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Candida krusei Fungemia
An Escalating Serious Infection in Immunocompromised Patients
Jalal Abbas, MD;
Gerald P. Bodey, MD;
Hend A. Hanna, MD, MPH;
Masoud Mardani, MD;
Essam Girgawy, MD;
Dima Abi-Said, PhD;
Estella Whimbey, MD;
Ray Hachem, MD;
Issam Raad, MD
Arch Intern Med. 2000;160:2659-2664.
ABSTRACT
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Background Candida krusei is inherently resistant to fluconazole and is emerging as a frequent cause of fungemia in patients with hematologic malignant neoplasms.
Objective To determine the risk and prognostic factors associated with C krusei fungemia in comparison with Candida albicans fungemia in patients with cancer.
Methods Retrospective study of 57 cases of C krusei fungemia occurring at the M. D. Anderson Cancer Center, Houston, Tex, from 1989 to 1996. The C krusei cases were compared with 57 cases of C albicans fungemia with respect to demographics, underlying cancer, Acute Physiology and Chronic Health Evaluation II score, immunosuppression status, chemotherapy, and the use of central venous catheters, as well as fluconazole prophylaxis.
Results At our institution, C krusei accounted for 5% of fungemias during 1989 through 1992 and for 10% during 1993 through 1996. Patients with C krusei fungemia more often had leukemia than patients with C albicans (77% vs 11%; P = .02), whereas catheter-related infections were more common among patients with C albicans fungemia (42% vs 0%; P<.001). Patients with C krusei fungemia had a lower response rate (51% vs 69%; P = .05), largely because they more frequently were neutropenic and had disseminated infection. Mortality related to fungemia was 49% in the cases with C krusei vs 28% in C albicans. Multiple logistic regression analysis showed that persistent neutropenia (P = .02) and septic shock (P = .002) were predictors of poor prognosis.
Conclusion In neutropenic patients, C krusei fungemia is associated with high mortality. It should be suspected in patients with leukemia who are receiving fluconazole prophylaxis and should be treated aggressively with an amphotericin B regimen.
INTRODUCTION
FOR MANY years, nearly all cases of candidemia were caused by Candida albicans. During the past decade, Candida tropicalis emerged as an important pathogen, especially among patients with cancer.1-3 More recently, other Candida species have proved to be responsible for an increased proportion of candidemias, and Candida krusei has become one of the most frequent of these emerging pathogens, especially among patients with acute leukemia.2, 4 Candida krusei is inherently resistant to fluconazole, and many of the infections caused by this organism have been associated with the prophylactic or therapeutic use of this antifungal agent.5-6 Since most institutions have had limited experience with C krusei fungemia, we reviewed all cases occurring at our institution during a 7-year period. A control group of patients with C albicans fungemia was selected to determine risk factors that were unique for the acquisition of C krusei fungemia.
PATIENTS AND METHODS
The records of the Microbiology Laboratory of The University of Texas M. D. Anderson Cancer Center, Houston, were reviewed for the period from January 1, 1989, through December 31, 1996, to identify all cases of hematogenous candidiasis. Of the 885 cases, 60 were caused by C krusei, and the medical records of 57 of these cases were available for review. A case-control study was conducted by selecting 57 patients with C albicans fungemia as the control group. The two groups were matched with respect to time of the first positive blood culture for C krusei and C albicans fungemia within each of the two periods, 1989 through 1992 and 1993 through 1996.
The medical records of all cases and controls were reviewed and the following information was determined for the 30 days before collection of the first positive blood culture and subsequently during the course of infection: age, sex, underlying malignant neoplasm, Acute Physiology and Chronic Health Evaluation II score (at onset of fungemia), duration of hospitalization, duration of stay in intensive care unit, and duration of neutropenia. In addition, we recorded during this interval the administration of antibiotics, adrenal corticosteroids, total body irradiation, cancer chemotherapeutic agents, immunosuppressive agents (cyclosporine, tacrolimus), parenteral alimentation, and antifungal prophylaxis.
DEFINITIONS
A patient was determined to have candidemia if C krusei or C albicans was isolated from at least 1 blood culture specimen, associated with fever or signs of organ infection. Fungemias occurring between 1989 and 1992 have been included in previous reports.2, 7 Patients were considered to have disseminated infection if, in addition to fungemia, there was clinical or histopathological evidence of infection in at least 1 internal organ and a Candida species was identified, or the same species was isolated from a tissue specimen. Infection was also considered to be disseminated when the Candida species was isolated from blood culture specimens collected on 3 separate days from a neutropenic patient in whom a catheter was not the source of fungemia.
