Fluconazole versus Amphotericin B in the treatment of Hematogenous Candidiasis: A matched cohort study

Fluconazole versus Amphotericin B in the Treatment of Hematogenous Candidiasis: A Matched Cohort Study Elias J. Anaissie, MD, Shahe E. Vartivarian, MD, Dima Abi-Said, PhD, Omrum Uzun, MD, Helio Pinczowski, MD, Dimitrios P. Kontoyiannis, MD, Pierre Khoury, MD, Kostas Papadakis, MD, Alison Gardner, MSN, RN, Issam I. Raad, MD, Joyce Gilbreath, RN, Gerald P. Bodey, MD, Houston, Texas

PURPOSE: TO compare the efficacy and toxicity of fluconazole and amphotericin B in the treatment of hematogenous candidiasis in cancer patients. PATIENTS AND METHODS: A matched cohort study of cancer patients with hematogenous candidiasis was conducted. Forty-five patients with hematogenous candidiasis who received fluconazole (200 to 600 mg/day) in an openlabel trial at the University of Texas M. D. Anderson Cancer Center, Houston, Texas, between February 1990 and June 1992 were matched to 45 patients treated with amphotericin B (0.3 to 1.2 mg/kg/day) for the same diagnosis. Criteria for matching included the following prognostic variables at the initiation of therapy: pneumonia, neutropenia (<1,000 cells/mm3), number of positive blood cultures before therapy, infecting Candida species, underlying disease, and the simplified acute physiology score. Response and survival at 48 hours, after 5 days of therapy, and at the end of therapy, as well as toxicity rates were obtained. Other post hoc analyses were performed. Differences in outcomes were assessed by the McNemar, the sign, and the log rank tests. RESULTS: Patients were similar with respect to the matching criteria, age, sex, status of underlying disease, use of antibiotics and growth factors, duration of treatment, presence and removal of central venous catheters, disseminated disease, and concomitant infections. Response rates at 48 hours and 5 days were similar between the two study

From the Department of Medical Specialties, Section of Infectious Diseases, the Universityof Texas M. D. Anderson Cancer Center, Houston, Texas. This study was supported by a grant from Roerig-PfizerPharmaceuticals. Requests for reprints should be addressed Elias Anaissie, MD, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 47, Houston, Texas 77030. Manuscript submitted February 17, 1995 and accepted in revised form May 9, 1996.

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groups. Overall response rates at the end of therapy were 73% for patients treated with fluconazole and 71% for patients treated with amphotericin B (P = 0.78). There were no differences in survival rates or causes of death. Toxicity was observed in 9% of patients treated with fluconazole and in 67% of patients treated with amphotericin B (P <0.0001). Toxic effects of amphotericin B included nephrotoxicity, hypokaliemia, and fever and chills. CONCLUSION: Fluconazole is effective and better tolerated than amphotericin B for the treatment of hematogenous candidiasis in cancer patients. Am J Med. 1996;101:170-176. ' e m a t o g e n o u s candidiasis is the fourth m o s t . c o m m o n cause of nosocomial b l o o d s t r e a m infection in the United States. ~This infection adds substantially to the morbidity and mortality of seriously ill patients and represents an independent factor for predicting risk of death and prolonged hospital stay. 2 Until recently, amphotericin B has been the cornerstone of antifungal c h e m o t h e r a p y for candidiasis. :3-~ However, administration of the drug is associated with significant dose-limiting side effects, 4-6 particularly when other agents with a similar toxicity profile are coadministered. Fluconazole is a well-tolerated triazole antifungal agent that is active against experimental h e m a t o g e n o u s candidiasis. ~ Open human trials are also encouraging, s-L~ The lack of cidal activity of fluconazole and the limited clinical data, however, have raised concerns a b o u t the usefulness of this agent in the t r e a t m e n t of h e m a t o g e n o u s candidiasis in cancer patients. We, therefore, undertook this study to c o m p a r e the efficacy and the safety of amphotericin B and fluconazole in the t r e a t m e n t of h e m a t o g e n o u s candidiasis in cancer patients.

