Breakthrough Candidemia Research Articles

Clinical and microbiological characteristics, and impact of therapeutic strategies on the outcomes of children with candidemia

We aimed to determine the clinical and microbiological characteristics of Candida bloodstream infections in children and the impact of therapeutic strategies on outcomes. All pediatric patients with candidemia from a medical center in Taiwan over a 13-year period (2003–2015) were included and a total of 262 patients with 319 episodes of candidemia were analyzed. Overall susceptibility to fluconazole was 86.1%. Cumulative mortality at 7 and 30 days after the first episode of candidemia was 13.4% and 25.2%, respectively. The overall in-hospital mortality rate was 35.1%. The treatment outcomes did not change over the study period. Multivariate analysis showed that delayed catheter removal (odds ratio [OR], 5.52; 95% confidence interval [CI]: 2.97–10.25), septic shock (OR, 5.49; 95% CI: 2.85–10.57), and breakthrough candidemia (OR, 3.66; 95% CI: 1.43–9.35) were independently associated with clinical treatment failure. In children with candidemia, underlying renal insufficiency and hematological/oncological malignancy, delayed catheter removal, and septic shock at onset were independently associated final in-hospital mortality. Analyzing the subgroup of non-neonatal children did not change the findings. We concluded overall mortality of pediatric candidemia remains high during the past decade. Prompt early catheter removal and aggressive treatment strategy in patients with septic shock would be critical to improve outcomes.

Clinical and Microbiological Characteristics of Breakthrough Candidemia in Allogeneic Hematopoietic Stem Cell Transplant Recipients in a Japanese Hospital.

Few data on breakthrough candidemia (BC), defined as candidemia that develops on administration of antifungal agents (AFAs), in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients are available. The medical and microbiological records of recipients of an allo-HSCT obtained between December 2008 and December 2014 were reviewed. Of 768 allo-HSCT cases, 26 developed BC. Among the 26 causative strains, 22 strains were stored and identified by sequencing. The following species were isolated: Candida parapsilosis (9 strains), C. glabrata (4 strains), C. guilliermondii (3 strains), and other Candida species (6 strains). The AFAs being used when BC developed were micafungin (17 cases), liposomal amphotericin B (5 cases), itraconazole (2 cases), and voriconazole (2 cases). All 17 cases who developed BC during micafungin administration were administered 150 mg/day of micafungin. The susceptibilities of the causative Candida species to the administered AFAs when breakthrough occurred ranged from susceptible to resistant. Especially, 85% of the Candida species that caused BC during micafungin administration were susceptible to micafungin. Additionally, 75% of the strains were wild type for susceptibility to the administered AFAs when breakthrough occurred. Systemic steroid administration and a longer severe neutropenic phase (≥5 days) were independent risk factors for BC (P = 0.016 and P = 0.015, respectively). BC developed in allo-HSCT recipients even when they received a sufficient dose of AFA, including micafungin, to which the causative Candida species were susceptible and/or had wild-type susceptibility in vitro Systemic steroid administration and a longer severe neutropenic phase were host-based factors associated with BC.

Breakthrough candidemia in children: clinical and microbiological characteristics, therapeutic strategies and impact on outcomes.

To assess the characteristics, treatments, risk factors and outcomes of breakthrough candidemia in children. Episodes of breakthrough candidemia in children were compared with the remaining episodes in a 13-year cohort study. Out of 319 episodes, 45 (14.1%) were breakthrough candidemia. Breakthrough candidemia occurred in patients with more acutely ill conditions, and the majority was caused by non-albicans Candida species (73.3%; 33 episodes). A total of 79.1% of breakthrough candidemia were caused by antifungal-susceptible Candida isolates and emergence of resistance was the mechanism in five cases of patients receiving fluconazole. Episodes of breakthrough candidemia had significantly higher illness severity and higher rates of fungemia-attributable mortality. Breakthrough candidemia independently contributed to unfavorable outcomes, and more aggressive treatment strategies are warranted when breakthrough candidemia is encountered.

