstrated an attributable mortality of 38%. For all episodes of nosocomial candidemia between 1 July 1997
and 30 June 2001, we matched control patients with case patients by age, sex, date of hospital admission, underlying disease(s),
length of time at risk, and surgical procedure(s). We analyzed 108 matched pairs. There were no statistically significant
differences in age, sex, underlying disease(s), time at risk, surgical procedure, or vital signs at admission between cases
and controls. The crude mortality among case patients was 61% (66 of 108 patients), compared with 12% (13 of 108) among control
patients, for an attributable mortality of 49% (95% CI, 38%–60%). Nosocomial candidemia is still associated with an extremely
high crude and attributable mortality—much higher than that expected from underlying disease alone.
This study evaluated the safety and efficacy of anidulafungin, a novel echinocandin, in patients with invasive candidiasis,
including candidemia. A total of 123 eligible patients were randomized to one of three intravenous regimens, 50, 75, or 100
mg once daily. Treatment continued for 2 weeks beyond resolution or improvement of signs and symptoms. The primary efficacy
criterion was a successful global response rate (i.e., clinical and microbiological success) in the evaluable population at
the follow-up (FU) visit, 2 weeks after end of therapy (EOT). One hundred twenty (120) patients received at least one dose
of anidulafungin; 68 were evaluable. Review of adverse events and laboratory data indicated no dose response for safety parameters.
Non-albicans Candida species accounted for approximately one-half of all isolates. Success rates at EOT were 84, 90, and 89% in the 50-, 75-,
and 100-mg groups, respectively. At FU, the success rates were 72, 85, and 83%. Phase 3 studies of anidulafungin for the treatment
of invasive candidiasis and candidemia are warranted.
Nosocomial bloodstream infections (BSIs) are important causes of morbidity and mortality in the United States.
Data from a nationwide, concurrent surveillance study (Surveillance and Control of Pathogens of Epidemiological Importance [SCOPE]) were used to examine the secular trends in the epidemiology and microbiology of nosocomial BSIs.
Our study detected 24,179 cases of nosocomial BSI in 49 US hospitals over a 7-year period from March 1995 through September 2002 (60 cases per 10,000 hospital admissions). Eighty-seven percent of BSIs were monomicrobial. Gram-positive organisms caused 65% of these BSIs, gram-negative organisms caused 25%, and fungi caused 9.5%. The crude mortality rate was 27%. The most-common organisms causing BSIs were coagulase-negative staphylococci (CoNS) (31% of isolates), Staphylococcus aureus (20%), enterococci (9%), and Candida species (9%). The mean interval between admission and infection was 13 days for infection with Escherichia coli, 16 days for S. aureus, 22 days for Candida species and Klebsiella species, 23 days for enterococci, and 26 days for Acinetobacter species. CoNS, Pseudomonas species, Enterobacter species, Serratia species, and Acinetobacter species were more likely to cause infections in patients in intensive care units (P<.001). In neutropenic patients, infections with Candida species, enterococci, and viridans group streptococci were significantly more common. The proportion of S. aureus isolates with methicillin resistance increased from 22% in 1995 to 57% in 2001 (P<.001, trend analysis). Vancomycin resistance was seen in 2% of Enterococcus faecalis isolates and in 60% of Enterococcus faecium isolates.
In this study, one of the largest multicenter studies performed to date, we found that the proportion of nosocomial BSIs due to antibiotic-resistant organisms is increasing in US hospitals.
Invasive mycoses are a significant and growing public health problem. Although bloodstream infections with Candida albicans may be decreasing in frequency, the number of persons at risk for them continues to grow. Moreover, infections with other
Candida species, such as Candida glabrata, are increasing in incidence. Invasive mould infections in general, and Aspergillus infections in particular, are becoming more frequent. Fungal opportunistic infections in persons with AIDS are no longer
a major problem in developed countries, but are resulting in significant morbidity and mortality in developing countries with
AIDS epidemics. Further studies are needed to define populations at very high risk for fungal opportunistic infections who
might benefit from targeted antifungal chemoprophylaxis, which remains the most promising of the potential prevention strategies.
This review highlights the changing patterns in risk factors, changes in epidemiology, the impact of changes in medical practice
in intensive care and organ transplantation on the incidence of systemic fungal infections, and gives an overview of fungal
infections in paediatric patients, patients with haematological malignancy, and the emergence of antifungal resistance.
Candida species are the fourth most common cause of bloodstream infection and are the leading cause of invasive fungal infection among hospitalized patients in the United States. However, the frequency and outcomes attributable to the infection are uncertain. This retrospective study set out to estimate the incidence of candidemia in hospitalized adults and children in the United States and to determine attributable mortality, length of hospital stay, and hospital charges related to candidemia.
We used the Nationwide Inpatient Sample 2000 for adult patients and the Kids' Inpatient Database 2000 for pediatric patients. We matched candidemia-exposed and candidemia-unexposed patients by the propensity scores for the probability of candidemia exposure, which were derived from patient characteristics. Attributable outcomes were calculated as the differences in estimates of outcomes between propensity score-matched patients with and without candidemia.
