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Fluconazole in the treatment of systemic candidiasis: an open-label, noncomparative, multinational study
CURRENT THERAPEUTIC RESEARCH” VOL. 59, NO. 4, APRIL 1998
FLUCONAZOLE IN THE TREATMENT OF SYSTEMIC CANDIDIASIS: AN OPEN-LABEL, NONCOMPARATIVE, MULTINATIONAL STUDY DAVID L. GIBBS
Pfizer, Znc, New York, New York
ABSTRACT The incidence of opportunistic fungal infections has been increasing
in recent years. Fluconazole has demonstrated significant clinical potential and is an attractive alternative to amphotericin B for the treatment of these infections. The present study investigated the efficacy and safety of fluconazole (100 to 400 mg/d) in severely ill patients with microbiologically documented systemic candidiasis. Of the 61 patients enrolled, 39 were assessable for efficacy. The predominant pathogen isolated was Candida albicans. At the end of treatment, clinical and mycologic response was 100%. At follow-up, one patient experienced a relapse caused by C albicans. The most common drug-related adverse events involved the gastrointestinal system (eg, diarrhea and vomiting); no patients withdrew from the study because of adverse events. Thus fluconazole appeared to be effective and safe in the treatment of systemic candidiasis. Key words: fluconazole, systemic candidiasis, noncomparative study. INTRODUCTION
The incidence of serious opportunistic fungal infections has increased significantly in recent years1 Factors recognized as increasing the risk of developing fungal infection include the use of immunosuppressive therapy, cytotoxic chemotherapy, corticosteroids, cyclosporine, ablative radiation therapy, extended-spectrum antibiotic therapy, organ transplantation, major surgery, long-term indwelling central catheter, bladder catheter, and hemodialysis. Other risk factors include diarrhea, neutropenia, acquired immunodeficiency syndrome, hospital transfer, and hospitalization in an intensive care unit.14 Recovery of Cundidu from surveillance culture sites (oropharynx or feces) and candiduria are risk factors for candidemia.3’4 Treatment of these infections poses a formidable challenge to clinicians. The usefulness of amphotericin B, which has remained the gold standard for decades, is limited by its acute and chronic toxicities.7 Among the available triazole antifungal agents, fluconazole has demonstrated significant clinical potential’ and is an attractive alternative to amphotericin B for the treatment of opportunistic fungal infections. Address correspondence to: David L. Gibbs, PhD, Pfizer, Inc, 235 East 42nd Street, New York, NY 10017. Received for publication on January 5, 1998. Printed in the USA. Reproduction in whole or part is not permitted.
197
0011-393x/98/$19.00
FLUCONAZOLE
IN SYSTEMIC
CANDIDIASIS
Fluconazole is available in both an oral and an intravenous formulation. It has high oral bioavailability (>90%) and a plasma half-life of approximately 30 hours.s Approximately 80% of the dose is excreted unchanged in urine. Fluconazole is readily distributed in body tissues’ because of its relatively low lipophilicity and low affinity for plasma proteins (12%). The drug is well tolerated, and reports of serious hepatic reactions have been rare.’ Results of a prospective, nonrandomized, observational study in patients with candidemiag indicated that fluconazole was as effective as amphotericin B. Two comparative, randomized trials, one involving surgical patients with systemic mycoses” and the other involving nonneutropenic patients with candidemia,” showed no significant difference in effectiveness between fluconazole and amphotericin B. On the basis of these results of fluconazole therapy, the present study was undertaken to investigate the efficacy and safety of fluconazole when administered in high doses for prolonged periods to severely ill patients with microbiologically documented systemic candidiasis.