Neutrophil counts were categorized as less than 0.50 x 109/L and less than 0.10 x 109/L. Neutropenia was defined in this study as a neutrophil count of less than 0.50 x 109/L, since the results were similar for the 2 categories of neutropenia. Shock was defined as a decrease in systolic blood pressure of 40 mm Hg or more, or a systolic blood pressure less than 90 mm Hg in a previously normotensive patient, not related to other possible causes. An infection was considered to be catheter related if the catheter tip was notably colonized with the same Candida species as the bloodstream ( 15 colony-forming units by the roll plate semiquantitative method) or the quantitative blood culture collected through the central venous catheter had a 10-fold greater colony count than the concurrent peripheral venous quantitative blood culture specimen.
Response was defined as the resolution of all clinical manifestations with blood cultures negative for Candida species for at least 1 week after therapy. Failure to respond was defined as the persistence of the clinical signs and symptoms of the fungal infection or persistent candidemia caused by the same Candida species after onset of therapy. Death was attributed to Candida infection if the patient had demonstrated no response to therapy and there was no other obvious cause of death, such as major hemorrhage or other infection.
DATA ANALYSIS
The incidence density of hematogenous candidiasis was computed as the number of cases during a period per 10,000 hospital discharges. Frequencies and descriptives of demographic and clinical characteristics of the patient population were performed. The  2 test and the Fisher exact test were used to determine categorical predictors of infections and outcome. Continuous variables were compared by means of the t test. Multiple predictors were examined for significance by multiple logistic regression with the use of backward elimination by the Wald test. P values of less than .05 were considered statistically significant. All statistical analyses were performed with SPSS, version 8.0 for Windows (SPSS, Inc, Chicago, Ill).8
RESULTS
FEATURES OF C krusei INFECTION
There were 57 cases of C krusei fungemia from 1989 to 1996. The frequency increased significantly from 2.5 per 10,000 hospital discharges during 1989 through 1992 to 5.7 per 10,000 during 1993 through 1996 (P = .004). Candida krusei accounted for 5% of all candidemias during the former period and 10% during the latter period. Nearly all patients had hematologic malignant neoplasms, especially acute leukemia (Table 1). Only 8 infections (14%) were considered to be community acquired.
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Table 1. Patient Demographics and Clinical Characteristics*
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Forty-nine patients (86%) with C krusei fungemia had received fluconazole prophylaxis; this proportion increased from 78% to 90% during the 2 periods, and the mean duration of prophylaxis increased from 12 days (range, 4-32 days) to 19 days (range, 6-47 days). The response rate for the 49 patients who received fluconazole prophylaxis was similar to that for the 8 patients who did not (51% [25 patients] vs 50% [4 patients]). One of the 8 patients was treated empirically with fluconazole and responded. Eleven patients (all with neutropenia) developed C krusei fungemia while receiving amphotericin B for persistent fever presumed to be caused by fungal infection. The dose administered was 0.35 to 0.5 mg/kg per day for 2 to 36 days (mean, 13 days). Only 3 of the patients recovered from their infection, which was associated with resolution of neutropenia and an increase in the dose of amphotericin B.
Fifty-one patients (89%) were neutropenic at the onset of their infection, and the mean duration of neutropenia before onset of infection was 18 days (range, 3-95 days). Twenty-one (37%) of the patients had disseminated infection, and 18 (86%) of these patients were neutropenic at the onset of their infection. None of the C krusei fungemias was considered to be catheter related.
Twenty-nine (51%) of the patients responded to therapy, and the remaining 28 patients died with their infection (Table 2). Twenty-four of the latter 28 patients were considered to have died primarily of their infection. Among those patients who died, 22 (79%) remained neutropenic throughout their infection and 18 (64%) had disseminated infection. The mortality rate was 81% (17 patients) for patients with persistent neutropenia and 86% (18 patients) for patients with disseminated infection. Only 11 patients (31%) who were not neutropenic or whose neutropenia resolved during therapy died of their infection. None of the patients who had solid tumors or were in remission of their malignant neoplasm died of their infection.
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Table 2. Differences in Outcome Between Candida krusei and Candida albicans
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Nine patients were initially treated with fluconazole, and 2 responded to this therapy. Both of these patients had neutropenia at the onset of their infection that resolved during therapy. The remaining 7 patients' therapy was changed to amphotericin B, usually when the fungus was identified as C krusei. Forty-nine patients received amphotericin B deoxycholate or a lipid formulation of amphotericin B, and 25 (51%) of the cases responded. Among the 25 responders, 21 (84%) were not neutropenic or had recovered from neutropenia.
