Impact of fluconazole prophylaxis on fungal colonization and infection rates in neutropenic patients

Michel Laverdièrea,*, Coleman Rotsteinb, Eric J. Bowc, Robin S. Robertsd, Stratis Ioannoue, Danielle Carre, Narguess Moghaddame and The Canadian Fluconazole Study Group{dagger}

a Department of Microbiology and Infectious Diseases, Hôpital Maisonneuve-Rosemont, 5415 Boulevard l'Assomption, Montréal, Québec, Canada H1T 2M4; b Division of Infectious Diseases, Henderson Site, McMaster University, Hamilton, Ontario, Canada; c The University of Manitoba and The Manitoba Cancer Treatment and Research Foundation, Health Sciences Centre Winnipeg, Manitoba, Canada; d Department of Clinical Epidemiology and Biostatistics McMaster University, Hamilton, Ontario, Canada; e Pharmaceuticals Group, Pfizer Canada Ltd, Pointe-Claire, Québec, Canada


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Fungal colonization profiles from four different anatomical sites were evaluated in 266 neutropenic cancer patients receiving intensive cytotoxic therapy for acute leukaemia or for autologous marrow transplantation. At the beginning of chemotherapy patients were allocated randomly to receive oral fluconazole 400 mg daily or an identical placebo until prophylaxis failure or marrow recovery. Candida albicans colonization was reduced from 30 to 10% in the fluconazole recipients while it increased from 32 to 57% in the placebo patients (P < 0.001). By the end of prophylaxis, colonization with non-albicans Candida species increased from 7 to 21% and 8 to 18% in the fluconazole and placebo patients, respectively (P = 0.396). Although Candida glabrata was isolated more frequently at the end of the prophylactic period in the fluconazole patients than in the placebo patients (16 versus 7%), only one definite invasive C. glabrata infection was noted. Overall, definite invasive fungal infections were documented in 26 patients [four fluconazole versus 22 placebo patients (P<= 0.001)]. In 23 (92%) patients the infections were caused by persistently colonizing or newly acquired organisms. While probable invasive fungal infections were noted in five fluconazole patients, 10 placebo patients were also affected (P = 0.19). An end-of-prophylaxis colonization index >0.25 was 76% sensitive but only 69% specific for invasive fungal infection. However, a colonization index <= 0.25 at baseline had a negative predictive value of 88% for development of invasive fungal infection. Fluconazole prophylaxis decreased colonization by fungi and subsequent invasive fungal infections in neutropenic cancer patients.


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Intensive cytotoxic therapy is an important risk factor for infections in cancer patients who are rendered neutropenic.1,2 Empirical therapy with broad-spectrum antibiotics has largely contributed to a reduction in the morbidity and mortality of bacterial infections that occur during the period of neutropenia. As a consequence, however, persistently neutropenic patients are predisposed to invasive fungal infections particularly those caused by Candida species.2–4

The pathogenesis of invasive fungal infection is not completely understood. Colonization of the gastrointestinal tract and other body sites is likely to be the initial step preceding systemic yeast invasion.2 Therefore, several systemically absorbed antifungal agents have been used in an attempt to prevent fungal infections in neutropenic patients with cancer.5–9 We evaluated the efficacy of oral fluconazole versus placebo in a prospective double-blind randomized trial conducted between January 1994 and November 1995 at Canadian university-affiliated centres.10 Although in our study fluconazole prophylaxis proved to be statistically no more successful than placebo in obviating the need for parenteral antifungal therapy (57 versus 50%), its use resulted in fewer superficial fungal infections (7 versus 18%), fewer definite invasive fungal infections (3 versus 17%) and fewer deaths attributable to invasive fungal infections (one of 15 versus six of 15). Although we inexplicably observed more skin rashes and vomiting in the placebo group, overall there were no other differences in adverse events between the groups. Because of the pivotal role of fungal colonization of various body sites in predisposing patients to invasive fungal diseases, we prospectively assessed the impact of fluconazole prophylaxis on colonization with fungal isolates. This paper specifically reports details about the fungal surveillance cultures that were performed in the study population, and documents the risk of developing invasive fungal infections in both the fluconazole and placebo groups.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study population

