ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1991, p. 365-367 0066-4804/91/020365-03$02.00/0
Vol. 35, No. 2
NOTES
Fluconazole in the Treatment of Candidiasis in Immunocompromised Children CLAUDIO VISCOLI,* ELIO CASTAGNOLA, FRANCESCA FIOREDDA, BARBARA CIRAVEGNA, GIANDOMENICO BARIGIONE, AND ALBERTO TERRAGNA First Department of Infectious Diseases, University of Genoa, G. Gaslini Children's Hospital, Largo G. Gaslini 5, 16148 Genoa, Italy Received 24 July 1990/Accepted 26 November 1990
Fluconazole, a new triazole derivative, was evaluated in a pilot study of 34 episodes of candidiasis in 24 children. All the patients had predisposing conditions; such as human immunodeficiency virus infection, cancer, organ or bone marrow transplantation, neonatal age and malnutrition, and obstructive uropathy. The drug was administered at 6 mg/kg (body weight) once daily either orally or intravenously. Two patients with fungemia due to Candida parapsilosis required an increased dosage of 12 mg/kg. Clinical and microbiological success was achieved in 30 of 34 cases (88%). Drug-related transaminase increases were observed in two cases (6%). Fluconazole may represent an effective alternative to amphotericin B in the treatment of candidiasis in children. Comparative trials are necessary to assess optimal dosages and efficacy.
Traditional drug therapy for patients with severe Candida infection is often limited by problems associated with tolerance and efficacy (5, 9). Suspected Candida infections are usually treated with amphotericin B; flucytosine is often added to increase antifungal activity or decrease total amphotericin B dosage. Newer antifungal agents may offer significant options for first-line treatment in this patient population. Fluconazole is a bistriazole antifungal agent which has been reported to be effective against several fungal pathogens, including most species of Candida with the possible exception of Candida krusei and Candida glabrata (8). Fluconazole combines good absorption in the oral form and water solubility, so that it can be administered both orally and intravenously (2). Clearance is predominantly renal, with most of the administered dose excreted unchanged in urine (2, 12). Studies with adult patients have shown that the drug is less toxic than amphotericin B (10) and more effective than ketoconazole (6). In particular, fluconazole seems not to be associated with the endocrine effect that has been reported for other azole compounds (11). Although the activity of fluconazole in the treatment of adult patients with fungal infections has already been assessed in some preliminary studies (1), there are no evaluative reports of the efficacy of fluconazole in the treatment of children. In an anectodal experience in our service, however, fluconazole was shown to be safe and effective in treating an episode of multiple Candida colonization in an underweight infant (18), and Bunin (3) reported the successful use of fluconazole in the treatment of disseminated Candida infection in a 6-year-old girl with acute lymphoblastic leukemia apparently not responding after a prolonged treatment course with amphotericin B and flucytosine. We report the results of the first open, noncomparative study of efficacy and tolerability of fluconazole in the treatment of candidiasis in immunocompromised children. *
Patients were children aged 14 years or younger with candidal infections treated at the G. Gaslini Children's Hospital, Genoa, Italy, from January to December 1989. Criteria for inclusion were the presence of a documented candidiasis with fever and local symptoms in the setting of predisposing conditions, such as human immunodeficiency virus infection, cancer, organ or bone marrow transplantation, neonatal age and malnutrition, and obstructive abnormalities of the urinary tract. Criteria for exclusion were parental refusal to participate in the study, history of hypersensitivity to azole compounds, and hepatic (bilirubin, >85 ,umol/liter) or renal (creatinine, >220 ,umol/liter) insufficiency. Candidiasis was defined as a clinical illness characterized by fever and symptoms and signs of localized infection, with isolation of Candida spp. from blood, urine, oral and throat swabs (with fever, local symptoms, and clinical evidence of oral thrush), or purulent material obtained by surgery or needle aspiration of localized infections. Isolation