Risk Factors for PulmonaryAspergillus terreusInfection in Patients With Positive Culture for Filamentous Fungi

CHEST

Original Research RESPIRATORY INFECTION

Risk Factors for Pulmonary Aspergillus terreus Infection in Patients With Positive Culture for Filamentous Fungi* Juan Jose´ Casto´n, MD; Marı´a Jose´ Linares, MD; Carolina Gallego, MD; Antonio Rivero, MD; Pilar Font, MD; Francisco Solı´s, MD; Manuel Casal, MD; and Julia´n Torre-Cisneros, MD

Background: Invasive aspergillosis (IA) is a common fungal infection in immunocompromised patients and has a high mortality rate. Among patients with IA, Aspergillus terreus infections have become a growing concern in the past few years. Objective: To determine the clinical risk factors for isolation of and respiratory infection by A terreus in patients with culture findings positive for filamentous fungi. Methods: Cohort study of 505 consecutive isolates of filamentous fungi in 332 patients from one center. A terreus was present in 46 isolates from 40 patients (9.1%). Clinical histories were reviewed to identify the risk factors related to isolation of and infection by A terreus, which were grouped into three categories (ie, host factors, factors related to immunosuppression, and factors related to hospitalization), and were analyzed using a multiple logistic regression model. Results: A total of 192 of 505 isolates studied (38%) were due to invasive respiratory infection. A total of 27 of 46 cultures (58.7%) that were positive for A terreus were due to invasive infection (odds ratio [OR], 2.53; 95% confidence interval [CI], 1.37 to 4.69; p ⴝ 0.034). The factors associated with invasive A terreus infection were prophylactic use of amphotericin B aerosols (OR, 27.8; 95% CI, 6.7 to 109.7; p ⴝ 0.001) and mechanical ventilation (OR, 3.3; 95% CI, 1.02 to 10.9; p ⴝ 0.04). Transplantation was associated with a lower risk of A terreus infection (OR, 0.2; 95% CI, 0.046 to 0.789; p ⴝ 0.02). Conclusions: In patients with culture findings positive for filamentous fungi, the prophylactic use of amphotericin B aerosols and mechanical ventilation are associated with a higher risk of A terreus infections. In these patients, transplantation is associated with a lower risk of isolation and respiratory infection by A terreus. (CHEST 2007; 131:230 –236) Key words: amphotericin B; Aspergillus terreus; fungal infection; risk factor Abbreviations: CI ⫽ confidence interval; IA ⫽ invasive aspergillosis; OR ⫽ odds ratio

aspergillosis (IA) is a common fungal I nvasive infection in immunocompromised patients and has a high mortality rate.1,2 Although few studies have been conducted, Aspergillus terreus infections have become a growing concern in the past few *From the Unit of Infectious Diseases (Drs. Casto´n, Rivero, Font, and Torre-Cisneros), and the Departments of Microbiology (Drs. Linares, Solı´s, and Casal) and Internal Medicine (Dr. Gallego), Reina Sofı´a University Hospital, Co´rdoba, Spain. This work was supported in part by Fondo Investigaciones Sanitarias de la Seguridad Social (grant No. G03/075 RESITRA). The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. 230

years.3– 8 This is because the available data indicate that this fungus may have differential epidemiologic features, a more aggressive clinical behavior, and a higher mortality rate than infection by other AsManuscript received March 24, 2006; revision accepted August 4, 2006. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Julian Torre-Cisneros, MD, Unidad de Sesho´u Clinico de Enfermedades Infecciosas, Hospital Universitario Reina Sofı´a, Avda Mene´ndez Pidal sn, 14004-Co´rdoba, Espan˜a; e-mail: [email protected] DOI: 10.1378/chest.06-0767 Original Research