H

PATIENTS AND METHODS Study Design and Patient Population This was a m a t c h e d cohort study of c a n c e r patients with h e m a t o g e n o u s candidiasis. Of the 249 patients with h e m a t o g e n o u s candidiasis b e t w e e n February 1, 1990, and June 5, 1992, at the University of Texas M. D. Anderson Cancer Center in Houston, Texas, patients receiving fluconazole for the treat0002-9343/96/$15.00 PII S0002-9343(96)00127-1

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m e n t of this infection in an open-label trial were included in the study. Patients w h o were enrolled in a concurrent randomized trial of fluconazole versus amphotericin B at this institution, patients who received only one dose of fluconazole, and those w h o received daily doses of 100 mg or less ( e x c e p t those w h o s e estimated creatinine clearance w a s 50 mL/ min or less) were excluded. The 434 patients with h e m a t o g e n o u s candidiasis w h o were treated with amphotericin B b e t w e e n January 5, 1988, and June 5, 1992, at the s a m e institution constituted the eligible pool of controls. Amphotericin B had to be adnfinistered daily and at full dose for inclusion. The minimal required daily dose was 0.3 mg/kg. Of the patients included in the amphotericin B group, 3 had concurrently received flucytosine at standard doses. Patients who received only one dose of amphotericin B were excluded. M a t c h i n g Variables Controls were individually m a t c h e d to cases on a 1:1 ratio. Matching criteria included the following well-established prognostic variables: (1) underlying disease ( l e u k e m i a a n d / o r b o n e m a r r o w transplantation, versus all other c a n c e r s ) , (2) p r e s e n c e of n e u t r o p e n i a at initiation of therapy ( < 1000 versus -> 1000 neutrophils/ram 3), (3) simplified acute physiologic score (---9 versus > 9 ) (12), (4) p r e s e n c e of p n e u m o n i a of any cause at initiation of therapy, (5) Candida species (albicans versus all o t h e r s ) , and (6) n u m b e r of positive blood cultures for Candida prior to therapy ( < 3 versus ->3). Concurrent m a t c h e s by date of initiation of therapy were obtained from the eligible pool of controls. If no adequate m a t c h was found within the s a m e m o n t h as the case, a matching control was substituted from an adjacent month. Eleven patients treated with fluconazole w e r e excluded b e c a u s e they could not be m a t c h e d to a control. These cases did not differ from the ones for w h o m m a t c h e s were available. Definitions Patients were considered to have h e m a t o g e n o u s candidiasis if Candida species were isolated from at least one blood culture s p e c i m e n in the p r e s e n c e of signs and s y m p t o m s of systemic infection (fever, hypotension, tachycardia, etc.) with or without evidence of infection in one or m o r e noncontiguous organs, such as pyelonephritis, w o u n d in.fection, signs and s y m p t o m s of p n e u m o n i a (cough, s p u t u m production, p u l m o n a r y infiltrates) that could not be attributed to any other pathogen, chorioretinitis, and multiple skin nodules suggestive of candidal dissemination. 13 Response w a s defined as the disappearance of all clinical and laboratory indicators of infection. Fail-