of Candida spp. from at least three colonization sites (defined as multiple Candida colonization) in the setting of persistent or relapsing fever after a prolonged period of antibacterial therapy in immunocompromised patients was considered suggestive of candidiasis and was treated accordingly. Fluconazole was provided by Pfizer-Italy in vials containing 100 mg of substance diluted in 50 ml of 0.9% NaCl for intravenous infusion and as 50-mg capsules or 5-mg/ml solutions for oral administration. The standard dosage regimen was 6 mg/kg of body weight once daily, administered intravenously or orally. Investigators were allowed to change from intravenous to oral treatment as soon as the patient was able to swallow oral medications. The efficacy of fluconazole was evaluated by both clinical and microbiological criteria. Treatment results were categorized as follows: (i) success-definite resolution of signs and symptoms of infection, with microbiological eradication; (ii) success with relapse-clinical and microbiological recurrence within 15 days after discontinuation of treatment; and
Corresponding author. 365
366
NOTES
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 1. Etiologies and outcomes of 34 episodes of candidiasis in children No. of clinical and
microbiological outcomes Diagnosis
Failure
Etiology
Success with Success with eradication with persistence of pathogen relapse of pathogen
Oral thrush
Candida spp. C. albicans C. tropicalis
7 1 1
3 1 3
1
Urinary tract
Candida spp. C. albicans C. tropicalis
1 3 1
3
1
Septicemia
C. parapsilosis
2
Otitis
Candida spp.
1
Subhepatic abscess
C. krusei
infection
1
Multiple coloni- Candida spp. zation C. albicans
2 1
1
(iii) failure-persistence of symptoms and signs of infection and positive cultures, with the consequent need to change antifungal therapy. Adverse effects were categorized as definitely related to fluconazole when they occurred in the absence of other apparent causes; all other episodes were designated as possibly related. Criteria for toxicity were those required by the EORTC International Antimicrobial Therapy Cooperative Group (7). In particular, hepatotoxicity was defined as a rise in transaminase, bilirubin, and/or alkaline phosphatase concentrations to at least two times above baseline values. Thiriy-four episodes of candidiasis in 24 patients, 12 males and 12 females, were treated. The age range of the patients was 13 days to 14 years (median, 6 years). Underlying conditions were human immunodeficiency virus infection (P2; 4) in eight patients, organ or bone marrow transplantation in seven patients, cancer in five patients, obstructive uropathy in three patients, and severe malnutrition in one patient (an underweight infant). Eighteen patients received one treathent course for one episode of candidiasis each, while the other six patients were treated for two episodes (three patients), three episodes (two patients), and four episodes (one patient). Fluconazole was administered intravenously in 15 of 34 episodes of candidiasis (44%); in three cases, treatment was continued orally, after 2 days for one patient and after 2 weeks for the other two patients. In the remaining 19 episodes, the drug was administered orally from the beginning. Overall, the patients received flucona-
zole for a median of 12 days (range, 8 to 50 days). In 30 of 34 cases, other drugs, including antibacterial agents, antiviral agents, anticonvulsants, and immunosuppressive and antineoplastic drugs, were administered concomitantly. Infectious localization, etiology, and response to treatment are summarized in Table 1. A total of 34 treatment courses in 24 patients resulted in 30 clinical and microbiological cures (88%). In two episodes of fungemia due to Candida parapsilosis, persistence of fever and positive blood cultures (in one patient despite removal of the source of infection [central intravenous catheter]) prompted us to increase the dosage to 12 mg/kg/day. Both patients responded to this increased dosage. Four episodes (12%) did not respond to treatment and improvement was obtained with amphotericin B, in one case in combination with flucytosine (Table 2). One of these patients had a subhepatic abscess due to C. krusei, which is considered to be resistant to fluconazole. Treatment was started when the laboratory reported the presence of yeast cells on direct examination and was modified 