pergillus species.5 Consequently, and particularly since the emergence of new therapeutic options such as modern triazoles, the identification of clinical risk factors for respiratory colonization and infection by A terreus vs other filamentous fungi may be useful in prescribing special management, which should consist of more intensive surveillance and the early institution of antifungal therapy for these patients. Our objective therefore was to identify the clinical risk factors for both the isolation of and infection by invasive A terreus in patients with positive culture findings for filamentous fungi from respiratory samples. Materials and Methods Study Population A retrospective cohort study was performed involving 505 consecutive isolates of filamentous fungi in 332 patients who had been hospitalized or treated as outpatients in a single hospital between 1994 and 2004. The identified isolates were from the following respiratory samples: (1) sputum (considered valid when ⬍ 10 epithelial cells and ⬎ 25 polymorphonuclear cells were observed on a Gram stain); (2) BAL fluid; (3) bronchial aspirate; (4) fine-needle aspiration; and (5) lung biopsy specimen. Isolation of the same type of filamentous fungus in more than one respiratory sample within a period of ⬍ 30 days was considered as a single episode, from either colonization or infection. Contamination was defined as the presence of several filamentous fungi in the respiratory sample without a clear predominance of any one type in an asymptomatic patient. Once isolates were obtained, cases corresponding to proven or probable invasive fungal infections were determined according to the criteria established by the European Organization for Research and Treatment of Cancer and the Mycoses Study Group of the National Institute of Allergy and Infectious Diseases.9 In summary, proven fungal infection was defined as the presence of a positive culture findings for a filamentous fungus and histopathologic evidence of tissue damage, or the recovery of positive culture findings from a normally sterile site and clinical

or radiologic signs consistent with infection. Probable fungal infection was defined as the isolation of a filamentous fungus from a valid respiratory sample in a susceptible symptomatic patient. Isolates that did not meet these criteria were considered to be colonizations. The variables analyzed as possible risk factors for positive culture and infection by A terreus were grouped into the following three categories (Table 1): patient characteristics; factors related to immunosuppression; and factors related to hospitalization. Some patients were included in two different categories with respect to their baseline disease because at the time of the different episodes of infection their baseline disease had changed (ie, patients with cystic fibrosis who subsequently underwent lung transplantation). Nosocomial infection was defined as an episode of infection due to a filamentous fungus that was absent at hospital admission and was diagnosed ⬎ 48 h after hospital admission, or if isolation of the fungus was obtained ⬍ 48 h after hospital discharge. Mechanical ventilation was considered in those patients who had required this procedure for ⬎ 3 days at the time of the isolation of the filamentous fungus. The different regimens of antifungal prophylaxis used in the cohort were as follows: fluconazole (400 mg/d); nystatin (500,000 IU/6 h); IV amphotericin B deoxycholate (0.5 mg/kg/d); and aerosol amphotericin B deoxycholate (15 mg/d). Aerosols were prepared by reconstituting a 50-mg vial of amphotericin B (Fungizone; Bristol-Myers Squibb; Princeton, NJ) with 10 mL of sterile water for injection. Once dissolved, 3 mL were taken with a syringe and brought to a volume of 15 mL with water for injection. The solution was then added to a 15-mL vial through a 5-␮m filter, labeled, and stored protected from light. Amphotericin B aerosols were considered to be related to the episode of infection or respiratory disease when the patient had received them in the month prior to the isolation of the filamentous fungus. Either amphotericin B deoxycholate (1 to 1.5 mg/kg/d) or liposomal amphotericin B (3 to 5 mg/kg/d) [AmBisome; Gilead; Foster City, CA] were used as antifungal treatment. Patients or guardians were required to give written informed consent before inclusion in the study. The protocol was approved by the Institutional Review Board. Statistical Analysis The episodes of invasive respiratory infection and colonization were divided into those caused by A terreus or those caused by

Table 1—Variables Included in Univariate and Multivariate Analysis Factors Host factors

Factors related to immunosuppression

Factors related to hospitalization

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Description Baseline pulmonary disease; Concomitant infections caused by bacteria, yeast-like fungi or viruses; and Transplantation Neutropenia (⬍ 500 neutrophils/␮L); Lymphopenia. (⬍ 500 lymphocytes/␮L); and Use of immunosuppressive therapy (including steroids) within 1 mo prior to the episode of infection Nosocomial infection; Days of hospitalization prior to the episode of infection; ICU stay (during the episode of infection or within the 15 previous days); Presence of a central venous catheter at the time of isolation or within the 3 previous days; Use of total parenteral nutrition during the episode of infection; Use of invasive mechanical ventilation; Prior use of broad-spectrum antibiotic therapy for ⬎ 7 d; Prior prophylactic or therapeutic use of an antifungal agent other than amphotericin B; and Prior prophylactic or therapeutic use of amphotericin B