PATIENTS AND METHODS
This was an open-label, noncomparative, multinational study conducted in 12 countries (Argentina, Belgium, Brazil, France, Italy, Korea, the Netherlands, New Zealand, Norway, Spain, Switzerland, and Turkey). Eligible patients were aged 16 to 80 years and satisfied the following criteria: (1) positive histology (tissue sample) or culture from a normally sterile site (excluding blood and urine) within 7 days before initiation of fluconazole treatment, or (2) at least one positive blood culture within 7 days before initiation of fluconazole treatment, and (3) at least two of the following risk factors: indwelling intravenous catheter, hospitalization in an intensivecare unit, hyperalimentation, severe trauma or major surgery, extendedspectrum antibiotic therapy, immunosuppressive therapy (corticosteroids, irradiation, or cytotoxic chemotherapy), severe neutropenia (c50O/~L), or significant lymphopenia. In addition, patients who satisfied the second criterion also must have had at least one of the following clinical signs or symptoms consistent with Cundidu infection: Candidu in urine on 2 separate days with evidence of renal enlargement but without an indwelling urinary catheter, fever with signs of sepsis unresponsive to antibiotic therapy for 72 hours, fever with signs of sepsis persisting 48 hours after removal of a venous or arterial catheter, retinal lesions, esophagitis with biopsy positive for Cundida, myositis syndrome, multiple hepatic lesions, or new macular or papular lesions. Patients who satisfied these inclusion criteria but had been started on another antifungal agent for the same infection were permitted to enroll in this study, provided that the antifimgal therapy had not been administered for longer than 48 hours. 198
D. L. GIBBS
The investigator at each site determined the fluconazole dosage (100 to 400 mg/d) and route of administration (oral or intravenous) on the basis of the severity of the mycosis and other pertinent patient characteristics (eg, renal function). Patients were assessed for efficacy and safety as follows: weekly during the first 6 weeks of treatment, monthly thereafter, at the end of treatment (48 hours to 15 days after the last dose), and at follow-up (2 weeks to 6 months after the end of treatment). Descriptive statistics were used to summarize demographic characteristics. Clinical and mycologic response rates were calculated at the end of treatment and at follow-up. Adverse events were tabulated. RESULTS
A total of 51 patients (34 men and 17 women) with a mean MD) age of 49.0 (k16.5) years were enrolled in the study and received at least one dose of fluconazole. The mean daily fluconazole dosage was 198 mg (range, 100 to 400 mg>, and the mean duration of therapy was 56 days (range, 4 to 183 days). Of the 51 patients, 12 were excluded from the efficacy analysis for the following reasons: protocol deviation (3 patients), no baseline confirmation of diagnosis or no baseline pathogen (6), did not meet entry criteria (l), and insufficient dosing because of an adverse event (2). Thus 39 patients were assessable for the efficacy analysis. A total of 78 baseline pathogens were isolated from the 39 assessable patients (2 patients had multiple pathogens, and 23 patients had multiple culture sources>. The predominant pathogen was Candida albicans, which was isolated from 53 (68%) of 78 culture specimens. Others included various Candida species (110/o), Candida tropicalis (8%), Candida glabrata (4%), and Candida parapsilosis (6%). Patients treated for positive blood cultures (51%) comprised the largest group, followed by those with positive cultures of peritoneal fluid and of the esophagus and peritoneum (8% each). Infections at other sites (knee, kidney, heart, endocardium, pleural exudate, abscess, tumor, and sinus) occurred at a frequency of 5% or less. Clinical and mycologic outcomes at the end of treatment and at followup are summarized in Table I. Fluconazole was 100% successful at the end of treatment, both clinically (cured and improved) and mycologically (eradicated). The one patient who experienced a relapse had baseline blood and peritoneal fluid cultures positive for C albicans. After 24 days of fluconazole treatment, all cultures were negative, and fluconazole was discontinued 4 days later. At follow-up 30 days later, this patient’s peritoneal fluid cultures remained negative, whereas blood cultures were positive for C albicans. Drug-related (definite or possible relationship to fluconazole) adverse events are summarized in Table II. All 51 patients were included in the safety analysis. The most frequent adverse events were those involving the 199
FLUCONAZOLE
IN SYSTEMIC
CANDIDIASIS
Table I. Clinical and mycologic outcomes at the end of treatment and at follow-up. End of Treatment*
Response Clitni;
Follow-upt n = 22 2; ;I)
(%)$
Im rovement P ;;s n = 371 37 100) 6A 0
Mycologic .(%)I’ Fex$;aon Failure
1 51 d n = 20
* End-of-treatment assessment occurred 48 hours to 15 days after administration of the last dose. t Follow-up assessment occurred 2 weeks to 6 months after the end of treatment. $ Cure = disappearance of all pretreatment signs and symptoms of mycosis; improvement = improvement in or partial disappearance of pretreatment signsandsymptoms;relapse= improvement in or disappearance of signs and symptoms at the end of treatment followed by worsening or reappearance of signs and symptoms at follow-up; failure = no change in signs or symptoms. $j One patient was assessed mycologically but not clinically. II Eradication = baseline pathogen could not be cultured from site of infection, or no material was available from which to obtain a culture specimen (resolution of lesions ; relapse = eradication at the end of treatment followed by reappearance of the same fungal pathogen at 1ollow-up and a clinical response of relapse; failure = organism was cultured from site of infection at the end of therapy. II Two patients were assessed clinically but not mycologically.