Breakthrough candidaemia in the era of broad-spectrum antifungal therapies

We aimed to assess the characteristics, treatment, risk factors and outcome of patients with breakthrough candidaemia (BrC) in the era of broad-spectrum antifungal therapies. We carried out a multicentre study of hospitalized adults with candidaemia at six hospitals in three countries. BrC episodes were compared with the remaining episodes (non-BrC). Of 409 episodes of candidaemia, 37 (9%) were BrC. Among them, antifungal treatment was administered as prophylaxis in 26 severely immunosuppressed patients (70%) and as a fever-driven approach in 11 (30%). Candida albicans was significantly less common in patients with BrC (24% versus 46%, p 0.010) whereas Candida krusei was more frequent (16% versus 2.4%, p < 0.001). BrC was associated with infections caused by fluconazole non-susceptible isolates (50% versus 18%, p < 0.001). Candida albicans BrC was associated with previous fluconazole treatment whereas Candida parapsilosis candidaemia was mostly catheter-related and/or associated with previous echinocandin therapy. The empirical antifungal therapy was more often appropriate in the non-BrC group (57% versus 74%, p 0.055). No significant differences were found in outcomes (early and overall mortality: 11% versus 13% p 0.802 and 40% versus 40% p 0.954, respectively). Fluconazole non-susceptibility was independently associated with the risk of BrC (adjusted OR 5.57; 95% CI 1.45–21.37). In conclusion, BrC accounted for 9% of the episodes in our multicentre cohort. The Candida spp. isolated were different depending on the previous antifungal therapy: previous azole treatment was associated with fluconazole non-susceptible strains and previous echinocandin treatment was associated with BrC caused by C. parapsilosis. These results should be taken into account to improve the empirical treatment of BrC.

Rate ofFKSMutations among Consecutive Candida Isolates Causing Bloodstream Infection

Precise FKS mutation rates among Candida species are undefined because studies have not systematically screened consecutive, disease-causing isolates. The Sensititre YeastOne (SYO) assay measures echinocandin MICs against Candida with less variability than reference broth microdilution methods. However, clinical breakpoint MICs may overstate caspofungin nonsusceptibility compared to other agents. Our objectives were to determine Candida FKS mutation rates by studying consecutive bloodstream isolates and to determine if discrepant susceptibility results were associated with FKS mutations. FKS hot spots were sequenced in echinocandin-intermediate and -resistant isolates and those from patients with breakthrough candidemia or ≥ 3 days of prior echinocandin exposure. Overall, 453 isolates from 384 patients underwent susceptibility testing; 16% were echinocandin intermediate or resistant. Intermediate susceptibility rates were higher for Candida glabrata than for other species (P < 0.0001) and higher for caspofungin than for other agents (P < 0.0001). Resistance rates were similar between agents. FKS mutations were detected in 5% of sequenced isolates and 2% of isolates overall. Corresponding rates among C. glabrata isolates were 8% and 4%, respectively. Among Candida albicans isolates, rates were 5% and <1%, respectively. Mutations occurred exclusively with prior echinocandin exposure and were not detected in other species. Isolates with discrepant susceptibility results did not harbor FKS mutations. Mutation rates among isolates resistant to ≥ 2, 1, and 0 agents were 75%, 13%, and 0%, respectively. In conclusion, FKS mutations were uncommon among non-C. glabrata species, even with prior echinocandin exposure. Discrepancies in echinocandin susceptibility by SYO testing were not driven by mutations and likely reflect imprecise caspofungin clinical breakpoints.

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

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

Serum (1,3)-beta-D-glucan is an inefficient marker of breakthrough candidemia.