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other filamentous fungi. Frequencies and percentages were calculated for qualitative variables. Quantitative variables were expressed as the mean ⫾ SD with 95% confidence intervals (CIs). The ␹2 test and Fisher exact test were used to study the relationship between two qualitative variables. Univariate logistic regression analysis was performed for each of the study variables to determine their association with the variable A terreus isolation and infection vs the remaining cases of isolates and infection by other filamentous fungi. The degree of association was estimated by the odds ratio (OR) and 95% CI. Variables with p values ⱖ 0.15 were eliminated one by one from the model. Comparison of the reduced model with the model including the eliminated variables was performed using the likelihood ratio test (G statistic). Variables with a significance of ⬎ 0.05 were studied as possible confounding factors and were considered as such if the percentage change in the coefficients was ⬎ 15%. Baseline disease was stratified into the following four groups: transplant recipients; cystic fibrosis; underlying lung disease; and other diseases (eg, chronic renal failure, multiple trauma, solid and hematological tumors, chronic liver disease, and heart disease). Then, they were entered into the analysis as a dummy variable, setting the transplant category as the reference group.

Results Description of Isolates and Population A total of 505 cultures positive for filamentous fungi (Table 2) were obtained in 332 patients with a mean age of 45 years (range, 3 months to 93 years). Of the 332 patients, 103 (31%) were recipients of either solid organ or hematopoietic stem cell transplants, 44 (13.2%) had cystic fibrosis, and 37 (11%) had COPD. The remaining patients had other diseases such as HIV infection (8.4%), hematologic malignancies (6.9%), and interstitial lung disease (5.4%). A different distribution for colonization and invasive fungal infection was founded in each spe-

Table 2—Distribution of Isolates of Filamentous Fungi from 1994 to 2004 Isolates

Episodes, No.

%

A fumigatus A terreus A niger Penicillium spp Scedosporium apiospermum Aspergillus flavus Alternaria spp Fusarium oxyosporum Fusarium solani Paecilomyces lilacinus Cladosporium spp Aspergillus nidulans Mucor racemosus Fusarium verticillioides Rhizomucor pusillus Aspergillus ustus Trichoderma longibrachiatum Total

300 46 41 40 27 16 7 5 5 4 4 3 3 1 1 1 1 505

59.4 9.1 8.1 7.9 5.3 3.2 1.4 1 1 0.8 0.8 0.6 0.6 0.2 0.2 0.2 0.2 100

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cific underlying disease (Fig 1). The overall incidence of isolates was 1.73 cases per 10,000 patients per year. The largest percentage of positive culture findings was observed from 1998, coinciding with a hospital renovation (Fig 2). Of the total number of isolates, 300 were due to Aspergillus fumigatus (59.4%), 46 were due to A terreus (9.1%), and 41 were due to Aspergillus niger (8.1%). When episodes of colonization and infection were analyzed for each filamentous fungus (Table 3), it was found that 127 of the 300 isolates of A fumigatus (42.3%) corresponded to infection, without a statistical difference compared to episodes of colonization. However, 27 of the 46 isolates of A terreus (58.7%) corresponded to invasive infection, and a significant difference was found compared to episodes of colonization (OR, 2.53; 95% CI, 1.37 to 4.69; p ⫽ 0.034). Risk Factors for Positive Culture by A terreus After the univariate analysis, multiple logistic regression analyses were performed with the variables that had been considered to be clinically significant (based on our experience and the literature). The variables included in the model were nosocomial infection, use of broad spectrum antibiotics, mechanical ventilation, immunosuppressive therapy, need for central venous catheter, lymphopenia, granulocytopenia, use of azoles, use of IV or aerosolized amphotericin B prophylaxis, concomitant cytomegalovirus infection, and transplantation. The multivariate analysis showed that prophylaxis with amphotericin B aerosols (OR, 31.4; 95% CI, 12.1 to 81.9; p ⫽ 0.001) and mechanical ventilation (OR, 2.7; 95% CI, 1.2 to 6.9; p ⫽ 0.01) were associated with a higher risk that the isolated filamentous fungus would be A terreus (Table 4). In contrast, transplantation was associated with a lower risk of A terreus infection (OR, 0.2; 95% CI, 0.1 to 0.6; p ⫽ 0.006). Risk Factors for Invasive Respiratory Infection by A terreus As in the case of cultures with positive findings, prophylaxis with amphotericin B aerosols (OR, 27.8; 95% CI, 6.7 to 109.7; p ⫽ 0.001) and use of mechanical ventilation (OR, 3.3; 95% CI, 1.1 to 11; p ⫽ 0.04) were associated with a higher risk of infection in these patients, whereas transplantation (OR, 0.191; 95% CI, 0.046 to 0.789; p ⫽ 0.02) was the variable associated with a lower risk of respiratory infection by A terreus (Table 5). Discussion In our study, 9.1% of the isolates of filamentous fungi observed over the 10-year period were due to Original Research

Figure 1. Distribution of colonization (first columns) and invasive infection (second columns) for the most important underlying diseases. colonization; invasive infection; * ⫽ includes COPD, bronchial asthma, bronchiestasis, and interstitial lung disease. Statistical analysis was based on the ␹2 test.