Participants, aged between 18 and 80 years, were eligible if they were to undergo cytotoxic chemotherapy for acute leukaemia or conditioning therapy for autologous bone marrow transplantation (ABMT). Patients with acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL) undergoing remission induction, re-induction therapy after primary relapse or post-remission consolidation therapy and patients undergoing ABMT were included if they were expected to remain neutropenic (<0.5 x 109 neutrophils/L) for >7 days. Patients were excluded from the study if they had received systemic and/or topical antifungal therapy within 1 week of randomization or had already undergone more than one re-induction chemotherapy for relapse after primary response. Patients who were febrile (>=38.5°C) at baseline due to documented or suspected fungal infection were also excluded from the study. The use of antibacterial prophylaxis (trimethoprim–sulphamethoxazole 160/800 mg bid or ciprofloxacin 500 mg bid orally) was employed at the investigator's discretion. The protocol recommended a regimen of piperacillin and gentamicin for empirical antibacterial therapy of febrile neutropenic episodes, but physicians were permitted to apply their own centre's standard of care. Informed written consent was obtained from each patient and the study was approved by the participating institutions' ethics review boards.

Interventions

This trial was prospective, randomized on a 1:1 basis and double blinded. Patients were allocated to receive either fluconazole 400 mg (two tablets of 200 mg each) or placebo of identical appearance orally once daily. Antifungal prophylaxis was started within 72 h of initiating chemotherapy or the conditioning therapy. Prophylaxis with the study drug was continued for a maximum of 60 days or until: (i) the neutropenia had resolved (>=0.5 x 109 neutrophils/L), or (ii) the initiation of parenteral amphotericin B for documented or suspected fungal infections. Intravenous administration of the antifungal prophylactic regimen was not allowed, and patients unable to tolerate oral medication were withdrawn from the study.

Fungal surveillance cultures of the nose, oropharynx, stool/rectal swab and urine were taken upon enrolment (baseline) and at discontinuation of the study drug (end of prophylaxis). Specimens were inoculated on to Sabouraud dextrose agar or Mycosel agar. They were incubated for 7 days at 25°C and examined for the presence of fungi. Each separate colony was further subcultured and identified by means of its microscopic appearance, ability to form germ tubes and its fermentation/assimilation pattern. Cultures of other suspected sites of infections were obtained whenever the patient's clinical condition suggested the possibility of fungal infection.

Definitions

Isolation of yeasts or other fungi from one or more surveillance culture sites in the absence of invasive, superficial or clinically apparent fungal infection was considered to represent colonization. Clearance was defined as the absence of the baseline colonizing fungus at the end of prophylaxis based on the surveillance cultures. Persistence was defined as the presence of the same fungal species in both the baseline and end of prophylaxis surveillance cultures. Acquisition was the presence of a new fungal species in the surveillance cultures at the end of prophylaxis which had not been present at baseline. The colonization index at baseline and the end of prophylaxis was determined by the ratio of the number of culture-positive surveillance sites to the number of sites cultured.11

A definite invasive fungal infection was defined as a positive fungal culture from a normally sterile body site or the presence of hyphal elements detected on biopsy. Definite invasive fungal infections included urinary tract infection defined as a midstream specimen yielding >=100 x 105 cfu/L of a fungus with signs and symptoms of infection such as fever or dysuria. A positive urine culture (i.e. >=100 x 105 cfu/L of a fungus) in the absence of symptoms was considered colonization. A probable invasive fungal infection was defined as the presence of prolonged fever despite broad-spectrum antibacterial therapy together with a clinically documented site consistent with fungal infection (e.g. mucositis or pneumonia presumed to be of fungal origin) without histological or culture-based proof of infection but with response to antifungal therapy. All other situations where intravenous amphotericin B therapy was initiated were considered possible invasive fungal infections.

Statistical methods

The patient baseline status in the two treatment groups was compared using chi-squared tests for categorical variables and t-tests (or the non-parametric equivalent) for quantitative variables. Colonization status at the end of study was compared by employing the Mantel–Haenszel test stratified by baseline colonization status. The same approach was used for site-specific colonization status. The treatment effect on invasive fungal infections was estimated and tested via logistic function regression to allow for adjustment for baseline colonization and evaluation of the constancies of treatment effect by baseline colonization status (i.e. test of interaction).