The aim of this study was to evaluate the usefulness of serum (1,3)-beta-D-glucan (BDG) for earlier detection of breakthrough candidemia. We reviewed the medical records of patients with candidemia from January 2008 to March 2013. Serum BDG was measured by Wako turbidimetric assay. During the study period, a total of 147 cases of candidemia were identified, and 31 patients met the criteria for breakthrough candidemia. Serum BDG levels were measured in 25 patients with breakthrough candidemia and 67 patients with nonbreakthrough candidemia. Almost all of the patients with breakthrough candidemia had hematological malignancies. More candidemia were caused by non-C. albicans Candida in the breakthrough group than in the nonbreakthrough group (92.0% vs. 61.8%, p = .005). The median BDG value was significantly lower in breakthrough episodes than in non-breakthrough episodes (18.5 pg/ml vs. 90.4 pg/ml, p = .01). Moreover, BDG values under the cutoff was significantly higher in patients with breakthrough candidemia than in those with nonbreakthrough candidemia (44% vs. 19%, p = .03). In summary, BDG alone was insufficient to detect breakthrough candidemia, and candidemia could occur in patients being treated with antifungal agents, even when the BDG value was under the cutoff value.

Breakthrough candidaemia caused by phenotypically susceptible Candida spp. in patients with haematological malignancies does not correlate with established interpretive breakpoints

In a study of 27,864 patients with haematological malignancies, 40 patients with candidaemia were identified, among whom 21 developed candidaemia while receiving systemic antifungal therapy [breakthrough candidaemia (BTC)]. Demographic, clinical, microbiological and molecular features of these episodes were analysed. Compared with 19 patients with de novo candidaemia, patients with BTC were more likely to have neutropenia (81% vs. 63%), longer median duration of neutropenia (27 days vs. 15 days), hypogammaglobulinaemia (62% vs. 37%) and central venous catheters (CVCs) (86% vs. 68%). The median duration of prior antifungal exposure was 46 days (range 3–108 days). Among the 18 available Candida spp. isolates, 15 (83%) were phenotypically susceptible to the antifungal agent that the patient was receiving. Emergence of resistance was the mechanism leading to BTC in three cases of patients receiving echinocandins. Other possible mechanisms of BTC were (i) elevated (≥2) minimum lethal concentration/minimum inhibitory concentration (MLC/MIC) ratio (reduced ability for a fungicidal agent to kill a fungal pathogen) in all patients receiving amphotericin B and (ii) elevated MLC/MIC ratios in all Candida parapsilosis isolates with MICs≤1μg/mL to echinocandins. DNA sequencing of the hotspot 1 region of the fks1 and fks2 genes in seven different isolates of C. parapsilosis group demonstrated P660A in Fks1 but no polymorphisms in fks2. In conclusion, mechanisms for BTC in the setting of prolonged neutropenia may be host-based (hypogammaglobulinaemia and CVC) and pathogen-based. CLSI interpretive breakpoints do not reliably predict BTC in patients with haematological malignancies and warrant further investigation.

Breakthrough Candidemia Due to Multidrug-Resistant Candida glabrata during Prophylaxis with a Low Dose of Micafungin

We identified a case of breakthrough candidemia in a 25-year-old patient receiving micafungin prophylaxis (50 mg/day). Five Candida glabrata isolates were obtained from blood cultures and were classified as multidrug-resistant isolates, since all of them exhibited high MICs for echinocandin and azole drugs. A mutation (S663F) in hot spot 1 of the FKS2 gene was found in all five isolates. This mutation yielded a 1,3-β-D-glucan synthase enzyme with highly reduced sensitivities to echinocandin drugs.

A prospective, cohort, multicentre study of candidaemia in hospitalized adult patients with haematological malignancies

Invasive candidiasis is a life-threatening infection in patients with haematological malignancies. The objective of our study was to determine the incidence, microbiological characteristics and clinical outcome of candidaemia among hospitalized adult patients with haematological malignancies. This is a population-based, prospective, multicentre study of patients ≥18 years admitted to haematology and/or haematopoietic stem cell transplantation units of nine tertiary care Greek hospitals from January 2009 through to February 2012. Within this cohort, we conducted a nested case-control study to determine the risk factors for candidaemia. Stepwise logistic regression was used to identify independent predictors of 28-day mortality. Candidaemia was detected in 40 of 27 864 patients with haematological malignancies vs. 967 of 1 158 018 non-haematology patients for an incidence of 1.4 cases/1000 admissions vs. 0.83/1000 respectively (p <0.001). Candidaemia was caused predominantly (35/40, 87.5%) by non-Candida albicans species, particularly Candida parapsilosis (20/40, 50%). In vitro resistance to at least one antifungal agent was observed in 27% of Candida isolates. Twenty-one patients (53%) developed breakthrough candidaemia while receiving antifungal agents. Central venous catheters, hypogammaglobulinaemia and a high APACHE II score were independent risk factors for the development of candidaemia. Crude mortality at day 28 was greater in those with candidaemia than in control cases (18/40 (45%) vs. 9/80 (11%); p <0.0001). In conclusion, despite antifungal prophylaxis, candidaemia is a relatively frequent infection associated with high mortality caused by non-C. albicans spp., especially C. parapsilosis. Central venous catheters and hypogammaglobulinaemia are independent risk factors for candidaemia that provide potential targets for improving the outcome.