A terreus. This fungus was the second most common cause of respiratory Aspergillus isolation, which contrasts with the findings reported in most previous studies.3,10,11 In our series, the overall incidence of culture findings positive for filamentous fungi, including A terreus, was 1.73 cases per 10,000 patients per year. This incidence was increased from 1998, coinciding with hospital renovation work, which has been reported in previous studies.12 Therefore, although we cannot rule out other causes, it is probable that hospital construction work was a decisive factor in this increased incidence. Such a likelihood

highlights the importance of maintaining close surveillance of susceptible patients during periods of hospital renovation. It is important to point out that of the 46 isolates of A terreus, 27 (58.7%) corresponded to infection and 19 (41.3%) corresponded to colonization, with a statistical difference between episodes (OR, 2.53; 95% CI, 1.37 to 4.69; p ⫽ 0.034). This contrasts with the situation in other filamentous fungi, such as A fumigatus, in which, of the 300 isolates identified, 127 (42.3%) corresponded to infection and 173 (57.7%) corresponded to colonization, without a

Figure 2. Annual distribution of the incidence of isolates of filamentous fungi from respiratory samples. www.chestjournal.org

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Table 3—Distribution of Colonization and Infection for Each Filamentous Fungus Total

Colonization

Infection

Isolates

No.

%

No.

%

No.

%

OR (95% CI)

A fumigatus A terreus A niger Penicillium spp A apiospermum A flavus Alternaria spp F oxysporum F solani P lilacinus Cladosporium spp A nidulans M racemosus R pusillus A ustus T longibrachiatum F verticillioides Total

300 46 41 40 27 16 7 5 5 4 4 3 3 1 1 1 1 505

59.4 9.1 8.1 7.9 5.3 3.2 1.4 1 1 0.8 0.8 0.6 0.6 0.2 0.2 0.2 0.2 100

173 19 34 40 14 10 7 1 1 4 4 2 1 1 1 1 1 314

57.7 41.3 82.9 100 51.9 62.5 100 20 20 100 100 66.7 33.3 100 100 100 100 62

127 27 7 0 13 6 0 4 4 0 0 1 2 0 0 0 0 191

42.3 58.7 17.1 0 48.1 37.5 0 80 80 0 0 33.3 66.7 0 0 0 0 38

1.58 (1.09–2.3) 2.53 (1.37–4.69) 0.31 (0.14–0.72)

*␹

2

p Value* ⬎ 0.05 0.034 ⬎ 0.05 0.000 ⬎ 0.05 ⬎ 0.05 ⬎ 0.05 ⬎ 0.05 ⬎ 0.05 ⬎ 0.05 ⬎ 0.05 ⬎ 0.05 ⬎ 0.05 ⬎ 0.05 ⬎ 0.05 ⬎ 0.05 ⬎ 0.05

1.55 (0.71–3.38) 0.98 (0.35–2.73) 6.64 (0.74–59.84) 6.64 (0.74–59.84)

0.81 (0.07–9.04) 3.28 (0.30–36.47) 0.81 (0.07–9.04)

test for tables of contingence 2 ⫻ 2 or Fisher exact test, with Bonferroni correction.

statistical difference between episodes. These results suggest that the presence of A terreus in a culture from a respiratory sample should be considered a pathologic finding and that aggressive antifungal therapy should be started early due to the greater

probability that this isolation is related to respiratory infection and not to colonization. Our results show that mechanical ventilation and prophylactic administration of amphotericin B aerosols are a risk factor for the occurrence of positive

Table 4 —Risk Factors for Isolation of A terreus in Patients With Positive Culture for Filamentous Fungi* Univariate Analysis

Multivariate Analysis

Variables

OR (95% CI)

p Value

OR (95% CI)

p Value

ICU stay Nosocomial infection Hospitalization days Immunosuppression Central catheter Parenteral nutrition Granulocytopenia Lymphopenia Bacterial infection Antibiotic therapy Nystatin therapy Azole prophylaxis Amphotericin B AB aerosols IV AB prophylaxis IV AB therapy Mechanical ventilation CMV infection Yeast infection Transplantation Cystic fibrosis† Baseline lung disease† Other†‡