12 days later due to lack of clinical response and identification of the infecting pathogen as a potentially resistant strain. In the other three cases, failure was due to lack of clinical response and persistence of positive cultures. Relapse occurred in 10 of the 30 responding episodes (33%) after discontinuation of treatment. Relapses were due to persistence of the predisposing conditions (human immunodeficiency virus infection in five patients, urinary tract obstruction in three patients, and cancer in two patients). Concerning adverse effects, abnormalities ofliver function were observed in eight treatment courses. However, such adverse effects were considered to be definitely related to fluconazole in only two of the episodes (6%). In one case, that of an underweight infant with multiple Candida colonization who responded to fluconazole, the dosage was decreased to 3 mg/kg (18). In the other case, that of a bone marrow transplant patient with oral thrush, fluconazole was discontinued because of clinical and microbiological failure. In both cases, liver function returned to normal after discontinuation of treatment. In the other six episodes, hepatotoxicity was more likely multifactorial in origin. In this noncomparative clinical study, fluconazole was shown to be effective in the treatment of candidiasis in immunocompromised children. Of the 34 episodes treated, only 4 (12%) failed to respond to treatment. In 10o of the episodes, relapses occurred within 15 days from discontinuation of fluconazole, probably reflecting persistence of the predisposing condition. Only two patients (6%) treated with standard dosages developed mild hepatotoxicity, which was categorized as being definitely related to fluconazole. Studies of fluconazole in the treatment of candidiasis in adult patients showed results that were comparable to those reported in the present study. Response rates ranged from
TABLE 2. Analysis of treatment failures Diagnosis
Underlying disease
Etiology
Time to failure
Subhepatic abscess Urinary tract infection
Cancer Obstructive uropathy Autologous bone marrow transplantation Autologous bone marrow transplantation
C. krusei C. albicans Candida spp.
12 11
Amphotericin B
Candida spp.
9
Amphotericin B
Oral thrush
Multiple colonization
(days)
i5
Subsequent treatment
Amphotericin B
Amphotericin B + flucytosine
VOL. 35, 1991
100% (6) to 78% (14) or 71% (15). Relapse rates ranged from 46% (6) to 27% (14). Liver function abnormalities were observed with incidences of 6% (6) and 5% (15). Until the advent of the imidazoles, amphotericin B was the only antifungal agent that was generally effective against Candida spp. However, serious side effects frequently associated with its use, particularly nephrotoxicity, caused considerable concern (9). Renal toxicity is reported with various incidences and degrees of severity in children receiving amphotericin B (13, 16, 17). Fluconazole may represent an attractive therapeutic alternative to amphotericin B in the treatment of candidiasis in immunocompromised children. However, its poor in vitro activity against C. krusei and C. glabrata requires some caution because of the possibility of colonization and superinfection. Further experience is needed to assess optimal dosages and possible pharmacologic interactions and to confirm these results in comparative trials.
NOTES
8.
9. 10. 11. 12.
367
Group. 1987. Ceftazidime combined with short or long course of amikacin for empirical therapy of Gram-negative bacteremia in cancer patients with granulocytopenia. N. Engl. J. Med. 317: 1692-1698. Fisher, M. A., S.-H. Shen, J. Haddad, and W. F. Tarry. 1989. Comparison of in vivo activity of fluconazole with that of amphotericin B against Candida tropicalis, Candida glabrata, and Candida krusei. Antimicrob. Agents Chemother. 33:14431446. Gallis, H. A., R. H. Drew, and W. W. Pickard. 1990. Amphotericin B: 30 years of clinical experience. Rev. Infect. Dis. 12:308-329. Graybill, J. R. 1989. New antifungal agents. Eur. J. Clin. Microbiol. Infect. Dis. 8:402-412. Hanger, D. P., S. Jevons, and J. T. B. Shaw. 1988. Fluconazole and testosterone: in vivo and in vitro studies. Antimicrob. Agents Chemother. 32:646-648. Humphrey, M. J., S. Jevons, and M. H. Tarbit. 1985. Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal drug, in animal and humans. Antimicrob. Agents
Chemother. 28:648-653. 1. 2.
3. 4.
5.
6. 7.