Treatment of fungal disease in the setting of neutropenia

Invasive fungal infections are important causes of morbidity and attributable mortality in neutropenic patients with hematological malignancies, myelodysplasia, and aplastic anemia. Successful risk-based strategies can be implemented for prophylaxis, empirical therapy, and preemptive therapy for the prevention and early treatment of invasive fungal infections in neutropenic hosts. The use of echinocandins for invasive candidiasis and voriconazole for invasive aspergillosis has significantly improved outcome. Recent studies demonstrate, however, that resistant fungal pathogens may emerge during the course of these antifungal interventions. Although triazole-resistant Candida spp. have been well described as causes of breakthrough candidemia, other organisms now pose a similar threat. Such organisms include echinocandin-resistant Candida glabrata and Candida parapsilosis species complex. The Mucorales, Fusarium spp., and Scedosporium spp. may emerge in the setting of voriconazole prophylaxis. The challenges of these emerging pathogens underscore the need for the development of new antifungal agents and strategies.

Impact of Port-A-Cath device management in cancer patients with candidaemia

This study investigated the impact of management of a totally implantable central venous access port device, Port-A-Cath (Smith Medical, St. Paul, MN, USA), on the outcome of 98 cancer patients with candidaemia. Port-A-Cath retention was found to be significantly associated with poorer outcome, independent of other significant adverse factors [breakthrough candidaemia, Acute Physiology and Chronic Health Evaluation (APACHE) II score ≥ 21, and worse Eastern Cooperative Oncology Group (ECOG) performance score (3-4)]. However, retention of Port-A-Cath devices could be considered in patients who do not have definite catheter-related candidaemia, are not using total parenteral nutrition, do not have poor ECOG performance scores or APACHE II scores, and do not have septic shock.

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

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

Fluoresan İn Situ Hibridizasyon (FISH) Yöntemi ile Saptanan Yüksek Oranda Çoklu Kandidemi: Klinik ve Prognostik Anlamı Nedir?

Objective: The fluorescence in situ hybridization (FISH) with rRNA-targeted probes is a molecular method that allows identification of microorganisms in mixed assemblages from direct clinical samples without cultivitation. The aim of this study was to investigate the clinical features and risk factors in patients with single and multiple-species candidemia detected with FISH method and also to evaluate the episodes of breakthrough candidemia. Material and Methods: A total of 325 positive blood culture samples were examined between January and August 2004 in medical microbiology laboratory of Mersin University Hospital. The demographic and clinical data of 45 patients with candidemia detected with conventional culture methods, FISH and PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) were analyzed retrospectively, single and multiple-species candidemia were investigated among patients with candidemia and these patients were compared with respect to risk factors. Results: Thirty five (77.8%) of 45 patients with candidemia had a single Candida species and 10 (22.2%) had multiple-species detected by FISH method. Of these 45 cases, 31.1% had associated solid and hematologic malignancies. The mean duration of hospitalization was 27 (2-180) days. All patients had at least one indwelling catheter (urinary catheter: 80%, peripheric venous catheter: 55.6%, central venous catheter: 26.7%). Most of the patients (95.6%) had been treated with broad spectrum antibiotics. The candidemias were mostly caused by non-albicans Candida spp., particularly Candida parapsilosis (71.1%). The rate of breakthrough candidemia was detected in 11.1% of the patients with candidemia and all of these were in patients with single species candidemia. Surprisingly, in case of single-species candidemia, the mortality rate (77.8%) was higher than that of multiple-species candidemia (22.2%). Conclusion: According to our data, the indwelling catheters and treatment with multiple antibiotics were considered as the risk factors for single and multiple-species candidemia. Although the rate of multiple-species candidemia detected with FISH method was found to be high, clinical and prognostic significance of multiple-species candidemia are still debatable.