4.6 (2.4–9) 3.8 (1.1–12.4) 1.1 (1.0–1.1) 1.9 (0.9–4.1) 5.3 (2.3–12.2) 2.7 (1.5–5.0) 0.6 (0.1–2.9) 1.2 (0.5–2.5) 2.5 (1.3–4.6) 1,127.2 (0–3.9) 0.6 (0.3–1.2) 3.9 (1.8–8.3) 15.8 (8.0–31.2) 21.3 (10.6–42.6) 5.9 (2.5–14.1) 2.0 (0.6–6.4) 4.7 (2.4–9.1) 2.8 (1.4–5.4) 0.9 (0.5–1.8) 1.7 (0.9–3.2) 0.9 (0.42–1.9) 0.2 (0.0–0.6) 0.7 (0.3–1.5)

0.000 0.028 0.000 0.077 0.000 0.001 0.598 0.621 0.003 0.604 0.182 0.000 0.000 0.000 0.000 0.197 0.000 0.002 0.921 0.074 0.786 0.008 0.378

3.2 (2.8–11.5) 4.1 (2.1–10.2) 1.8 (1.1–2-1) 1.4 (0.5–3.2) 3.6 (1.5–15.2) 1.9 (2.1–7.1)

0.07 0.12 0.23 0.33 0.09 0.15

3.4 (2.3–6.7)

0.11

3.1 (1.2–7.5) 12.2 (5–28) 31.4 (12.1–81.9) 3.2 (1.7–11.2)

0.45 0.08 0.001 0.11

2.7 (1.2–6.9) 2.1 (2.9–8.7)

0.01 0.34

0.2 (0.1–0.6)

0.00

0.9 (0.4–0.9)

0.31

*CMV ⫽ cytomegalovirus; AB ⫽ amphotericin B. †Reference group, transplant recipients. ‡Chronic renal failure, solid tumors, chronic liver disease, multiple trauma, and heart disease. 234

Original Research

Table 5—Risk factors for Invasive A terreus Infection in Patients With Positive Culture for Filamentous Fungi* Univariate Analysis

Multivariate Analysis

Variables

OR (95% CI)

p Value

OR (95% CI)

p Value

ICU stay Nosocomial infection Hospitalization days Immunosuppression Central catheter Parenteral nutrition Granulocytopenia Lymphopenia Bacterial infection Antibiotic therapy Nystatin therapy Azole prophylaxis AB AB aerosols IV AB prophylaxis IV AB therapy Mechanical ventilation CMV infection Yeast infection Transplantation Cystic fibrosis† Baseline lung disease† Other†‡

4.7 (1.7–13.2) 225.0 (0–9) 1.0 (1.0–1.1) 1.2 (0.4–3.9) 7.2 (0.9–55.2) 2.2 (0.9–5.2) 0.4 (0.1–2.1) 0.8 (0.3–2.0) 0.9 (0.4–2.0) 223.6 (0–2.3) 0.7 (0.3–1.7) 1.4 (0.5–4.0) 11.8 (4.6–30.5) 14.5 (5.7–36.6) 3.6 (1.2–10.7) 1.7 (0.5–5.7) 4.7 (2.4–9.1) 1.6 (0.7–3.8) 0.5 (0.2–1.3) 1.5 (0.9–3.2) 0.8 (0.1–4.2) 0.3 (0.0–1.3) 0.7 (0.3–1.9)

0.003 0.768 0.018 0.672 0.056 0.058 0.325 0.770 0.830 0.798 0.521 0.477 0.000 0.000 0.019 0.361 0.002 0.213 0.192 0.271 0.832 0.124 0.552

3.6 (2.4–16.1)

0.09

2.2 (0.9–4)

0.36

4.3 (1.1–34.2) 1.7 (1.4–5.9)

0.14 0.21

7.6 (2.7–21.8) 27.1 (6.7–109.7) 2.3 (1.1–12.6)

0.09 0.001 0.23

3.3 (1.1–10.9)

0.045

0.1 (0.04–1.7)

0.022

0.4 (0.2–2.1)

0.25

*See Table 4 for abbreviations not used in the text. †Reference group, transplant recipients ‡Chronic renal failure, solid tumors, chronic liver disease, multiple trauma, and heart disease.