In the United States in 2000, candidemia was diagnosed in an estimated 1118 hospital admissions of pediatric patients and 8949 hospital admissions of adult patients, yielding a frequency of 43 cases per 100,000 pediatric admissions (95% confidence interval [CI], 35-52 cases per 100,000 pediatric admissions) and 30 cases per 100,000 adult admissions (95% CI, 26-34 cases per 100,000 adult admissions). In pediatric patients, candidemia was associated with a 10.0% increase in mortality (95% CI, 6.2%-13.8%), a mean 21.1-day increase in length of stay (95% CI, 14.4-27.8 days), and a mean increase in total per-patient hospital charges of 92,266 dollars (95% CI, 65,058 dollars-119,474 dollars). In adult patients, candidemia was associated with a 14.5% increase in mortality (95% CI, 12.1%-16.9%), a mean 10.1-day increase in length of stay (95% CI, 8.9-11.3 days), and a mean increase in hospital charges of 39,331 dollars (95% CI, 33,604 dollars-45,602 dollars).
The impact of candidemia on excess mortality, increased length of stay, and the burden of cost of hospitalization underscores the need for improved means of prevention and treatment of candidemia in adults and children.
Candida parapsilosis has emerged as an important yeast species causing fungemia. We describe the incidence and epidemiology of C. parapsilosis fungemia. Data from active population-based surveillance in Barcelona, Spain, from January 2002 to December 2003 were analyzed.
We focused on 78 episodes of C. parapsilosis fungemia, and we compared them with 175 Candida albicans controls. C. parapsilosis accounted for 23% of all fungemias. The annual incidences were 1 episode per 105 patients, 1.2 episodes per 104 discharges, and 1.7 episodes per 105 patient days. All isolates but one (99%) were fluconazole susceptible. Seventy-two isolates (92%) were inpatient candidemias.
Forty-two episodes (51%) were considered catheter-related fungemia, 35 (45%) were considered primary fungemia, and 3 (4%)
were considered secondary fungemia. Risk factors for candidemia were vascular catheterization (97%), prior antibiotic therapy
(91%), parenteral nutrition (54%), prior surgery (46%), prior immunosuppressive therapy (38%), malignancy (27%), prior antifungal
infection (26%), transplant recipient (16%), neutropenia (12%), and prior colonization (11%). Multivariate analysis of the
differential characteristics showed that the factors that independently predicted the presence of C. parapsilosis fungemia were neonate patients (odds ratio [OR], 7.5; 95% confidence interval [CI], 2.1 to 26.8; P = 0.002), transplant recipients (OR, 9.2; 95% CI, 1.9 to 43.3; P = 0.005), patients with a history of prior antifungal therapy (OR, 5.4; 95% CI, 1.8 to 15.9; P = 0.002), and patients who received parenteral nutrition (OR, 2.2; 95% CI, 1.09 to 4.6; P = 0.028). The overall mortality rate was lower than that associated with C. albicans candidemia (23% versus 43%; P < 0.01). In summary, C. parapsilosis was responsible for 23% of all candidemias and was more frequent in neonates, in transplant recipients, and in patients who
received parenteral nutrition or previous antifungal therapy, mainly fluconazole. The mortality rate was lower than that associated
with C. albicans fungemia.
Amphotericin B is a widely used broad-spectrum antifungal agent, despite being associated with significant adverse events, including nephrotoxicity.
The present prospective study collected data on outcomes for 418 adult patients treated consecutively with polyenes in hematology and oncology wards in 20 hospitals in Europe.
Patients initially received amphotericin B deoxycholate (62% of patients), liposomal amphotericin B (27%), or other lipid formulations of amphotericin B (11%). Of the patients initially treated with amphotericin B deoxycholate, 36% had therapy switched to lipid formulations of amphotericin B, primarily because of increased serum creatinine levels (in 45.7% of patients) or other amphotericin B-attributable adverse events (in 41.3% of patients). Nephrotoxicity, which was defined as a > or = 50% increase in the serum creatinine level, developed in 57% of patients with normal kidney function at baseline. Predictors of nephrotoxicity included formulation type and duration of treatment. Compared with patients without nephrotoxicity, patients with nephrotoxicity had a higher mortality rate (24%), and their mean length of stay in the hospital was prolonged by 8.6 days. Slight increases in the serum creatinine level (i.e., > or = 50%) were associated with a significantly longer stay in the hospital. Severe nephrotoxicity (i.e., a > or = 200% increase in the serum creatinine level) was a significant predictor of death, as were severe underlying medical conditions and documented fungal infection.
This prospective study confirmed that, in European hospitals, amphotericin B formulations have a major influence on the length of stay in the hospital and nephrotoxicity-associated mortality.