REFERENCES Bennett, J. E. 1990. Fluconazole: a novel advance in therapy for systemic fungal infections. Overview of the symposium. Rev. Infect. Dis. 12(Suppl. 3):S263-S266. Brammer, K. W., and M. H. Tarbit. 1987. A review of the pharmacokinetics of fluconazole (UK-49,858) in laboratory animals and man, p. 141-149. In R. A. Fromtling (ed.), Recent trends in discovery, development and evaluation of antifungal agents. J. R. Prous Science, Paris. Bunin, N. 1989. Oral fluconazole for treatment of disseminated fungal infection. Pediatr. Infect. Dis. J. 8:62. Centers for Disease Control. 1987. CDC classification system for human immunodeficiency virus (HIV) infection in children under 13 years of age. Morbid. Mortal. Weekly Rep. 36:225236. Crislip, M. A., and J. E. Edwards, Jr. 1989. Candidiasis. Infect. Dis. Clin. North Am. 3:103-133. De Wit, S., H. Goossens, D. Weerts, and N. Clumeck. 1989. Comparison of fluconazole and ketoconazole for oropharyngeal candidiasis in AIDS. Lancet i:746-748. EORTC International Antimicrobial Therapy Cooperative
13. Koren, G., A. Lau, J. Klein, C. Golas, M. Bologa-Campeanu, S. Soldin, S. M. MacLeod, and C. Prober. 1988. Pharmacokinetics and adverse effects of amphotericin B in infants and children. J.
Pediatr. 113:559-563. 14. Meunier, F., M. Aoun, and M. Gerard. 1990. Therapy for oropharyngeal candidiasis in the immunocompromised host: a randomized double-blind study of fluconazole vs. ketoconazole. Rev. Infect. Dis. 12(Suppl. 3):S364-S368. 15. Robinson, P. A., A. K. Knirsch, and J. A. Joseph. 1990. Fluconazole for life-threatening fungal infections in patients who cannot be treated with conventional antifungal agents. Rev.
Infect. Dis. 12(Suppl. 3):S349-S363. 16. Starke, J. R., E. 0. Mason, Jr., W. G. Kramer, and S. L. Kaplan. 1987. Pharmacokinetics of amphotericin B in infants
and children. J. Infect. Dis. 155:766-774. 17. Turner, R. B., L. G. Donowitz, and 0. J. Hendley. 1985. Consequences of candidemia for pediatric patients. Am. J. Dis.
Child. 139:178-180. 18. Viscoli, C., E. Castagnola, M. Corsini, R. Gastaldi, M. Soliani, and A. Terragna. 1989. Fluconazole therapy in an underweight infant. Eur. J. Clin. Microbiol. Infect. Dis. 8:925-926.
Vol. 35, No. 2
NOTES
Fluconazole in the Treatment of Candidiasis in Immunocompromised Children CLAUDIO VISCOLI,* ELIO CASTAGNOLA, FRANCESCA FIOREDDA, BARBARA CIRAVEGNA, GIANDOMENICO BARIGIONE, AND ALBERTO TERRAGNA First Department of Infectious Diseases, University of Genoa, G. Gaslini Children's Hospital, Largo G. Gaslini 5, 16148 Genoa, Italy Received 24 July 1990/Accepted 26 November 1990
Fluconazole, a new triazole derivative, was evaluated in a pilot study of 34 episodes of candidiasis in 24 children. All the patients had predisposing conditions; such as human immunodeficiency virus infection, cancer, organ or bone marrow transplantation, neonatal age and malnutrition, and obstructive uropathy. The drug was administered at 6 mg/kg (body weight) once daily either orally or intravenously. Two patients with fungemia due to Candida parapsilosis required an increased dosage of 12 mg/kg. Clinical and microbiological success was achieved in 30 of 34 cases (88%). Drug-related transaminase increases were observed in two cases (6%). Fluconazole may represent an effective alternative to amphotericin B in the treatment of candidiasis in children. Comparative trials are necessary to assess optimal dosages and efficacy.