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients

Of the 274 patients included in our study, eight subjects were excluded due to an unevaluable mycological response because of missing fungal surveillance cultures. The impact of fluconazole prophylaxis on fungal colonization was evaluated in the remaining 266 patients. One hundred and thirty five evaluable patients received fluconazole and 131 received placebo. The characteristics of the patients are detailed in Table IGo. The study groups were similar with the exception of the numbers of subjects with ALL allocated to the fluconazole and placebo groups (six versus 19, respectively), the median duration of on-study days (22 versus 18, respectively) and the median days with absolute neutrophil count <=0.5 x 109/L (14 versus 11, respectively).


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Table I. Characteristics of the study population
 
Mycological response

At the onset of prophylaxis (baseline), a similar proportion of patients was colonized by one or more fungi in both groups (39% for fluconazole, 37% placebo) (Table IIGo). By the end of the prophylaxis period, the proportion of patients receiving placebo who were colonized by fungi increased to 73% while the proportion of colonized individuals in the fluconazole group dropped slightly to 36%. The difference in colonization rates by any fungus between the groups at the end of prophylaxis was statistically significant (P < 0.001 based on a Mantel–Haenszel test adjusting for baseline colonization status). Candida albicans colonization dropped from 30 to 10% in the patients receiving fluconazole while it increased from 32 to 57% (P < 0.0001) in the placebo group. Colonization by non-albicans Candida increased by a similar amount in both groups of patients (P = 0.396).


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Table II. Frequency of fungal colonization
 
C. glabrata was the most common non-albicans Candida species encountered in both groups. This species was recovered more frequently at the end of prophylaxis, in the patients receiving fluconazole than in the patients receiving placebo (16 versus 7%). Candida krusei was isolated at the end of prophylaxis in seven of 135 patients (5%) given fluconazole and four of 131 (3%) patients given placebo.

A larger proportion of patients receiving fluconazole than those receiving placebo remained free of fungal colonization during the prophylaxis period. Sixty-three (47%) treated patients compared with 32 (24%) (P < 0.001) patients receiving placebo remained free of fungi, while 23 (17%) fluconazole-treated patients versus four (3%) (P < 0.001) patients given placebo cleared their initial colonizing fungi during the prophylaxis period. Moreover, persistence of baseline fungi during the prophylaxis period was observed more frequently in the placebo group than in the group receiving fluconazole [45 (34%) versus 29 (22%); P < 0.003]. Acquisition of new fungi was noted in 50 (38%) of the placebo group compared with 20 (15%) (P = 0.001) of the fluconazole group.

The risk of definite or probable invasive fungal infection according to surveillance culture status is documented in Table IIIGo. Overall, the patients receiving placebo were more predisposed to invasive fungal infections (24.4 versus 6.7%) (P < 0.001) than those receiving fluconazole. Moreover this effect resulted predominantly from the acquisition and subsequent persistence of fungal isolates during the study period.


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Table III. Risk of invasive fungal infection by surveillance culture status
 
Definite invasive fungal infections were documented in 26 patients. Of the four fluconazole recipients with invasive fungal infections, one was infected by C. krusei (candidaemia), one by C. albicans (candidaemia) and one by C. glabrata (urinary tract infection). In addition one patient was infected by Candida tropicalis and Aspergillus spp. (pulmonary infection), which were undetected in the surveillance cultures. In the 22 placebo recipients, 10 patients were infected by newly acquired C. albicans (one hepatosplenic candidosis, one candidaemia and one urinary tract infection), C. tropicalis (two urinary tract infections), Candida lusitaniae (one candidaemia and one urinary tract infection), C. krusei (one candidaemia), Candida parapsilosis (one urinary tract infection) and C. albicans with Aspergillus spp. (one urinary tract infection) while 11 placebo recipients were infected by persisting colonizing C. albicans (three candidaemia, four urinary tract infections, one hepatosplenic candidosis and one oesophagitis) and an unspeciated yeast (one urinary tract infection). Only one placebo recipient had a urinary tract infection caused by a C. tropicalis, which remained undetected by the surveillance cultures.