gastrointestinal system. No adverse events were judged by the investigator to be severe, and no patients were withdrawn from the study because of drug-related adverse events. Eight patients died; all the deaths were attributed to concurrent illness or underlying disease. DISCUSSION
These results confirm the efficacy and safety of fluconazole in patients with systemic candidiasis. However, it must be remembered that this was an
Table II. Drug-related (definite or possible) adverse events in 51 patients treated with fluconazole. No. (%) of Patients
Body System (preferred term) At least one adverse event Gastrointestinal Diarrhea Nausea Vomiting Hepatic function, abnormal Increased alkaline phosphatase Cardiovascular Cardiac failure Metabolic and nutritional system Increased creatinine
200
D. L. GIBBS
open-label, noncomparative study. The prevalence of C albicans as a pathogen in this study is consistent with findings in the published literature1*3p4’12* however, there is an increasing shift toward Candida species Among these other than C albicuns as a cause of f&gal infection.6P11*13 species, C tropicalis, C glubrutu, and C parupsilosis appear to be most common~La,W,ia This also was the case in our study. Fluconazole was effective in eradicating all Cundidu species at the end of treatment, with one relapse caused by C albicuns observed at follow-up. This is consistent with published response rates of 60% to 100% for fluconazole.7 However, fluconazole’s limited activity against Candida species such as C krusei and C gZabruta1,7,14 has caused concern, although a high minimal inhibitory concentration does not necessarily predict clinical failure.14 A recently published literature survey of cases of non-ulbicans candidal infections treated with fluconazole revealed an overall efficacy rate of 77%.13 Fluconazole appeared to be particularly effective against infections caused by C purupsilosis and C tropic&s, whereas efficacy varied in cases of C glubratu infection, depending on the dose of fluconazole administered. It is difficult without controls to determine the efficacy of treatment, particularly when those host factors predisposing the patients to candidiasis are not known (eg, withdrawal of a urinary catheter, abscess drainage). Thus this study should serve as an observational study of the use of fluconazole among patients colonized with or culture-positive for C albicans who had underlying disorders. The most common adverse events were those involving the gastrointestinal tract, including diarrhea, nausea, vomiting, and hepatic effects. All adverse events occurred with a frequency of less than 4%, none of which necessitated withdrawal from the study. Our findings are consistent with those reported in other clinical trials of fluconazole.’ CONCLUSIONS
Fluconazole, administered orally or intravenously in dosages of 100 to 400 mg once daily, appeared to be effective and safe in patients with systemic candidiasis. Additional studies are needed to further define the role of fluconazole in the treatment of infections caused by non-ulbicuns candid& species. Acknowledgment
Financial support and fluconazole were provided by Pfizer, Inc, New York, New York. References: 1. Kramer KM, Skaar DJ, Ackerman
BH. The fluconazole 201
era: Management
of hematog-
FLUCONAZOLE
IN SYSTEMIC
CANDJDIASIS
enously disseminated candidiasis in the nonneutropenic patient. Pharmacotherapy. 1997;17:53%548. 2. Rubin RH. Fungal and bacterial infections in the immunocompromised host. Eur J Qin Microbial Infect Dis. 1993;12(Suppl 1):4248. 3. Bross J, Talbot GH, Maislin G, et al. Risk factors for nosocomial candidemia: A casecontrol study in adults without leukemia. Am J Med. 1989;87:614-620. 4. Karabinis A, Hill C, Leclercq B, et al. Risk factors for candidemia in cancer patients: A case-control study. J Clin Microbial. 1988;26:429-432. 5. Swerdloff JN, Filler SG, Edwards JE Jr. Severe candidal infections in neutropenic patients. Clin Infect Dis. 1993;7(Suppl2):8457-S467. 