Invasive candidiasis (IC) is a leading cause of mycosis-associated mortality in the United States. We examined data from the National Center for Health Statistics and reviewed recent literature in order to update the epidemiology of IC. IC-associated mortality has remained stable, at approximately 0.4 deaths per 100,000 population, since 1997, while mortality associated with invasive aspergillosis has continued to decline. Candida albicans remains the predominant cause of IC, accounting for over half of all cases, but Candida glabrata has emerged as the second most common cause of IC in the United States, and several less common Candida species may be emerging, some of which can exhibit resistance to triazoles and/or amphotericin B. Crude and attributable rates of mortality due to IC remain unacceptably high and unchanged for the past 2 decades. Nonpharmacologic preventive strategies should be emphasized, including hand hygiene; appropriate use, placement, and care of central venous catheters; and prudent use of antimicrobial therapy. Given that delays in appropriate antifungal therapy are associated with increased mortality, improved use of early empirical, preemptive, and prophylactic therapies should also help reduce IC-associated mortality. Several studies have now identified important variables that can be used to predict risk of IC and to help guide preventive strategies such as antifungal prophylaxis and early empirical therapy. However, improved non-culture-based diagnostics are needed to expand the potential for preemptive (or early directed) therapy. Further research to improve diagnostic, preventive, and therapeutic strategies is necessary to reduce the considerable morbidity and mortality associated with IC.
Studies conducted in tertiary care hospitals of different European countries and the United States have shown incidence rates of candidemia ranging from 0.17 to 0.76 and 0.28 to 0.96 per 1,000 admissions, respectively. So far, only 1 study has evaluated the incidence rates of candidemia in tertiary care hospitals in Latin American countries.
To evaluate the epidemiology of candidemia in 4 tertiary care hospitals in São Paulo, Brazil.
Multicenter, laboratory-based surveillance of candidemia.
A total of 7,038 episodes of bloodstream infection were identified, and Candida species accounted for 282 cases (4%). The incidence rate of candidemia was 1.66 candidemic episodes per 1,000 hospital admissions. Candida albicans was the most frequently isolated Candida species in all hospitals, but Candida species other than C. albicans accounted for 62% of isolates, including predominantly Candida parapsilosis and Candida tropicalis. Azole resistance was restricted to only 2% of all Candida isolates (1 isolate of Candida glabrata and 4 isolates of Candida rugosa). Candidemia was mostly documented in surgical patients with long durations of hospital stay. The crude mortality rate was 61%, and advanced age and high Acute Physiology and Chronic Health Evaluation II score were both conditions independently associated with risk of death.
We observed in our series a higher incidence rate of candidemia than that reported in European countries and the United States. Advanced age and a high Acute Physiology and Chronic Health Evaluation II score were factors associated with a higher probability of death in candidemic patients. Fluconazole-resistant Candida strains are still a rare finding in our case-based study of candidemia.
Invasive candidosis is increasingly prevalent in seriously ill patients. Our aim was to compare micafungin with liposomal amphotericin B for the treatment of adult patients with candidaemia or invasive candidosis.
We did a double-blind, randomised, multinational non-inferiority study to compare micafungin (100 mg/day) with liposomal amphotericin B (3 mg/kg per day) as first-line treatment of candidaemia and invasive candidosis. The primary endpoint was treatment success, defined as both a clinical and a mycological response at the end of treatment. Primary analyses were done on a per-protocol basis. This trial is registered with ClinicalTrials.gov, number NCT00106288.
264 individuals were randomly assigned to treatment with micafungin; 267 were randomly assigned to receive liposomal amphotericin B. 202 individuals in the micafungin group and 190 in the liposomal amphotericin B group were included in the per-protocol analyses. Treatment success was observed for 181 (89.6%) patients treated with micafungin and 170 (89.5%) patients treated with liposomal amphotericin B. The difference in proportions, after stratification by neutropenic status at baseline, was 0.7% (95% CI -5.3 to 6.7). Efficacy was independent of the Candida spp and primary site of infection, as well as neutropenic status, APACHE II score, and whether a catheter was removed or replaced during the study. There were fewer treatment-related adverse events--including those that were serious or led to treatment discontinuation--with micafungin than there were with liposomal amphotericin B.
Micafungin was as effective as--and caused fewer adverse events than--liposomal amphotericin B as first-line treatment of candidaemia and invasive candidosis.
Clin Microbiol Infect 2012; 18 (Suppl. 7): 19–37
This part of the EFISG guidelines focuses on non-neutropenic adult patients. Only a few of the numerous recommendations can be summarized in the abstract. Prophylactic usage of fluconazole is supported in patients with recent abdominal surgery and recurrent gastrointestinal perforations or anastomotic leakages. Candida isolation from respiratory secretions alone should never prompt treatment. For the targeted initial treatment of candidaemia, echinocandins are strongly recommended while liposomal amphotericin B and voriconazole are supported with moderate, and fluconazole with marginal strength. Treatment duration for candidaemia should be a minimum of 14 days after the end of candidaemia, which can be determined by one blood culture per day until negativity. Switching to oral treatment after 10 days of intravenous therapy has been safe in stable patients with susceptible Candida species. In candidaemia, removal of indwelling catheters is strongly recommended. If catheters cannot be removed, lipid-based amphotericin B or echinocandins should be preferred over azoles. Transoesophageal echocardiography and fundoscopy should be performed to detect organ involvement. Native valve endocarditis requires surgery within a week, while in prosthetic valve endocarditis, earlier surgery may be beneficial. The antifungal regimen of choice is liposomal amphotericin B +/− flucytosine. In ocular candidiasis, liposomal amphotericin B +/− flucytosine is recommended when the susceptibility of the isolate is unknown, and in susceptible isolates, fluconazole and voriconazole are alternatives. Amphotericin B deoxycholate is not recommended for any indication due to severe side effects.