ure to respond was defined as: (1) no change or worsening of clinical signs and s y m p t o m s of fungal infection; (2) persistence of candidal infection at originally infected sites; (3) d e v e l o p m e n t of candidal infection in new body sites; or (4) drug toxicity requiring discontinuation of study drug. Relapse was defined as recurrence of the infection with the s a m e organism at any body site. Response and survival were assessed at 48 hours, after 5 days of therapy, and at the end of therapy. Relapse was assessed within 3 m o n t h s after discontinuation of study drugs. Death was considered to be caused by candidiasis if autopsy findings suggested disseminated candidal infection, or, if autopsy was not performed, the patient died while signs and s y m p t o m s of infection had not resolved. Adverse Events To avoid any potential bias, toxicity was examined after response was evaluated. Adverse reactions were assessed from clinical observation data and laboratory monitoring of hematopoietic, renal, and hepatic functions. Nephrotoxicity was defined as an increase in senm~ creatinine at least 1.5 times above the u p p e r limit for normal value, and hepatotoxicity as an increase in s e r u m transaminases at least 1.5 times above the u p p e r limit for normal value. Data Collection The o u t c o m e of the infectious episodes was collected from the patients' charts and was reevaluated by a blinded reviewer according to predetermined criteria. Data on a n u m b e r of covariates with a potential influence on response w e r e controlled for in the analysis. Patients were observed for up to 3 months f r o m the end of the antifungal therapy for the episode under study. Data Analysis Differences in unpaired baseline characteristics w e r e assessed using the chi-square test and the Mann-Whitney test, for categorical and continuous variables, respectively. The McNemar ~4 and the sign '5 tests were used to analyze paired data. The Fisher exact test was substituted for the McNemar test in situations w h e r e the latter test could not be used. Computations of 95% confidence intervals were p e r f o r m e d for differences in o u t c o m e s bet w e e n the two t r e a t m e n t groups. Time-to-event variables w e r e estimated according to the m e t h o d of Kaplan and Meier ~6and c o m p a r e d using the log rank test. An intent-to-treat analysis on all patients treated with fluconazole or amphotericin B during the study period (including those with one dose of drug, and so forth) w a s done. U n m a t c h e d logistic regression 17 was used in this instance. August 1996 The American Journal of Medicine® Volume 101

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RESULTS

TABLE I

Patient Characteristics

Ninety patients (45 pairs) matched on all six variables ( T a b l e I). No significant difference was found in the distributions of the simplified acute physiology score between the two groups ( P = 0.51; median score, 8; range 2 to 16 for both the fluconazole and amphotericin B groups). There were no significant differences between the two groups with respect to other characteristics that may have affected outcome such as age, sex, catheter removal, infection diagnosis, and duration of threatment ( T a b l e II). Twenty-one patients treated with amphotericin B and 18 treated with fluconazole had only one positive blood culture prior to therapy. Data are not available on the number of patients with positive blood cultures on the day of initiation of therapy. The two groups were also similar with respect to the status of the underlying disease (active disease, ie, new diagnosis or relapse, versus remission), the use of broad spectrmn antibiotics and growth factors, and the presence of concomitant infections (Table II). No patients had septic shock, but 1 patient in the fluconazole group had septic thrombophlebitis. The median daily dose of fluconazole was 400 mg (range 200 to 600 mg). The median total dose of amphotericin B was 350 mg (range 37.5 to 1,280.0 mg) and the median dally dose per kilogram was 0.6 mg (range 0.3 to 1.2 mg/kg). Response

The response rate to fluconazole was 73% at the end of therapy. This rate did not significantly change when the 11 patients who were not matched were added to the analysis (68%). Responses to both antiflmgal agents were similar when examined at 48 hours, after 5 days, and at the end of therapy ( T a b l e I I I ) . Response at the end of therapy was also similar when an intent-to-treat analysis on all patients with fluconazole or amphotericin B during the study period was done. In this intent-to-treat analysis, there was a significant difference in response by drug favoring fluconazole ( P <0.0001) at the univariate level. However, after correcting for other variables in an unmatched multivariate logistic regression model (presence of disseminated disease, status of neutropenia, SAPS score, abdominal surgery, steroids, chemotherapy, growth factors or white blood cell transfusions, Candida species, the type of drug administered (fluconazole versus amphotericin B) did not appear to have an effect on response ( P = 0.55). The species of Candida (albicans versus non-a/bicans) did not seem to influence the response rate at the end of therapy for the two drug regimens (Table III). Although the n u m b e r of patients infected 172

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Matching Criteria

Characteristic

No. of Patients (%) Fluconazole Amphotericin B n = 45 n = 45

Underlying disease Leukemia and/or bone marrow transplantation 9 (20) 9 (20 Other cancers 36 (80) 36 (80) Neutropenia at enrollment (< 1,000/mm3) * 11 (24) 11 (24) Simplified acute physiology score <=9 26 (58) 26 (58) >9 19 (42) 19 (42) Median (range) 8 (2-16) 8 (2-16) Number of positive blood cultures prior to therapyt <3 31 (69) 31 (69) ->3 14 (31) 14 (31) Median (range) 2 (1-10) 2 (1-5) Candida species Albicans 23 (51) 23 (51) Non-albicanst 22 (49) 22 (49) Pneumonia 5 (11) 5 (11) * Amongthesepatients,therewere8 pairswith < 100 cells/mm3, 3 pairs with ~ 100 cells/mm3. t Twenty-onepatients receivingamphotericinB and 18 receivingfluconazolehad only one positiveblood culture. t Includes patients on fluconazoleand amphotericinB, respectively; C. tropicalis (4,5); Torulopsis glabrata (11,5); C. krusei (0, ] ); C. parapsilosis (7,11).