Univariate analysis indicated that a poor response was associated with persistent neutropenia, disseminated infection, septic shock, other concomitant fungal infection, and immunosuppressive therapy (Table 3). Multiple logistic regression analysis identified that persistent neutropenia (P = .02) and septic shock (P = .002) were the only significant multiple predictors for a poor prognosis.
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Table 3. Effect of Different Prognostic Factors on Response of Candida krusei Infection*
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DEMOGRAPHIC AND CLINICAL GROUP CHARACTERISTICS
The characteristics of the 2 patient groups are described in Table 1. Several statistically significant differences (P .05) were identified between the patients with C krusei and C albicans fungemia. Patients in the former group were somewhat younger and were predominantly patients with acute leukemia. A greater proportion of these patients had received cancer chemotherapy or total body irradiation, received a bone marrow transplant within the preceding year, were neutropenic, and had prolonged neutropenia. The proportion of patients who received fluconazole prophylaxis was significantly higher among patients with C krusei fungemia. Catheter-related fungemia occurred only among patients with C albicans fungemia. Disseminated infection occurred more often in patients with C krusei fungemia (37% vs 21%; P = .06). Interestingly, 18 (86%) of the 21 patients with disseminated C krusei infection were neutropenic, compared with only 4 (33%) of the 12 patients with disseminated C albicans infection. The majority of both C krusei and C albicans infections were considered to be nosocomial.
A significantly greater proportion of patients with C krusei fungemia had leukemia (P = .02) and had received antifungal prophylaxis (P<.002), most often with fluconazole (P = .03). On the other hand, a significantly greater proportion of patients with C albicans fungemia had catheter-related infections (P<.001).
The response rate was higher among patients with C albicans infections (69% vs 51%; P = .05), largely because more patients with C krusei fungemia were neutropenic and had disseminated infection (Table 2). Among patients who died, a higher proportion of patients with C albicans fungemia were not neutropenic or had recovered from neutropenia (11 patients [69%] vs 11 [39%]; P = .06). Fluconazole and amphotericin B were equally efficacious for treatment of C albicans fungemia (79% vs 71%). A trend was found to suggest that amphotericin B was more effective for the treatment of C albicans than C krusei infection (71% vs 51%; P = .18).
COMMENT
Candida krusei is an infrequent cause of fungemia. At most institutions, this Candida species accounts for only 3.5% to 4.5% of fungemias.2, 9-10 In a literature review of candidemias, Wingard1 found that only 4% were caused by C krusei. Our analysis represents the largest series of C krusei fungemias from a single institution. The largest previous report was a collated review of 62 cases.6 Approximately 90% of cases have occurred in patients with acute leukemia or aplastic anemia or bone marrow transplant recipients, and very few cases have been reported in patients who did not have cancer. Neutropenia has been present in 80% to 90% of patients with this infection.6, 9-10 In our matched-pair analysis, acute leukemia and neutropenia were significant predisposing factors for C krusei fungemia.
The frequency of C krusei fungemia has increased substantially at several institutions, beginning in the early 1990s. Candida krusei is inherently resistant to fluconazole, and this increase in infections has been attributed to the use of fluconazole, especially for fungal prophylaxis. Wingard et al5 first reported this association among neutropenic patients treated in 1989 to 1990. Candida krusei colonization was found in 41% of patients who received fluconazole prophylaxis compared with 17% of patients who received no prophylaxis. The frequency of disseminated infection was 8% and 1%, respectively. They also found that norfloxacin antibacterial prophylaxis increased the risk of C krusei colonization. However, Merz et al11 reported an increase in C krusei colonization and infection among neutropenic patients treated at the same institution from 1977 to 1985, before fluconazole was available. At that time, the frequency of colonization was 12.4%, and 1.2% developed fungemia. Some of these patients had received miconazole prophylaxis.