A randomized trial was conducted to compare the efficacy and safety of fluconazole versus that of amphotericin B in the treatment of candidemia in non-neutropenic adults. Enrollment was stratified by disease severity (APACHE II score). Patients were randomized (1::1) to receive amphotericin B 0.6 mg/kg/day (cumulative dose 8 mg/kg) or fluconazole 800 mg intravenous loading dose, then 400 mg daily for four weeks (intravenous for at least 10 days). Patients were monitored for six months. A total of 106 patients were enrolled. A protocol amendment implemented midway through the trial required patients to be removed from the study and treated with amphotericin B if species identification indicated candidemia due toCandida glabrata orCandida krusei. Baseline characteristics were similar for the two groups; 103 patients (fluconazole, 50; amphotericin B, 53) met the major enrollment criteria. The intention-to-treat analysis indicated successful therapy in 50% of fluconazole recipients compared to 58% of the amphotericin B group (p=0.39; one-sided 95% Cl, -8 to 24%). The efficacy analysis included 84 patients (fluconazole, 42; amphotericin B, 42); successful outcomes were observed in 57% and 62% of cases in the fluconazole and amphotericin B groups, respectively (p=0.66: one-sided 95% Cl, -12 to 22%). The mortality at day 14 for the fluconazole group was 26% and for the amphotericin B group 21% (p=0.52; chi-square test) and remained similar throughout the course of follow-up. Drug-related adverse events were more frequent with amphotericin B than with fluconazole and prompted switching of therapy for two (4%) and zero cases, respectively. Fluconazole and amphotericin B were associated with similar clinical response rates and survival in the treatment of candidemia among non-neutropenic patients; however, drug-related adverse events were more frequent with amphotericin B.
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.
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.
A national surveillance program of nosocomial blood stream infections (BSI) in the USA between April 1995 and June 1996 revealed that Candida was the fourth leading cause of nosocomial BSI, accounting for 8% of all infections. Forty-eight percent of 379 episodes of candidemia were due to species other than Candida albicans. The rank order of non-C. albicans species was C. glabrata (20%) > C. tropicalis (11%) > C. parapsilosis (8%) > C. krusei (5%) > other Candida spp. (4%). The species distribution varied according to geographic region, with non-C. albicans species predominating in the Northeast (54%) and Southeast (53%) regions, and C. albicans predominating in the Northwest (60%) and Southwest (70%) regions. In vitro susceptibility studies demonstrated that 95% of non-C. albicans isolates were susceptible to 5-fluorocytosine, and 84% and 75% were susceptible to fluconazole and itraconazole, respectively. Geographic variation in susceptibility to itraconazole, but not other agents, was observed. Isolates from the Northwest and Southeast regions were more frequently resistant to itraconazole (29–30%) than those from the Northeast and Southwest regions (17–18%). Molecular epidemiologic studies revealed possible nosocomial transmission (five medical centers). Continued surveillance for the presence of non-C. albicans species among hospitalized patients is recommended.
Infection with Candida glabrata and Candida krusei represents a major challenge. We sought to describe outcomes for patients with candidaemia/invasive candidiasis (C/IC) due to these pathogens who were treated with micafungin.
We pooled two randomized trials of micafungin versus comparator. We identified patients infected with either C. glabrata or C. krusei. One trial compared micafungin (100 mg/day with option for dose escalation) with liposomal amphotericin B, while the other compared micafungin (either 100 or 150 mg/day) and caspofungin (NCT00106288 and NCT00105144). Clinical cure was our primary endpoint while 28 day mortality represented a secondary endpoint.
Among 1070 subjects with C/IC, 183 were infected with either C. glabrata (n = 144) or C. krusei (n = 39). One hundred and seventeen received micafungin. Clinical cure rates in those receiving micafungin were similar to those randomized to comparator [73.5% (86/117) versus 62.1% (41/66), P = not significant]. Mortality at 28 days was also similar [29.1% (34/117) with micafungin versus 34.8% (23/66) with comparator, P = not significant]. In logistic regression, treatment agent correlated with neither cure nor mortality. Factors independently linked with lower cure rates included: IC neutropenia; higher severity of illness; and medical admission. Higher severity of illness and failure to remove a central venous catheter were associated with 28 day mortality. Crude and adjusted outcomes were comparable irrespective of micafungin dose administered.