Abc1p Is a Multidrug Efflux Transporter That Tips the Balance in Favor of Innate Azole Resistance in Candida krusei

Most Candida krusei strains are innately resistant to fluconazole (FLC) and can cause breakthrough candidemia in immunocompromised individuals receiving long-term prophylactic FLC treatment. Although the azole drug target, Erg11p, of C. krusei has a relatively low affinity for FLC, drug efflux pumps are also believed to be involved in its innate FLC resistance. We describe here the isolation and characterization of Abc1p, a constitutively expressed multidrug efflux pump, and investigate ERG11 and ABC1 expression in C. krusei. Examination of the ERG11 promoter revealed a conserved azole responsive element that has been shown to be necessary for the transcription factor Upc2p mediated upregulation by azoles in related yeast. Extensive cloning and sequencing identified three distinct ERG11 alleles in one of two C. krusei strains. Functional overexpression of ERG11 and ABC1 in Saccharomyces cerevisiae conferred high levels of resistance to azoles and a range of unrelated Abc1p pump substrates, while small molecule inhibitors of Abc1p chemosensitized C. krusei to azole antifungals. Our data show that despite the presence of multiple alleles of ERG11 in some, likely aneuploid, C. krusei strains, it is mainly the low affinity of Erg11p for FLC, together with the constitutive but low level of expression of the multidrug efflux pump Abc1p, that are responsible for the innate FLC resistance of C. krusei.

In Vitro Susceptibility of Breakthrough Candida Bloodstream Isolates Correlates with Daily and Cumulative Doses of Fluconazole

We determined MICs for 28 Candida isolates recovered from patients who developed breakthrough candidemia while receiving fluconazole. MICs correlated with daily and cumulative doses of fluconazole. Patients receiving > or =2,000 mg cumulatively or >200 mg daily were more likely to be infected with isolates that were not fluconazole susceptible.

Risk factors and outcome for breakthrough candidaemia in patients with cancer

While candidaemia that develops during systemic antifungal prophylaxis or therapy [breakthrough (BT) candidaemia] has been reported increasingly, the risk factors and outcome of BT candidaemia are not yet known definitely. We evaluated a consecutive series of cancer patients with candidaemia at Asan Medical Center during 6 years to identify risk factors and outcome in BT candidaemia comparing with non-BT candidaemia. Fifty-four episodes of candidaemia in cancer patients diagnosed during this period were reviewed retrospectively. There were 10 episodes (18.5%) of BT candidaemia in which the species distribution and frequency of catheter-related infection in the BT and non-BT groups were similar. BT candidaemia had a tendency to occur more frequently in patients with haematological than non-haematological diseases. Profound neutropenia and disseminated candidiasis were more common in the BT group; however, these differences were not statistically significant (P = 0.17 and 0.07 respectively). The duration of prior antibiotic therapy and duration of profound neutropenia (<100 mm(-3)) were identified as risk factors for BT candidaemia (P < 0.01 and 0.02 respectively) in univariate analysis and the latter was the only risk factor in multivariate analysis. The death rates due to candidaemia were 85.7% in the BT group and 42.9% in the non-BT group (P = 0.08); however, BT candidaemia alone did not increase mortality rate.