culture findings and infection by A terreus in patients with culture findings positive for filamentous fungi. The relationship between mechanical ventilation and invasive fungal infection has been previously reported in other studies.13–15 Both mechanical ventilation and endotracheal intubation, and the resulting aspiration, are procedures that injure the bronchial mucosa and lung parenchyma, altering mucociliary mechanics and facilitating invasion by highly aggressive microorganisms in critically ill patients. Furthermore, mechanical ventilation is a marker of severity, and patients requiring it have longer hospital stays, and a greater probability of receiving broad-spectrum antibiotic therapy and of undergoing aggressive diagnostic and therapeutic procedures. In our series, the prophylactic use of amphotericin B aerosols was a marker of risk for both positive culture findings from respiratory samples and infection by A terreus in patients with culture findings positive for filamentous fungi. These results could be explained by the fact that exposure to amphotericin B aerosols may favor colonization of the respiratory tract by fungi that are resistant to this antifungal agent in a way that is similar to that observed with selection of Candida species resistant to fluconazole.16 –18 This does not mean www.chestjournal.org

that these results question the usefulness of amphotericin B aerosols for the prophylaxis of IA, which has been shown in various studies.19 –21 Our study was not designed to demonstrate a causal relationship between exposure to nebulized amphotericin B and a greater risk of infection by resistant filamentous fungi. What our results do show, however, is that when a filamentous fungus is isolated in a respiratory sample from a patient who has received prophylaxis with amphotericin B aerosols (and therefore is at high risk of IA), there is a greater probability that this filamentous fungus will be A terreus. Moreover, our results show that the most of the isolates of A terreus corresponded with infection. Therefore, according to the data published in the literature showing a poor outcome for patients with A terreus infection,3,5,22,23 we must perform early, aggressive antifungal therapy that furthermore does not include amphotericin B. The fact that transplantation is associated with a lower risk for isolation and infection by A terreus, unlike other procedures such as mechanical ventilation, could suggest that infections by this fungus are primarily associated with prolonged hospitalization of critically ill patients, who have been subjected to a greater number of diagnostic and therapeutic proceCHEST / 131 / 1 / JANUARY, 2007

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dures. rather than with the degree of immunosuppression or neutropenia induced after transplantation. We may therefore conclude that in patients with culture findings positive for filamentous fungi from a respiratory sample, mechanical ventilation and amphotericin B aerosols are risk factors for the isolation of A terreus as the causative fungus, whether it is an episode of colonization or infection. In contrast, transplantation is associated with a lower risk of A terreus colonization and infection in patients with culture findings positive for filamentous fungi. These results should be confirmed by prospective studies to determine whether there is a causal relationship between the administration of amphotericin B aerosols and the increased frequency of A terreus colonization and infection. References 1 Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis 2001; 32:358 –366 2 Denning DW, Marinus A, Cohen J, et al. An EORT multicenter prospective survey of invasive aspergillosis in hematological patients: diagnosis and therapeutic outcome. J Infect Dis 1998; 37:173–180 3 Iwen P, Rupp ME, Langnas, et al. Invasive pulmonary aspergillosis due to Aspergillus terreus: 12-year experience and review of the literature. Clin Infect Dis 1998; 26:1092– 1097 4 Hachem RY, Kontoyiannis DP, Boktour MR, et al. Aspergillus terreus, an emerging amphotericin B-resistant opportunistic mold in patients with hematologic malignancies. Cancer 2004; 101:1594 –1600 5 Steinbach WJ, Benjamin DK, Kontoyiannis DP, et al. Infections due to Aspergillus terreus: a multicenter retrospective analysis of 83 cases. Clin Infect Dis 2004; 39:192–198 6 Walsh TJ, Petraitis V, Petraitiene R, et al. Experimental pulmonary aspergillosis due to Aspergillus terreus: pathogenesis and treatment of an emerging fungal pathogen resistant to amphotericin B. J Infect Dis 2003; 188:305–319 7 Steinbach WJ, Perfect JR, Schell WA, et al. In vitro analyses, animal models, and 60 clinical cases of invasive Aspergillus terreus infection. Antimicrob Agents Chemother 2004; 48: 3217–3225 8 Perfect JR, Cox GM, Lee JY, et al. The impact of culture isolation of Aspergillus species: a hospital based-survey of aspergillosis. Clin Infect Dis 2001; 33:1824 –1833

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Original Research