Micafungin results in similar outcomes to comparators for C/IC due to C. glabrata and C. krusei. The 100 mg/day dose represents an acceptable option in this setting. Patient characteristics and catheter management appear to be more important factors affecting clinical outcomes.
Candidemia is among the leading causes of nosocomial bloodstream infections and is associated with significant mortality. Several centers have published data regarding the incidence and relative frequency of Candida spp.
We performed a systematic review to summarize and evaluate the available evidence regarding the distribution of the relative frequency of Candida spp isolated from blood, according to geographic region and study design, during the period 1996 to 2009.
We searched PubMed and Scopus and retrieved 81 relevant articles reporting data on the relative frequency of Candida spp.
C. albicans was the predominant species in almost all studies. The highest proportion of C. albicans was found in North and Central Europe and the USA. Non-albicans species were more common in South America, Asia, and South Europe. C. glabrata was commonly isolated in the USA and North and Central Europe; C. parapsilosis in South America, South Europe, and several parts of Asia; and C. tropicalis in South America and Asia. The relative frequency of C. krusei was low in all regions. Significant differences were noted depending on study design (surveillance study, multicenter or single centre, prospective or retrospective) and setting (hospital or intensive care unit).
Significant geographic variation is evident among cases of candidemia in different parts of the world. Local epidemiological data continue to be of major significance.
Clin Microbiol Infect 2011; 17: 1538–1545
The risk factors and clinical features of patients with Candida tropicalis fungaemia have not been fully defined. We performed a case–control study comparing 59 cases of C. tropicalis fungaemia with 177 episodes of fungaemia caused by other species of Candida in our hospital over a 24-year period (January 1985 to December 2008). Patients with C. tropicalis fungaemia were more likely to be older (median age, 67 vs. 56 years; p 0.01), to have cancer (45.5% vs. 31.6%, p 0.04), and to have the abdomen as the portal of entry (32.2% vs. 11.9%, p 0.001), and had a higher in-hospital mortality rate (61% vs. 44%, p 0.03). Multivariate analysis showed that the independent risk factors for C. tropicalis fungaemia were cancer (OR 4.5; 95% CI 1.05–3.83; p 0.03) and the abdomen as the portal of entry (OR 13.6; 95% CI 1.9–8.2; p <0.001). When survivors were compared with non-survivors, the risk factors associated with a poor outcome were neutropenia (19.4% vs. 0; p 0.03), corticosteroid treatment (36% vs. 13%; p 0.07), and septic shock (50% vs. 17.4%; p 0.01). The independent risk factors for mortality in the multivariate analysis were corticosteroid treatment (OR 8.2; 95% CI 0.9–27.7; p 0.04) and septic shock (OR 14.6; 95% CI 2.4–90.2; p 0.004), whereas urinary tract infection (OR 0.07; 95% CI 0.01–0.8; p 0.03) and catheter removal (OR 0.06; 95% CI 0.01–0.4; p 0.002) were protective factors. C. tropicalis is the fourth most common cause of fungaemia in our hospital. It is associated with underlying malignancy, the abdomen as the portal of entry, and poor outcome.
Candidemia remains a major cause of morbidity and mortality in the health care setting, and the epidemiology of Candida infection is changing.
Clinical data from patients with candidemia were extracted from the Prospective Antifungal Therapy (PATH) Alliance database, a comprehensive registry that collects information regarding invasive fungal infections. A total of 2019 patients, enrolled from 1 July 2004 through 5 March 2008, were identified. Data regarding the candidemia episode were analyzed, including the specific fungal species and patient survival at 12 weeks after diagnosis.
The incidence of candidemia caused by non-Candida albicans Candida species (54.4%) was higher than the incidence of candidemia caused by C. albicans (45.6%). The overall, crude 12-week mortality rate was 35.2%. Patients with Candida parapsilosis candidemia had the lowest mortality rate (23.7%; P<.001) and were less likely to be neutropenic (5.1%; P<.001) and to receive corticosteroids (33.5%; P<.001) or other immunosuppressive drugs (7.9%; P=.002), compared with patients infected with other Candida species. Candida krusei candidemia was most commonly associated with prior use of antifungal agents (70.6%; P<.001), hematologic malignancy (52.9%; P<.001) or stem cell transplantation (17.7%; P<.001), neutropenia (45.1%; P<.001), and corticosteroid treatment (60.8%; P<.001). Patients with C. krusei candidemia had the highest crude 12-week mortality in this series (52.9%; P<.001). Fluconazole was the most commonly administered antimicrobial, followed by the echinocandins, and amphotericin B products were infrequently administered.
The epidemiology and choice of therapy for candidemia are rapidly changing. Additional study is warranted to differentiate host factors and differences in virulence among Candida species and to determine the best therapeutic regimen.