6. Walsh TJ, Hiemenz JW, Anaissie E. Recent progress and current problems in treatment of invasive fungal infections in neutropenic patients. Infect Dis Clin North Am. 1996;10:365-400. 7. Uzun 0, Anaissie EJ. Problems and controversies in the management of hematogenous candid&is. CZin Infect Dis. 1996;22@uppl2):S95-S101. 8. Brammer KW, Farrow PR, Faulkner JK. Pharmacokinetics and tissue penetration of fluconazole in humans. Rev Infect Dis. 1990;12(Suppl 3):3318-S326. 9. Nguyen MH, Peacock JE Jr, Tanner DC, et al. Therapeutic approaches in patients with candidemia. Evaluation in a multicenter, prospective, observational study. Arch Intern Med. 1995;155:2429-2435. 10. Kujath P, Lerch K, Kochendorfer P, Boos C. Comparative study of the efficacy of fluconazole versus amphotericin B/flucytosine in surgical patients with systemic mycoses. Znfection. 1993;21:37w82. 11. Rex JH, Bennett JE, Sugar AM, et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. NEJM. 1994;331:1325-1330. 12. Meunier F, Aoun M, Bitar N. Candidemia in immunocompromised patients. Clin Znfect Dis. 1992;14(Suppl l):S12O-S125. 13. van’t Wout JW. Fluconazole treatment of candidal infections caused by non-albicans Candida species. Eur J Clin Microbial Infect Dis. 1996;15:23&242. 14. Rex JH, Pfaller MA, Barry AL, et al. Antifungal susceptibility testing of isolates from a randomized multicenter trial of fluconazole versus amphotericin B as treatment of nonneutropenic patients with candidemia. Antimicrob Agents Chemother. 1995;39:40-44.
202
FLUCONAZOLE IN THE TREATMENT OF SYSTEMIC CANDIDIASIS: AN OPEN-LABEL, NONCOMPARATIVE, MULTINATIONAL STUDY DAVID L. GIBBS
Pfizer, Znc, New York, New York
ABSTRACT The incidence of opportunistic fungal infections has been increasing
in recent years. Fluconazole has demonstrated significant clinical potential and is an attractive alternative to amphotericin B for the treatment of these infections. The present study investigated the efficacy and safety of fluconazole (100 to 400 mg/d) in severely ill patients with microbiologically documented systemic candidiasis. Of the 61 patients enrolled, 39 were assessable for efficacy. The predominant pathogen isolated was Candida albicans. At the end of treatment, clinical and mycologic response was 100%. At follow-up, one patient experienced a relapse caused by C albicans. The most common drug-related adverse events involved the gastrointestinal system (eg, diarrhea and vomiting); no patients withdrew from the study because of adverse events. Thus fluconazole appeared to be effective and safe in the treatment of systemic candidiasis. Key words: fluconazole, systemic candidiasis, noncomparative study. INTRODUCTION
The incidence of serious opportunistic fungal infections has increased significantly in recent years1 Factors recognized as increasing the risk of developing fungal infection include the use of immunosuppressive therapy, cytotoxic chemotherapy, corticosteroids, cyclosporine, ablative radiation therapy, extended-spectrum antibiotic therapy, organ transplantation, major surgery, long-term indwelling central catheter, bladder catheter, and hemodialysis. Other risk factors include diarrhea, neutropenia, acquired immunodeficiency syndrome, hospital transfer, and hospitalization in an intensive care unit.14 Recovery of Cundidu from surveillance culture sites (oropharynx or feces) and candiduria are risk factors for candidemia.3’4 Treatment of these infections poses a formidable challenge to clinicians. The usefulness of amphotericin B, which has remained the gold standard for decades, is limited by its acute and chronic toxicities.7 Among the available triazole antifungal agents, fluconazole has demonstrated significant clinical potential’ and is an attractive alternative to amphotericin B for the treatment of opportunistic fungal infections. Address correspondence to: David L. Gibbs, PhD, Pfizer, Inc, 235 East 42nd Street, New York, NY 10017. Received for publication on January 5, 1998. Printed in the USA. Reproduction in whole or part is not permitted.