Probable invasive fungal infections were noted in 15 patients; five in the fluconazole and 10 in the placebo group. Candida spp. were the observed pathogens in each of the five fluconazole recipients who all developed a probable invasive fungal pneumonia. In three of these patients, there was a clearance of the colonizing baseline fungus. However, one patient was infected with a persistently colonizing fungus and another with a newly acquired Candida spp. In contrast, five placebo recipients developed gastrointestinal mucositis caused by C. tropicalis and Aspergillus spp., while two had oesophagitis precipitated by C. albicans and Aspergillus spp. and three had a pulmonary infection caused by Candida spp. (P = 0.19). In one of these patients fungus was never isolated in the surveillance cultures, whereas four individuals acquired a new organism throughout the study.

At the end of prophylaxis marked variations in the prevalence of fungal colonization in both groups of patients occurred at a variety of anatomical sites with the exception of the nose (Table IVGo). Fluconazole was associated with an increase in colonization at most sites but with a reduction in the oropharynx, whereas in the placebo group there was an increase in colonization at all sites. The mean colonization index was identified in both groups at baseline. By the end of prophylaxis there was a small reduction (–0.02) in colonization index for the fluconazole group whereas in the placebo group the colonization index increased by 0.21. The difference in the change in the colonization index between treatment groups from baseline to the end of prophylaxis was highly significant (P < 0.001). The mean colonization index at baseline was highly predictive of invasive fungal infection.The mean colonization index for the 41 patients in both groups who experienced definite or probable invasive infection was 0.286 compared with 0.161 for non-infected patients (P = 0.006). At the end of prophylaxis a colonization index of >0.25 was 76% sensitive but only 69% specific for invasive fungal infection, whereas a colonization index of <=0.25 had a negative predictive value of 88% at the baseline and 94% at the end of prophylaxis for development of invasive fungal infection (Table VGo).


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Table IV. Surveillance cultures profiles
 

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Table V. Colonization indices and predictive values for invasive fungal infection
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
As C. albicans is a normal human commensal, it is not surprising that this organism is the most common opportunistic fungal pathogen in immunocompromised patients.6,12,13 Colonization of the oropharynx and/or the alimentary tract often precedes invasive yeast infections.3,13–21 Strategies for antifungal prophylaxis in cancer patients receiving intensive cytotoxic chemotherapy have been based on the principle of reducing fungal colonization in the alimentary tract in order to reduce systemic invasive fungal infections during the period of greatest risk due to profound neutropenia.

In our study, prophylaxis with fluconazole markedly reduced oropharyngeal, rectal and urinary fungal colonization. Similar observations have been reported by others.9,16,18,19 The reduction in colonization of the gastrointestinal tract demonstrated in our study produced a corresponding decrease in definite and probable invasive fungal infections amongst fluconazole recipients. Fluconazole significantly cleared pre-existing colonizing fungi, in particular C. albicans and prevented the acquisition of new organisms. This was underscored by the fact that comparable colonization indices were observed at baseline in both groups, but higher indices were observed at the end of prophylaxis in the placebo recipients.

A major concern with the use of antimicrobial prophylaxis has always been the potential for selection of resistant organisms that may cause subsequent superinfections. An increase in azole-resistant fungal colonization and infection has been reported with the use of prophylactic antifungal agents, particularly involving non-albicans Candida spp. such as C. krusei and C. glabrata in fluconazole recipients.7,22 In our study only two patients (one in each group) had candidaemia due to C. krusei. Despite a higher incidence of C. glabrata colonization in fluconazole recipients, only one patient (compared with none in the placebo group) developed an invasive C. glabrata infection.

Our results contrast with some previous reports, in which the use of fluconazole enhanced the emergence of C. krusei infections.7,8,12 However, it should be noted that these studies were retrospective, uncontrolled analyses conducted in single centres, and were thus subject to observer bias and would have been affected by the baseline prevalence of C. krusei in the institution. In contrast, two prospective placebo-controlled multicentre studies could not demonstrate a predisposition toward the emergence of resistant yeast infections in fluconazole recipients.9,19 Our study is consistent with these latter observations. We must, however, acknowledge that three of the four definite invasive fungal infections in the fluconazole recipients were due to fungi either known to be fluconazole resistant (C. krusei and Aspergillus spp.) or to fungi frequently resistant to fluconazole (C. glabrata). Moreover, although this colonization with non-albicans Candida species was observed in a patient population who received remission-induction cytotoxic chemotherapy (e.g. cytarabine and anthracycline ‘7+3’ regimens) known to cause extensive gut epithelial damage, thus providing an important portal of entry for these fungi, no increase in invasive infection with non- albicans strains occurred.23