A number of advances have been made in the prevention and treatment of invasive fungal infections (IFIs) in transplant recipients. However, despite best clinical efforts, patient outcomes are often disappointing. The study of prognostic indicators of IFI for transplant patients may aid in the development of improved prevention measures, or determine more aggressive treatment pathways. Owing to the rarity of IFI, appropriately powered studies are often difficult to achieve; moreover, a lack of standardized outcome definitions make study comparisons difficult. Herein, prognostic indicators for mortality in transplant patients with IFI are reviewed, with a focus on invasive aspergillosis and invasive candidiasis.
We prospectively studied treatment and outcome of 5030 patients in intensive care units at 13 tertiary care hospitals. We stratified each hospital's patients by individual risk of death using diagnosis, indication for treatment, and Acute Physiology and Chronic Health Evaluation (APACHE) II score. We then compared actual and predicted death rates using group results as the standard. One hospital had significantly better results with 69 predicted but 41 observed deaths (p < 0.0001). Another hospital had significantly inferior results with 58% more deaths than expected (p < 0.0001). These differences occurred within specific diagnostic categories, for medical patients alone and for medical and surgical patients combined, and were related more to the interaction and coordination of each hospital's intensive care unit staff than to the unit's administrative structure, amount of specialized treatment used, or the hospital's teaching status. Our findings support the hypothesis that the degree of coordination of intensive care significantly influences its effectiveness.
We prospectively studied treatment and outcome in 5030 patients in intensive care units at 13 tertiary care hospitals. We stratified each hospital's patients by individual risk of death using diagnosis, indication for treatment, and Acute Physiology and Chronic Health Evaluation (APACHE) II score. We then compared actual and predicted death rates using group results as the standard. One hospital had significantly better results with 69 predicted but 41 observed deaths (p less than 0.0001). Another hospital had significantly inferior results with 58% more deaths than expected (p less than 0.0001). These differences occurred within specific diagnostic categories, for medical patients alone and for medical and surgical patients combined, and were related more to the interaction and coordination of each hospital's intensive care unit staff than to the unit's administrative structure, amount of specialized treatment used, or the hospital's teaching status. Our findings support the hypothesis that the degree of coordination of intensive care significantly influences its effectiveness.
To assess the changing epidemiology of candidemia in the 1990s, to evaluate the clinical implications for the presence of non-Candida albicans in blood, and to evaluate the presence of antifungal resistance in relation to prior antifungal administration.
Multicenter prospective observational study of patients with positive blood cultures for Candida species or Torulopsis glabrata.
Four tertiary care medical centers.
Four hundred twenty-seven consecutive patients were enrolled. The frequency of candidemia due to non-C. albicans species significantly increased in each hospital throughout the 3.5-year study period (P = 0.01). Thirteen percent of candidemias occurred in patients who were already receiving systemic antifungal agents. Candidemias developing while receiving antifungal therapy were more likely caused by non-C. albicans species than by C. albicans species (P = 0.0005). C. parapsilosis and C. krusei were more commonly seen with prior fluconazole therapy, whereas T. glabrata was more commonly seen with prior amphotericin B therapy. Candida species isolated during episodes of breakthrough candidemia exhibited a significantly higher MIC to the antifungal agent being administered (P < 0.001).
In this large scale study, the non-C. albicans species, especially T. glabrata, emerged as important and frequent pathogens causing fungemia. This finding has major clinical implications given the higher complication and mortality rate associated with the non-C. albicans species. The change in the pattern of candidemia might be partly attributed to the increase in number of immunocompromised hosts and the widespread use of prophylactic or empiric antifungal therapy. This is an ominous sign given the in vitro resistance of the non-C. albicans species to currently available antifungal agents.
Emerging trends in invasive candidiasis are notable for a dramatic increase in infections due to non-albicans Candida species. An increasing number of immunocompromised patients at risk from fungal infections, an overall greater acuity of illness in the hospitalized patients, particularly those in the critical care units, escalating rates of broad-spectrum antibiotic usage, and wide utilization of azoles as prophylaxis have probably contributed towards the changing epidemiology of invasive candidiasis. Given the inherent decreased susceptibility of many of the non-albicans Candida species to currently available antifungal agents, these evolving trends have far-reaching clinical relevance.
We describe the annual incidence of primary bloodstream infection (BSI) associated with Candida albicans and common non-albicans species of Candida among patients in intensive care units that participated in the National Nosocomial Infections Surveillance system from 1
January 1989 through 31 December 1999. During the study period, there was a significant decrease in the incidence of C. albicans BSI (P < .001) and a significant increase in the incidence of Candida glabrata BSI (P = .05).
Caspofungin is an echinocandin agent with fungicidal activity against candida species. We performed a double-blind trial to compare caspofungin with amphotericin B deoxycholate for the primary treatment of invasive candidiasis.
We enrolled patients who had clinical evidence of infection and a positive culture for candida species from blood or another site. Patients were stratified according to the severity of disease, as indicated by the Acute Physiology and Chronic Health Evaluation (APACHE II) score, and the presence or absence of neutropenia and were randomly assigned to receive either caspofungin or amphotericin B. The study was designed to compare the efficacy of caspofungin with that of amphotericin B in patients with invasive candidiasis and in a subgroup with candidemia.