197
0011-393x/98/$19.00
FLUCONAZOLE
IN SYSTEMIC
CANDIDIASIS
Fluconazole is available in both an oral and an intravenous formulation. It has high oral bioavailability (>90%) and a plasma half-life of approximately 30 hours.s Approximately 80% of the dose is excreted unchanged in urine. Fluconazole is readily distributed in body tissues’ because of its relatively low lipophilicity and low affinity for plasma proteins (12%). The drug is well tolerated, and reports of serious hepatic reactions have been rare.’ Results of a prospective, nonrandomized, observational study in patients with candidemiag indicated that fluconazole was as effective as amphotericin B. Two comparative, randomized trials, one involving surgical patients with systemic mycoses” and the other involving nonneutropenic patients with candidemia,” showed no significant difference in effectiveness between fluconazole and amphotericin B. On the basis of these results of fluconazole therapy, the present study was undertaken to investigate the efficacy and safety of fluconazole when administered in high doses for prolonged periods to severely ill patients with microbiologically documented systemic candidiasis.
PATIENTS AND METHODS
This was an open-label, noncomparative, multinational study conducted in 12 countries (Argentina, Belgium, Brazil, France, Italy, Korea, the Netherlands, New Zealand, Norway, Spain, Switzerland, and Turkey). Eligible patients were aged 16 to 80 years and satisfied the following criteria: (1) positive histology (tissue sample) or culture from a normally sterile site (excluding blood and urine) within 7 days before initiation of fluconazole treatment, or (2) at least one positive blood culture within 7 days before initiation of fluconazole treatment, and (3) at least two of the following risk factors: indwelling intravenous catheter, hospitalization in an intensivecare unit, hyperalimentation, severe trauma or major surgery, extendedspectrum antibiotic therapy, immunosuppressive therapy (corticosteroids, irradiation, or cytotoxic chemotherapy), severe neutropenia (c50O/~L), or significant lymphopenia. In addition, patients who satisfied the second criterion also must have had at least one of the following clinical signs or symptoms consistent with Cundidu infection: Candidu in urine on 2 separate days with evidence of renal enlargement but without an indwelling urinary catheter, fever with signs of sepsis unresponsive to antibiotic therapy for 72 hours, fever with signs of sepsis persisting 48 hours after removal of a venous or arterial catheter, retinal lesions, esophagitis with biopsy positive for Cundida, myositis syndrome, multiple hepatic lesions, or new macular or papular lesions. Patients who satisfied these inclusion criteria but had been started on another antifungal agent for the same infection were permitted to enroll in this study, provided that the antifimgal therapy had not been administered for longer than 48 hours. 198
D. L. GIBBS
The investigator at each site determined the fluconazole dosage (100 to 400 mg/d) and route of administration (oral or intravenous) on the basis of the severity of the mycosis and other pertinent patient characteristics (eg, renal function). Patients were assessed for efficacy and safety as follows: weekly during the first 6 weeks of treatment, monthly thereafter, at the end of treatment (48 hours to 15 days after the last dose), and at follow-up (2 weeks to 6 months after the end of treatment). Descriptive statistics were used to summarize demographic characteristics. Clinical and mycologic response rates were calculated at the end of treatment and at follow-up. Adverse events were tabulated. RESULTS