with some of the various non-albicans species was small, there did not seem to be a significant difference in response rates according to the species (data not shown). We also examined response at the end of therapy in relation to patients' neutrophil counts ( T a b l e IV). Response to both regimens was similar for neutropenic and nonneutropenic patients. There were no relapses. Analysis of survival and death from candidiasis failed to show any differences between the two treatment regimens (Table III). The log rank test evaluating the difference in time to death of patients who died while receiving fluconazole or amphotericin B did not yield statistically significant results. Causes of Failure

Therapy failed in 25 patients. Failure was due to persistent or fatal infection in 18 patients ( 10 receiving fluconazole and 8 receiving amphotericin B, P = 0.53), persistent infection and toxicity in 4 patients (all receiving amphotericin B, P = 0.05), and drug toxicity alone in 3 patients (2 receiving fluconazole and 1 receiving amphotericin B, P = 0.56). All 25 patients had received at least 6 days of therapy. Of those 25 patients in w h o m treatment failed, 12 died of candidiasis during the course of primary therapy,

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TABLE II Unmatched Patient Characteristics at Study Entry

Characteristic

No. of Patients (%) Fluconazole Amphotericin B n = 45 n = 45

P Value*

Median age (range, y) 53 (20-76) 55 (20-78) 0.79 t Male 25 (56) 27 (60) Female 20 (44) 18 (40) 0.67 Status of the underlyingdisease New diagnosis/relapse~ 38 (84) 40 (89) Remission 7 (16) 5 (11) 0.54 Presence of central venous catheters§ 36 (80) 42 (93) 0.06 Central venous catheter removalII 22 (61) 18 (43) 0.11 Use of broad-spectrum antibiotics -<2 33 (73) 28 (62) >2 12 (27) 17 (38) 0.26 Use of growth factors 7 (16) 4 (9) 0.33 Concomitant infections 26 (58) 31 (69) 0.27 Median duration of treatment (range), days 13 (2-65) 10 (2-40) 0.14t • Chi-squaretest. TMann-Whitneytest. The distributionsof newlydiagnosedversusrelapseddiseaseweresimilarbetweenthe two drugs. §Withthe exceptionof six surgicallyimplantedcatheters,the centralvenouscatheterswereimplantedpercutaneously. HAmongpatientswho had a catheter.

TABLE III Outcome of Therapy

Outcome Variable

No. of Patients Responding (%) Fluconazole Amphotericin B n = 45 n = 45

Response rate from initiation of therapy After 48 days After 5 days Response rate at end of therapy Survival from initiation of therapy After 48 hours After 5 days Survival at end of therapy Death due to candidiasis Response at the end of therapy by Candida species Albicans Non-albicans • Confidenceinterval.

4 patients (2 on each treatment regimen) died of candidiasis despite having received other antiflmgal therapy, whereas infections in 6 patients (5 receiving fluconazole and 1 receiving mnphotericin B) responded to treatment with other systemic antifungal agents (amphotericin B and fluconazole, respectively). The infecting Candida species in the 5 patients who failed on fluconazole and ultimately responded to amphotericin B were C glabrata (3 patients), C tropicalis (1 patient), and C albicans ( 1 patient). The patient who failed on amphotericin B and ultimately responded to fluconazole was infected with C albicans. Amphotericin B as primary therapy failed in 3 patients who died of candidiasis after the study drug was discontinued.