Of the 239 patients enrolled, 224 were included in the modified intention-to-treat analysis. Base-line characteristics, including the percentage of patients with neutropenia and the mean APACHE II score, were similar in the two treatment groups. A modified intention-to-treat analysis showed that the efficacy of caspofungin was similar to that of amphotericin B, with successful outcomes in 73.4 percent of the patients treated with caspofungin and in 61.7 percent of those treated with amphotericin B (difference after adjustment for APACHE II score and neutropenic status, 12.7 percentage points; 95.6 percent confidence interval, -0.7 to 26.0). An analysis of patients who met prespecified criteria for evaluation showed that caspofungin was superior, with a favorable response in 80.7 percent of patients, as compared with 64.9 percent of those who received amphotericin B (difference, 15.4 percentage points; 95.6 percent confidence interval, 1.1 to 29.7). Caspofungin was as effective as amphotericin B in patients who had candidemia, with a favorable response in 71.7 percent and 62.8 percent of patients, respectively (difference, 10.0 percentage points; 95.0 percent confidence interval, -4.5 to 24.5). There were significantly fewer drug-related adverse events in the caspofungin group than in the amphotericin B group.
Caspofungin is at least as effective as amphotericin B for the treatment of invasive candidiasis and, more specifically, candidemia.
In order to update the epidemiological and mycological profile of candidaemia in Europe, the European Confederation of Medical Mycology conducted a prospective, sequential, hospital population-based study from September 1997 to December 1999. A total of 2,089 cases were documented by 106 institutions in seven European countries. Rates of candidaemia ranging from 0.20 to 0.38 per 1,000 admissions were reported. Candida albicans was identified in 56% of cases. Non-albicans Candida species were most frequently isolated from patients with haematological malignancies (65%). With increasing age, an increasing incidence of Candida glabrata was seen. The 30-day mortality rate was 37.9%. The survey results underline the burden of candidaemia in a wide range of patient populations, confirm the importance of non- albicans species, and provide baseline data for future surveillance studies at a European level.
The echinocandins anidulafungin and micafungin and the triazole posaconazole are currently undergoing phase III clinical trials. Caspofungin and voriconazole have recently been licensed for the treatment of aspergillosis (both agents), other less common mould (voriconazole) and candidal (caspofungin) infections. This review summarizes the published in vitro data obtained by NCCLS or NCCLS modified methods on the in vitro fungistatic and fungicidal activities of these five agents for yeasts and moulds in comparison to the established agents, amphotericin B, fluconazole, itraconazole, and flucytosine. Among the yeasts, the echinocandins have less activity for Candida parapsilosis and Candida guilliermondii, no activity for Cryptococcus neoformans and Trichosporon spp., but good fungistatic and fungicidal activity in vivo and in vitro for most of the other Candida spp.; this fungicidal activity has been reported by minimum fungicidal concentrations (MFCs) or time kill curve results. The new triazoles exhibit good fungistatic activity (but not fungicidal) for most Candida spp., C. neoformans, and Trichosporon spp. For the Aspergillus spp. evaluated, the echinocandins have similar or better fungistatic activity than those of amphotericin B and the triazoles, but fungicidal activity has been demonstrated only with amphotericin B and the triazoles, with the exception of fluconazole. Most studies showed posaconazole and voriconazole minimum inhibitory concentrations (MICs) ranging from 0.25 to 8 microg/ml for non-solani Fusarium spp., while MIC and minimum effective concentration (MEC) endpoints of the echinocandins were >8 microg/ml. The fungistatic activity of the triazoles is also superior to that of the echinocandins for most of the dimorphic fungi and the Zygomycetes. However, micafungin has activity for the mould phase of most dimorphic fungi, but not for the parasitic or yeast phase of Paracoccidioides brasiliensis. The echinocandins appear to have variable and species dependent fungistatic activity for the dematiaceous fungi, but all agents have poor or no activity against most isolates of Scedosporium prolificans. Only amphotericin B exhibit good fungistatic activity against the Zygomycetes. The combination of caspofungin with some triazoles, amphotericin B or liposomal amphotericin B has been synergistic in vitro, in animal models and in patients. Breakpoints are not available for any mould and antifungal agent combination. In vitro/in vivo correlations should aid in the interpretation of these results, but standard testing conditions are needed for the echinocandins, especially for mould testing, to obtain reliable results.
On 8 February 2003, the second in a series of meetings in honor of John E. Bennett, M.D., was convened in New York City. A
report from the previous meeting was published in 2003. The goal of this second meeting was to discuss the design of clinical
trials in prophylaxis and combination therapy. This supplement presents 12 articles by leading clinicians who are currently
active in trials in this area and presents a current view of the unmet needs and challenges.