A total of 51 patients (34 men and 17 women) with a mean MD) age of 49.0 (k16.5) years were enrolled in the study and received at least one dose of fluconazole. The mean daily fluconazole dosage was 198 mg (range, 100 to 400 mg>, and the mean duration of therapy was 56 days (range, 4 to 183 days). Of the 51 patients, 12 were excluded from the efficacy analysis for the following reasons: protocol deviation (3 patients), no baseline confirmation of diagnosis or no baseline pathogen (6), did not meet entry criteria (l), and insufficient dosing because of an adverse event (2). Thus 39 patients were assessable for the efficacy analysis. A total of 78 baseline pathogens were isolated from the 39 assessable patients (2 patients had multiple pathogens, and 23 patients had multiple culture sources>. The predominant pathogen was Candida albicans, which was isolated from 53 (68%) of 78 culture specimens. Others included various Candida species (110/o), Candida tropicalis (8%), Candida glabrata (4%), and Candida parapsilosis (6%). Patients treated for positive blood cultures (51%) comprised the largest group, followed by those with positive cultures of peritoneal fluid and of the esophagus and peritoneum (8% each). Infections at other sites (knee, kidney, heart, endocardium, pleural exudate, abscess, tumor, and sinus) occurred at a frequency of 5% or less. Clinical and mycologic outcomes at the end of treatment and at followup are summarized in Table I. Fluconazole was 100% successful at the end of treatment, both clinically (cured and improved) and mycologically (eradicated). The one patient who experienced a relapse had baseline blood and peritoneal fluid cultures positive for C albicans. After 24 days of fluconazole treatment, all cultures were negative, and fluconazole was discontinued 4 days later. At follow-up 30 days later, this patient’s peritoneal fluid cultures remained negative, whereas blood cultures were positive for C albicans. Drug-related (definite or possible relationship to fluconazole) adverse events are summarized in Table II. All 51 patients were included in the safety analysis. The most frequent adverse events were those involving the 199
FLUCONAZOLE
IN SYSTEMIC
CANDIDIASIS
Table I. Clinical and mycologic outcomes at the end of treatment and at follow-up. End of Treatment*
Response Clitni;
Follow-upt n = 22 2; ;I)
(%)$
Im rovement P ;;s n = 371 37 100) 6A 0
Mycologic .(%)I’ Fex$;aon Failure
1 51 d n = 20
* End-of-treatment assessment occurred 48 hours to 15 days after administration of the last dose. t Follow-up assessment occurred 2 weeks to 6 months after the end of treatment. $ Cure = disappearance of all pretreatment signs and symptoms of mycosis; improvement = improvement in or partial disappearance of pretreatment signsandsymptoms;relapse= improvement in or disappearance of signs and symptoms at the end of treatment followed by worsening or reappearance of signs and symptoms at follow-up; failure = no change in signs or symptoms. $j One patient was assessed mycologically but not clinically. II Eradication = baseline pathogen could not be cultured from site of infection, or no material was available from which to obtain a culture specimen (resolution of lesions ; relapse = eradication at the end of treatment followed by reappearance of the same fungal pathogen at 1ollow-up and a clinical response of relapse; failure = organism was cultured from site of infection at the end of therapy. II Two patients were assessed clinically but not mycologically.
gastrointestinal system. No adverse events were judged by the investigator to be severe, and no patients were withdrawn from the study because of drug-related adverse events. Eight patients died; all the deaths were attributed to concurrent illness or underlying disease. DISCUSSION
These results confirm the efficacy and safety of fluconazole in patients with systemic candidiasis. However, it must be remembered that this was an
Table II. Drug-related (definite or possible) adverse events in 51 patients treated with fluconazole. No. (%) of Patients
Body System (preferred term) At least one adverse event Gastrointestinal Diarrhea Nausea Vomiting Hepatic function, abnormal Increased alkaline phosphatase Cardiovascular Cardiac failure Metabolic and nutritional system Increased creatinine
200
D. L. GIBBS