Also of importance was the observation that a baseline colonization index of <=0.25 confers a negative predictive value for invasive fungal infection. This observation suggests that fungal surveillance cultures are of value as negative predictors but have little use in positively predicting who will actually develop an invasive fungal infection. Similar observations have been reported previously.21

Unfortunately in our multicentre study we were unable to compare the antifungal drug susceptibilities of the isolates recovered at baseline and at the end of prophylaxis with those of the invasive isolates.

In conclusion, fluconazole prevented and reduced fungal colonization of the alimentary tract and subsequent invasive fungal infections. Despite increased colonization with isolates other than C. albicans in the patients receiving fluconazole, we observed a comparable number of invasive fungal infections caused by non-albicans Candida strains in both groups of patients and did not witness a rapid emergence of invasive infections caused by non-albicans fluconazole-resistant species. Moreover, in cancer patients, a colonization index of <=0.25 at the initiation of antineoplastic therapy clearly predicts a low risk of invasive fungal infection. Future investigations utilizing the colonization index may clarify the patient populations for whom antifungal prophylaxis may be warranted.


    Acknowledgments
 
Investigators and participating centres in the Canadian Fluconazole Prophylaxis Study Group include: Dr E. J. Bow, Health Sciences Centre, Winnipeg, Manitoba; Dr G. Evans, Kingston General Hospital, Kingston, Ontario; Dr I. W. Fong, St Michael's Hospital, Toronto, Ontario; Dr G. Garber, Ottawa General Hospital, Ottawa, Ontario; Dr D. Haase, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia; Dr R. Horn, Royal Victoria Hospital, Montréal, Québec; Dr M. Laverdière, Hôpital Maisonneuve-Rosemont, Montréal, Québec; Dr P. Phillips, St Paul's Hospital, Vancouver, British Columbia; Dr C. Rotstein, Henderson Site, Hamilton, Ontario; Dr R. Saginur, Ottawa Civic Hospital, Ottawa, Ontario; Dr I. Salit, The Toronto Hospital, Toronto, Ontario; Dr C. Sinave, Centre U. Santé l'Estrie-Fleurimont, Sherbrooke, Québec; Dr F. Smaill, McMaster Site, Hamilton, Ontario. This study was supported by a grant-in-aid from the Pharmaceuticals Group, Pfizer Canada Ltd, Pointe-Claire, Québec. Presented in part at the 37th ICAAC, Toronto, Ontario (Abstract LM-85).


    Notes
 
* Corresponding author. Tel: +1-514-252-3817; Fax: +1-514-252-3898; E-mail: laverdim{at}ere.umontreal.ca Back

{dagger} Other study participants are listed in the Acknowledgements. Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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16 . Chandrasekar, P. N., Gatny, C. M. & the Bone Marrow Transplantation Team. (1994). The effect of fluconazole on fungal colonization in neutropenic cancer patients. Journal of Antimicrobial Chemotherapy 33, 309–18.[Abstract]

17 . De Gregorio, M. W., Lee, W. M. & Ries, C. A. (1982). Candida infections in patients with acute leukemia: ineffectiveness of nystatin prophlaxis and relationship between oropharyngeal and systemic candidiasis. Cancer 50, 2780–4.[ISI][Medline]

18 . Ellis, M. E., Qadri, S. M., Spence, D., Halim, M. A., Ernst, P., Clink, H. et al. (1994). The effect of fluconazole as prophylaxis for neutropenic patients on the isolation of Candida spp. from surveillance cultures. Journal of Antimicrobial Chemotherapy 33, 1223–8.[ISI][Medline]

19 . Goodman, J. L., Winston, D. J., Greenfield, R. A., Chandrasekar, P. H., Fox, B., Kaizer, H. et al. (1992). A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. New England Journal of Medicine 326, 845–51.[Abstract]

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Received 24 November 1999; returned 17 April 2000; revised 3 July 2000; accepted 9 August 2000