95% CI* for the Difference

18 (40) 24 (53) 33 (73)

16 (36) 27 (60) 32 (71)

-18;27 -30;16 -16;20

45 (100) 45 (100) 39 (87) 5 (11)

45 (100) 43 (96) 35 (78) 7 (16)

--13;4 -25;7 -19;10

18 (78) 15 (68)

17 (74) 15 (68)

-19;28 -30;30

Catheter

Data

Seventy-eight patients had a central venous catheter in place at the start of therapy. Response at the end of therapy in these patients was 74% compared with 58% in the 12 patients without a catheter (P >0.25). When the effect of catheter removal was investigated, response at the end of therapy was 78% in the 40 patients whose catheters were removed and 71% in those whose catheters were left in place (P >0.5). No relapses occurred in either group of patients. Catheters were exchanged over guidewires in 11 patients receiving amphotericin B and 10 patients receiving fluconazole. Removal of the venous catheters did not appear to influence survival rates at the end of therapy. Catheter presence or removal did not August 1996 The American Journal of Medicine® Volume 101

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TABLE IV Response at the End of Therapy by Neutrophil Count No. of Patients (% Response) Fluconazole Amphotericin B

Neutrophil Count (per mm 3) >-1,000 at enrollment <1,000 at enrollmentt < 1,000 throughout study < 1,000 at enrollment with onset of recovery during study

34 (76) 11 (64) 6 (50) 5 (80)§

34 (74) 11 (64) 4 (75) 7 (57)§

P Value 0.71 ° 1.00" 0.57* 0.58*

* McNemar test. t There were 8 pairs of patients with neutropenia of < 100 cells/mm 3. All neutropenic patients reached a neutrophil count of < 100 cells/mm 3 during the study. Fisher exact test. § Recovery of neutrophil count preceded response in all patients.

TABLE V Drug-Related Toxicity No. of Patients with Toxicity (% of Total) Fluconazole Amphotericin B n = 45 n = 45

Toxicity Number of patients with toxicity Number of toxicity episodes (median; range) Chills Hypokalemia Hepatotoxicity Nephrotoxicity Fever

4 (9) 7 (0; 0-3) 1 (2) 2 (4) 2 (4) 0 (0) 2 (4)

30 (67) 42 (1; 0-4) 5 (11) 12 (27) 0 (0) 18 (40) 7 (16)

P Value* <0.0001 <0.0001 t 0.10 0.01 0.16 <0.001 0.06

* McNemar test. t Sign test.

affect the outcome by drug. Catheter-related candidemia was felt to be present in only a small number of patients (1 of the patients who received amphotericin B and 5 who received fluconazole).

Adverse Events Analysis of toxicity significantly favored fluconazole over amphotericin B ( T a b l e V). Nephrotoxicity, hypokalemia, and fever and chills were the most commonly encountered adverse events among patients treated with amphotericin B. Nephrotoxicity was severe (serum creatinine >3.5 m g / d L ) in 5 of those patients and required discontinuation of amphotericin B. One patient treated with amphotericin B suffered severe hypokalemia. Liver function tests showed mild elevations in 2 patients receiving fluconazole and fluconazole therapy was discontinued in both patients. One of the 2 patients who encountered toxicity with fluconazole was switched to amphotericin B and subsequently recovered from neutropenia and survived the infection. The other 2 patients in whom treatment failed because of drug toxicity (1 in each group) did not receive further antifungal therapy and died of disseminated candidiasis. All toxic events were reversible, except for 2 174

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cases of nephrotoxicity in patients treated with amphotericin B.

DISCUSSION The optimal approach to compare two drug regimens is a prospective randomized trial. One such trial of patients with documented or suspected candidiasis conducted at our institution ~8 enrolled only a small number of patients with hematogenous candidiasis. As a result, the trial had limited power in this specific subgroup of patients. Moreover, the trial failed to guard against imbalances in important k n o w n - - a n d possibly u n k n o w n - - p r o g n o s t i c factors in that subgroup. The matched cohort study was conducted to evaluate the efficacy of fluconazole as compared with that of amphotericin B in patients with hematogenous candidiasis. This design has the following features: one, ensuring comparable distributions across the predetermined strata of prognostic factors, and two, utilizing readily available data. One potential limitation of the study is that the sample used may not be representative of the patients with hematogenous candidiasis during the study period. While this problem somewhat limits our ability to generalize the results and conclusions to low-risk