open-label, noncomparative study. The prevalence of C albicans as a pathogen in this study is consistent with findings in the published literature1*3p4’12* however, there is an increasing shift toward Candida species Among these other than C albicuns as a cause of f&gal infection.6P11*13 species, C tropicalis, C glubrutu, and C parupsilosis appear to be most common~La,W,ia This also was the case in our study. Fluconazole was effective in eradicating all Cundidu species at the end of treatment, with one relapse caused by C albicuns observed at follow-up. This is consistent with published response rates of 60% to 100% for fluconazole.7 However, fluconazole’s limited activity against Candida species such as C krusei and C gZabruta1,7,14 has caused concern, although a high minimal inhibitory concentration does not necessarily predict clinical failure.14 A recently published literature survey of cases of non-ulbicans candidal infections treated with fluconazole revealed an overall efficacy rate of 77%.13 Fluconazole appeared to be particularly effective against infections caused by C purupsilosis and C tropic&s, whereas efficacy varied in cases of C glubratu infection, depending on the dose of fluconazole administered. It is difficult without controls to determine the efficacy of treatment, particularly when those host factors predisposing the patients to candidiasis are not known (eg, withdrawal of a urinary catheter, abscess drainage). Thus this study should serve as an observational study of the use of fluconazole among patients colonized with or culture-positive for C albicans who had underlying disorders. The most common adverse events were those involving the gastrointestinal tract, including diarrhea, nausea, vomiting, and hepatic effects. All adverse events occurred with a frequency of less than 4%, none of which necessitated withdrawal from the study. Our findings are consistent with those reported in other clinical trials of fluconazole.’ CONCLUSIONS
Fluconazole, administered orally or intravenously in dosages of 100 to 400 mg once daily, appeared to be effective and safe in patients with systemic candidiasis. Additional studies are needed to further define the role of fluconazole in the treatment of infections caused by non-ulbicuns candid& species. Acknowledgment
Financial support and fluconazole were provided by Pfizer, Inc, New York, New York. References: 1. Kramer KM, Skaar DJ, Ackerman
BH. The fluconazole 201
era: Management
of hematog-
FLUCONAZOLE
IN SYSTEMIC
CANDJDIASIS
enously disseminated candidiasis in the nonneutropenic patient. Pharmacotherapy. 1997;17:53%548. 2. Rubin RH. Fungal and bacterial infections in the immunocompromised host. Eur J Qin Microbial Infect Dis. 1993;12(Suppl 1):4248. 3. Bross J, Talbot GH, Maislin G, et al. Risk factors for nosocomial candidemia: A casecontrol study in adults without leukemia. Am J Med. 1989;87:614-620. 4. Karabinis A, Hill C, Leclercq B, et al. Risk factors for candidemia in cancer patients: A case-control study. J Clin Microbial. 1988;26:429-432. 5. Swerdloff JN, Filler SG, Edwards JE Jr. Severe candidal infections in neutropenic patients. Clin Infect Dis. 1993;7(Suppl2):8457-S467. 6. Walsh TJ, Hiemenz JW, Anaissie E. Recent progress and current problems in treatment of invasive fungal infections in neutropenic patients. Infect Dis Clin North Am. 1996;10:365-400. 7. Uzun 0, Anaissie EJ. Problems and controversies in the management of hematogenous candid&is. CZin Infect Dis. 1996;22@uppl2):S95-S101. 8. Brammer KW, Farrow PR, Faulkner JK. Pharmacokinetics and tissue penetration of fluconazole in humans. Rev Infect Dis. 1990;12(Suppl 3):3318-S326. 9. Nguyen MH, Peacock JE Jr, Tanner DC, et al. Therapeutic approaches in patients with candidemia. Evaluation in a multicenter, prospective, observational study. Arch Intern Med. 1995;155:2429-2435. 10. Kujath P, Lerch K, Kochendorfer P, Boos C. Comparative study of the efficacy of fluconazole versus amphotericin B/flucytosine in surgical patients with systemic mycoses. Znfection. 1993;21:37w82. 11. Rex JH, Bennett JE, Sugar AM, et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. NEJM. 1994;331:1325-1330. 12. Meunier F, Aoun M, Bitar N. Candidemia in immunocompromised patients. Clin Znfect Dis. 1992;14(Suppl l):S12O-S125. 13. van’t Wout JW. Fluconazole treatment of candidal infections caused by non-albicans Candida species. Eur J Clin Microbial Infect Dis. 1996;15:23&242. 14. Rex JH, Pfaller MA, Barry AL, et al. Antifungal susceptibility testing of isolates from a randomized multicenter trial of fluconazole versus amphotericin B as treatment of nonneutropenic patients with candidemia. Antimicrob Agents Chemother. 1995;39:40-44.
202