Early Presumptive Therapy with Fluconazole for Occult Candida Infection after Gastrointestinal Surgery

The objective of this retrospective comparative study was to improve the outcome of patients with suspected occult Candida infection after gastrointestinal surgery by early presumptive therapy. It was conducted in the National Cheng Kung University Hospital in Taiwan. A total of 36 patients with prolonged ileus with fever after gastrointestinal tract surgery between January 1995 and December 2002 were examined for two time periods: those treated before and those treated after January 1999. One set of patients did not receive early presumptive therapy (EPT) until Candida infection was confirmed, and they were designated EPT(-). Another group of patients with suspected occult Candida infection received EPT and were designated EPT(+). Fluconazole, 400 mg/day, was given as EPT. Urine, wound, intraperitoneal drainage, and blood specimens were obtained from patients for fungus culture before starting treatment and weekly until symptoms subsided. The primary endpoints were the frequency of candidiasis and the persistence of candidemia; the secondary endpoint was the efficiency of EPT in the clinical outcome. There was no difference in Candida peritonitis, wound colonization, or urine colonization in the two treatment groups. Candida albicans accounted for 87.5%% of the isolated Candida species: 84.6%% in the EPT(+) group and 89.5%% in the EPT(-) group. In the EPT(+) group, the positive blood culture rate was 66.7%%. The fever subsided rapidly in 17 patients (94%%), the hospital stay and intensive care unit stay were shorter, and the mortality decreased significantly: 11%% vs. 78%%, P < 0.001. Persistent gastrointestinal ileus was the main cause of breakthrough candidemia. We concluded that EPT with fluconazole improves the prognosis of patients with occult Candida infection after gastrointestinal surgery. Surgical intervention was required in patients with breakthrough candidemia.

Breakthrough Invasive Infection Due to Debaryomyces hansenii (teleomorph Candida famata) and Scopulariopsis brevicaulis in a Stem Cell Transplant Patient Receiving Liposomal Amphotericin B and Caspofungin for Suspected Aspergillosis

An allogeneic stem cell transplant recipient developed pulmonary infiltrates and Aspergillus antigenemia during prophylactic low-dose liposomal amphotericin B. No response to therapy was observed after increasing the dose of liposomal amphotericin B and addition of caspofungin, and breakthrough candidemia developed. Therapy switch to voriconazole did not prevent the development of lethal septic shock. Shortly before death, Scopulariopsis brevicaulis was cultured from bronchial secretions, and positive blood cultures demonstrated persistent candidemia due to Debaryomyces hansenii, teleomorph of Candida famata.

Galactomannan and Computed Tomography-Based Preemptive Antifungal Therapy in Neutropenic Patients at High Risk for Invasive Fungal Infection: A Prospective Feasibility Study

Empirical antifungal therapy is the standard treatment for persistent or relapsing antibiotic-resistant neutropenic fever. However, overtreatment resulting in increased toxicity and treatment-related cost is a major shortcoming of such therapy. We assessed the feasibility of a "preemptive" approach based on the incorporation of sensitive, noninvasive diagnostic tests for consecutive high-risk neutropenic patients who had received fluconazole prophylaxis while avoiding empirical therapy. A total of 136 treatment episodes for persons who were at risk of acquiring invasive fungal infection (IFI) were screened for the presence of galactomannan with an enzyme immunoassay. A diagnostic evaluation, which included thoracic computed tomography scanning (HRCT) and bronchoscopy with lavage, was performed on the basis of well-defined clinical, radiological, and microbiological criteria. Only seropositive patients and patients with a positive microbiological test result plus supportive radiological findings received liposomal amphotericin B. Neutropenic fever developed in 117 episodes, of which at least 41 episodes (35%) satisfied existing criteria for empirical antifungal therapy. However, our protocol-driven preemptive approach reduced the rate of antifungal use for these episodes from 35% to 7.7% (a 78% reduction) and led to the early initiation of antifungal therapy in 10 episodes (7.3%) that were clinically not suspected of being IFI. No undetected cases of invasive aspergillosis were identified; 1 case of zygomycosis was missed. Breakthrough candidemia was diagnosed by conventional culture techniques and was treated successfully. With use of a preemptive approach, the 12-week survival rate for patients with IFI was 63.6% (it was 63.1% for those with invasive aspergillosis). Preemptive therapy based on enzyme immunoassay and HRCT reduced the exposure to expensive and potentially toxic drugs and offered effective antifungal control, but it failed to detect non-Aspergillus IFI.