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patients, the p r o b l e m does not affect the validity of the results and conclusions. The current study design did p r o t e c t for potential selection bias by matching the amphotericin B and fluconazole cases on the m o s t important and well-established prognostic factors for the o u t c o m e of h e m a t o g e n o u s candidiasis. ~') As a p p e a r s from the data s h o w n in Tables I and II, the two groups had c o m p a r a b l e distributions of these and other potential prognostic factors. Moreover, w h e n a difference in response b e t w e e n the two drugs was assessed using all patients with h e m a t o g e n o u s candidiasis during the study period, fluconazole s h o w e d a significantly better response than amphotericin B only in the univariate analysis. When important prognostic factors were controlled for in a multivariate logistic regression model, there was no significant difference in response b e t w e e n the two drugs. The findings of this s t u d y w e r e similar to t h o s e of o u r r a n d o m i z e d study.~8 The t w o studies confirm the o b s e r v a t i o n s f r o m s e v e r a l c o n t r o l l e d and u n c o n t r o l l e d studies that s u g g e s t t h a t fluconazole is safe and effective in p a t i e n t s with invasive candidiasis.9-ILl8,',0-~.~ The findings of o u r t w o studies w e r e c o m p a r a b l e to t h o s e of Rex et al, ',4 indicating that fluconazole is as effective as yet b e t t e r tolera t e d t h a n a m p h o t e r i c i n B. It should be n o t e d that the s t u d y by Rex et al w a s p e r f o r m e d in n o n n e u t r o p e n i c patients. Our study is the first to compare the efficacy of fluconazole and amphotericin B in cancer patients with hematogenous candidiasis. Several of these patients were neutropenic at start of therapy. Although our findings suggest that the efficacy of both agents is comparable in this setting, it should be emphasized that the small n u m b e r of neutropenic patients does not permit sufficient p o w e r to reliably detect a true difference. The trend, however, is worthy of noting. Our study also c o m p a r e d the efficacy of fluconazole and amphotericin B in patients infected with albicans versus non-albicans Candida species. Again, while our findings suggest a c o m p a r a b l e efficacy of b o t h agents in this setting, the possibility of a type II error m u s t be kept in mind. The median duration of therapy in our patients treated with fluconazole and amphotericin B w a s 13 and 10 days, respectively, and was shorter than those reported by others (range 16 to 19 days). 8-]L2°''L~'~4 This short duration of therapy is in a g r e e m e n t with the findings of our randomized multicenter study ( m e d i a n duration of therapy, 9 days).~8 Because the o u t c o m e of our patients w a s c o m p a r a b l e to that reported by others, it is possible that a shorter duration of therapy m a y be sufficient in certain settings. Whether removal of the central venous catheter (CVC) is n e c e s s a r y for patients with Candida infec-

tion of the b l o o d s t r e a m remains controversial. None of the studies looking at this question were designed to specifically a n s w e r the question. Most reports, including this one, lacked adequate p o w e r to s h o w an effect and failed to d o c u m e n t the reasons for catheter removal. Moreover, m o s t reports failed to control for potential confounders. Three retrospective studies in pediatric patients have suggested that removal of the CVC is important to decrease the complications of candidiasisY -28 The prospective randomized study by Rex et al, 2~ the largest study on h e m a t o g e n o u s candidiasis, w a s designed to c o m p a r e fluconazole to an~photericin B in the m a n a g e m e n t of h e m a t o g e n o u s candidiasis. In a p o s t hoc analysis, the authors s h o w e d that r e p l a c e m e n t of all vascular lines prior to or at start of therapy shortened the duration of h e m a t o g e n o u s candidiasis f r o m 5.5 to 4.2 days. The authors r e c o m m e n d e d that all vascular catheters be discontinued in all patients with this infection. Removal of the CVC in patients with hematogenous candidiasis did not significantly improve o u t c o m e in our current study. Unfortunately, the n u m b e r of patients studied was small and catheter removal was not a matching variable. Recent data '~° (C. Girmenia, personal c o m m t m i c a t i o n ) indicate that candidemias are m o r e frequently catheter-related w h e n caused by C parapsilosis (77%) than w h e n caused by other Candida species (3%; P <0.001). Hence, the question may not be w h e t h e r removal of all venous catheters should take place in all patients with candidemia but in which clinical settIngs and in which patient populations p r o m p t removal of venous catheters should occur. Further investigation of this question in studies with sufficient p o w e r s and adequate control of confounding is warranted. In conclusion, this study lends support to other studies in showing that fluconazole therapy for hem a t o g e n o u s candidiasis is effective and better tolerated than amphotericin B. While the findings of two randomized multicenter studies ~8,24and one prospective observational study, e5 together with the findings of the current study, s e e m to suggest that fluconazole is as effective as amphotericin B in treating h e m a t o g e n o u s candidiasis, a definitive conclusion as to the equivalent efficacy of the t w o drugs In all populations cannot yet be substantiated. The majority of those studies, including ours, had small sample sizes and inadequate powers, especially in highrisk groups (those with p o o r prognostic variables). Moreover, all these studies had a small n u m b e r of patients infected with various Candida species including those that are resistant to fiuconazole 3' or amphotericin B. 32 Because of the higher morbidity and mortality rates a m o n g high-risk patients with h e m a t o g e n o u s August 1996 The American Journal of Medicine® Volume 101