At our institution, the frequency of C krusei fungemia doubled from 5% in 1989 to 1992 to 10% in 1993 to 1996. In 1993, fluconazole became widely used as a prophylactic agent in patients with hematologic malignant neoplasms. In addition, fluconazole usage was a significant predisposing factor in our analysis. In the review by Goldman et al,6 82% of the patients had received fluconazole before their infection. Nguyen et al10 reported 34 cases of candidemia occurring while patients were receiving fluconazole, and 7 were caused by C krusei. They found fluconazole use to be an important predisposing factor for C krusei fungemia. However, not all studies have linked fluconazole use to increased colonization and infection by this yeast. Iwen et al12 found that 4% of invasive Candida infections were caused by C krusei and none of the patients had received fluconazole. In 2 multi-institutional randomized studies of fluconazole prophylaxis in neutropenic patients, the frequency of C krusei colonization and infection was similar among patients receiving fluconazole and placebo.13-14 Likewise, in a randomized study of bone marrow transplant recipients who received fluconazole or placebo for 75 days after transplantation, there was no significant difference in colonization rates and no infections in either group.15 It may be that there are nosocomial sources of C krusei within some hospitals and that colonization and infection are facilitated by the selective effect of fluconazole usage.
Several studies have found that about 70% of patients develop colonization by C krusei before the onset of infection.6, 9-10 Merz et al11 found that the gastrointestinal tract was the most frequent site of colonization, followed by the respiratory tract. Goldman et al6 found mucosal damage of the gastrointestinal tract in 68% of infected patients. Hence, the sequence of events leading to C krusei infection may be colonization facilitated by fluconazole administration, local infection caused by mucositis, and subsequent hematogenous dissemination caused by neutropenia. Although the majority of patients have intravascular catheters inserted before infection, our study and that of Merz et al11 did not find these catheters to be a source of fungemia.
In our study, only 37% of patients were considered to have disseminated infection, which may be an underestimate. The true frequency of disseminated infection is often difficult to ascertain because this infection is usually manifested by many small abscesses involving multiple organs that do not cause organ-specific symptoms. Hence, many disseminated infections are detected only at autopsy examination. In 2 studies among patients with C krusei fungemia who died and underwent autopsy examination, 67% and 100% were found to have disseminated infection.9, 11
The mortality rate in our study among patients with C krusei fungemia was 49% overall but was 93% among patients with persistent neutropenia and 83% among those with disseminated infection. The mortality rate was lower among patients with C albicans fungemia (28%), which was because of a lower frequency of neutropenia and a higher frequency of catheter-related fungemias. Previous studies of candidemia have found mortality rates of 90% or higher among patients with cancer who have persistent neutropenia or disseminated infection.16-17 Other studies have found mortality rates of 60% to 80% in patients with C krusei fungemia.6, 9, 11
Several studies have demonstrated that isolates of C krusei may be less susceptible to amphotericin B in vitro than isolates of C albicans.18-19 Berrouane et al20 considered C krusei to be a multiple-drug–resistant pathogen. In our study, 19% of C krusei fungemias first occurred while patients were receiving 0.35 to 0.5 mg of amphotericin B per kilogram per day, and Blumberg and Reboli21 reported breakthrough fungemia when even higher doses of amphotericin B were administered. In our study, response rates have been higher when daily doses of 1 mg or more of amphotericin B per kilogram were used. It is somewhat difficult to interpret these data because most infections occur in neutropenic patients and response to amphotericin B is dependent on neutrophil recovery.16 Although C krusei is inherently resistant to fluconazole, occasional infections have responded to fluconazole, including those in 2 neutropenic patients in our study whose neutrophil counts recovered during therapy. Itraconazole usually is active against C krusei in vitro, but its use for the treatment of serious infections has been limited because of the lack of an intravenous preparation and the variability of absorption of the initial oral preparation.22
Candida species other than C albicans now account for nearly half of the cases of hematogenously disseminated candidiasis at many institutions.1, 10 Although C krusei accounts for only a modest proportion of these infections, it is increasing substantially at some leukemia and bone marrow transplant centers where fluconazole is being used extensively for prophylaxis. While the association is obviously of concern, it is offset by the overall beneficial effect of this antifungal prophylaxis against other Candida species.2, 15 In patients with hematologic malignant neoplasms, C krusei fungemia is associated with a high frequency of dissemination and mortality. Since C krusei may be less susceptible to amphotericin B than other Candida species, the daily dose of amphotericin B used as empirical antifungal therapy probably should be 1 mg/kg at institutions where C krusei infections are prevalent.
AUTHOR INFORMATION
Accepted for publication February 1, 2000.
We thank Jack Thornby, PhD, for his revision of the study and for his valuable comments.
Reprints: Hend A. Hanna, MD, MPH, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
From the Sections of Infection Control and Infectious Diseases, Department of Internal Medicine Specialties (Drs Abbas, Bodey, Hanna, Mardani, Girgawy, Whimbey, Hachem, Raad) and Department of Neurosurgery (Dr Abi-Said), The University of Texas M. D. Anderson Cancer Center, Houston.
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