To determine the mortality, hospital stay, and total hospital charges and cost of hospitalization attributable to candidemia by comparing patients with candidemia with control-patients who have otherwise similar illnesses. Prior studies lack broad patient and hospital representation or cost-related information that accurately reflects current medical practices.
Our case-control study included case-patients with candidemia and their cost-related data, ascertained from laboratory-based candidemia surveillance conducted among all residents of Connecticut and Baltimore and Baltimore County, Maryland, during 1998 to 2000. Control-patients were matched on age, hospital type, admission year, discharge diagnoses, and duration of hospitalization prior to candidemia onset.
We identified 214 and 529 sets of matched case-patients and control-patients from the two locations, respectively. Mortality attributable to candidemia ranged between 19% and 24%. On multivariable analysis, candidemia was associated with mortality (OR, 5.3 for Connecticut and 8.5 for Baltimore and Baltimore County; P < .05), whereas receiving adequate treatment was protective (OR, 0.5 and 0.4 for the two locations, respectively; P < .05). Candidemia itself did not increase the total hospital charges and cost of hospitalization; when treatment status was accounted for, having received adequate treatment for candidemia significantly increased the total hospital charges and cost of hospitalization (29,000 and 22,000, respectively) and the length of stay (3 to 13 days).
Our findings underscore the burden of candidemia, particularly regarding the risk of death, length of hospitalization, and cost associated with treatment.
Voriconazole has proven efficacy against invasive aspergillosis and oesophageal candidiasis. This multicentre, randomised, non-inferiority study compared voriconazole with a regimen of amphotericin B followed by fluconazole for the treatment of candidaemia in non-neutropenic patients.
Non-neutropenic patients with a positive blood culture for a species of candida and clinical evidence of infection were enrolled. Patients were randomly assigned, in a 2:1 ratio, either voriconazole (n=283) or amphotericin B followed by fluconazole (n=139). The primary efficacy analysis was based on clinical and mycological response 12 weeks after the end of treatment, assessed by an independent data-review committee unaware of treatment assignment.
Of 422 patients randomised, 370 were included in the modified intention-to-treat population. Voriconazole was non-inferior to amphotericin B/fluconazole in the primary efficacy analysis, with successful outcomes in 41% of patients in both treatment groups (95% CI for difference -10.6% to 10.6%). At the last evaluable assessment, outcome was successful in 162 (65%) patients assigned voriconazole and 87 (71%) assigned amphotericin B/fluconazole (p=0.25). Voriconazole cleared blood cultures as quickly as amphotericin B/fluconazole (median time to negative blood culture, 2.0 days). Treatment discontinuations due to all-cause adverse events were more frequent in the voriconazole group, although most discontinuations were due to non-drug-related events and there were significantly fewer serious adverse events and cases of renal toxicity than in the amphotericin B/fluconazole group.
Voriconazole was as effective as the regimen of amphotericin B followed by fluconazole in the treatment of candidaemia in non-neutropenic patients, and with fewer toxic effects.
There are several options for treatment of candidaemia in non-neutropenic patients, including amphotericin B, fluconazole, voriconazole, and echinocandins. Voriconazole can be given both as initial intravenous treatment and as an oral stepdown agent.
Despite the widespread use of antifungals for prophylaxis, Candida bloodstream infection (BSI) remains the most frequent life-threatening fungal disease. From an analysis of multi-institutional surveys of Candida BSIs performed in Europe, including the large prospective survey by the European Confederation of Medical Mycology (2089 episodes from seven countries), a limited role of species with decreased susceptibility to azoles in causing BSIs and a low proportion of antifungal resistance was evident. Large prospective epidemiological surveys using common databases are needed to monitor trends in incidence and changes in species distribution, to identify new at-risk patients and to evaluate the impact of the introduction into the market of new antifungal agents.
In order to characterize the epidemiology, microbiology and outcome of candidemia due to Candida parapsilosis, we examined a database of 282 episodes of candidemia prospectively collected from four tertiary care hospitals in São Paulo, Brazil between March 2002 and February 2003, and compared the characteristics of patients with candidemia due to C. parapsilosis (n=64) with those caused by Candida albicans (n=107). C. parapsilosis candidemia was associated with neutropenia (p=0.005), tunneled central venous catheter (p=0.005) and cancer chemotherapy (p=0.03). By multivariate analysis, candidemia due to C. parapsilosis was associated with the presence of a tunneled central venous catheter (relative risk 3.71, 95% confidence interval 1.28-10.70). Except for a single isolate of C. parapsilosis that exhibited MIC >1 microg/ml to amphotericin B, no resistance was observed in 166 isolates tested against fluconazole, itraconazole, 5-flucytosine and amphotericin B. The caspofungin MIC values of C. parapsilosis isolates were significantly higher than those exhibited by C. albicans isolates (p<0.001). The overall mortality of patients with candidemia due to C. parapsilosis was significantly lower (45% vs. 62%, p=0.03). The association between C. parapsilosis candidemia and a tunneled central venous catheter supports the idea that the main mode of acquisition of C. parapsilosis is from an external source.
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.