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candidiasis and the different patterns of antifungal susceptibility of the various Candida species, further investigations that include a large number of patients in the various risk groups are needed. Stratification by risk group should be based on the important prognostic variables, including the status of the underlying disease, the immune and physiologic status of the host, the extent of the infection and the Candida species causing infection.19 Results of such studies would enable us to offer recommendations for risk- and species-adjusted therapy. Unfortunately, such studies" would require the enrollment of more than 1,000 patients and hence are unlikely to be conducted, at least in the near future. Until such studies are conducted, and despite the inadequacy of the data on the equivalent efficacy of the two drugs in all settings, the good activity and superior safety of fluconazole, combined with the convenience and decreased cost of administering it in oral form, are in support of the reconunendation that fluconazole is an appropriate regimen for the treatment of hematogenous candidiasis caused by fluconazolesusceptible pathogens in this setting.

REFERENCES 1. Jarvis WR, Martone WJ. Predominant pathogens in hospital infections. J Antimicroh Chemother. 1992;29(suppI.A):19-24. 2. Wey SB, Mori M, Pfaller MA, et al. Hospital-acquired candidemia. The attributable mortality and excess length of stay. Arch Intern Med. 1988; 148:26422645. 3. Meunier F. Candidiasis. Eur J Microbiol infect Dis. 1989;8:438-447. 4. Bodey GP. Hematogenous and major organ candidiasis. In: Bodey GP, ed. Candidiasis: Pathogenesis, Diagnosis, and Treatment. New York: Raven Press, 1992;279-329. 5. Gallis HA, Drew R, Pickard WW. Amphotericin B: 30 years of clinical experience. Rev Infect Dis. 1990;12:308-329. 6. Patterson TF, Andriole VT. The role of liposomal amphotericin B in the treatment of systemic fungal infections. Eur J Cancer Clin OncoL 1989;25(suppl.2):S63-68. 7. Walsh TJ, Aoki S, Mechinaud F, et al. Effects of preventive, early and late antifungai chemotherapy with fluconazole in different granulocytopenic models of experimental disseminated candidiasis. J Infect Dis. 1990;161:755-760. 8. Hibberd PL, Rubin RH. Clinical aspects of fungal infections in organ transplant recipients. Clin InfectDis. 1994;19(suppl 1):533-540. 9. Van't Wout JW, Mattie H, van Furth R. A prospective study of the efficacy of fluconazole (UK-49,858) against deep-seated fungal infections. J Antimicrob Chemother. 1988;21:665-672. 10. Kujath P, Lerch K. Secondary mycosis in surgery: treatment with fluconazole. Infection. 1989; 17:111-117. 11. Nolla-SalasJ, Leon C, Torres-RodriguezJM, et al. Treatment of candidemia in critically ill surgical patients with intravenous fluconazole. C//n Infect Dis. 1992;14:952-954.

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