Traditional drug therapy for patients with severe Candida infection is often limited by problems associated with tolerance and efficacy (5, 9). Suspected Candida infections are usually treated with amphotericin B; flucytosine is often added to increase antifungal activity or decrease total amphotericin B dosage. Newer antifungal agents may offer significant options for first-line treatment in this patient population. Fluconazole is a bistriazole antifungal agent which has been reported to be effective against several fungal pathogens, including most species of Candida with the possible exception of Candida krusei and Candida glabrata (8). Fluconazole combines good absorption in the oral form and water solubility, so that it can be administered both orally and intravenously (2). Clearance is predominantly renal, with most of the administered dose excreted unchanged in urine (2, 12). Studies with adult patients have shown that the drug is less toxic than amphotericin B (10) and more effective than ketoconazole (6). In particular, fluconazole seems not to be associated with the endocrine effect that has been reported for other azole compounds (11). Although the activity of fluconazole in the treatment of adult patients with fungal infections has already been assessed in some preliminary studies (1), there are no evaluative reports of the efficacy of fluconazole in the treatment of children. In an anectodal experience in our service, however, fluconazole was shown to be safe and effective in treating an episode of multiple Candida colonization in an underweight infant (18), and Bunin (3) reported the successful use of fluconazole in the treatment of disseminated Candida infection in a 6-year-old girl with acute lymphoblastic leukemia apparently not responding after a prolonged treatment course with amphotericin B and flucytosine. We report the results of the first open, noncomparative study of efficacy and tolerability of fluconazole in the treatment of candidiasis in immunocompromised children. *
Patients were children aged 14 years or younger with candidal infections treated at the G. Gaslini Children's Hospital, Genoa, Italy, from January to December 1989. Criteria for inclusion were the presence of a documented candidiasis with fever and local symptoms in the setting of predisposing conditions, such as human immunodeficiency virus infection, cancer, organ or bone marrow transplantation, neonatal age and malnutrition, and obstructive abnormalities of the urinary tract. Criteria for exclusion were parental refusal to participate in the study, history of hypersensitivity to azole compounds, and hepatic (bilirubin, >85 ,umol/liter) or renal (creatinine, >220 ,umol/liter) insufficiency. Candidiasis was defined as a clinical illness characterized by fever and symptoms and signs of localized infection, with isolation of Candida spp. from blood, urine, oral and throat swabs (with fever, local symptoms, and clinical evidence of oral thrush), or purulent material obtained by surgery or needle aspiration of localized infections. Isolation of Candida spp. from at least three colonization sites (defined as multiple Candida colonization) in the setting of persistent or relapsing fever after a prolonged period of antibacterial therapy in immunocompromised patients was considered suggestive of candidiasis and was treated accordingly. Fluconazole was provided by Pfizer-Italy in vials containing 100 mg of substance diluted in 50 ml of 0.9% NaCl for intravenous infusion and as 50-mg capsules or 5-mg/ml solutions for oral administration. The standard dosage regimen was 6 mg/kg of body weight once daily, administered intravenously or orally. Investigators were allowed to change from intravenous to oral treatment as soon as the patient was able to swallow oral medications. The efficacy of fluconazole was evaluated by both clinical and microbiological criteria. Treatment results were categorized as follows: (i) success-definite resolution of signs and symptoms of infection, with microbiological eradication; (ii) success with relapse-clinical and microbiological recurrence within 15 days after discontinuation of treatment; and
Corresponding author. 365
366
NOTES
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 1. Etiologies and outcomes of 34 episodes of candidiasis in children No. of clinical and
microbiological outcomes Diagnosis
Failure
Etiology
Success with Success with eradication with persistence of pathogen relapse of pathogen
Oral thrush
Candida spp. C. albicans C. tropicalis
7 1 1
3 1 3
1
Urinary tract
Candida spp. C. albicans C. tropicalis
1 3 1
3
1
Septicemia
C. parapsilosis
2
Otitis
Candida spp.
1
Subhepatic abscess
C. krusei
infection
1
Multiple coloni- Candida spp. zation C. albicans
2 1
1
(iii) failure-persistence of symptoms and signs of infection and positive cultures, with the consequent need to change antifungal therapy. Adverse effects were categorized as definitely related to fluconazole when they occurred in the absence of other apparent causes; all other episodes were designated as possibly related. Criteria for toxicity were those required by the EORTC International Antimicrobial Therapy Cooperative Group (7). In particular, hepatotoxicity was defined as a rise in transaminase, bilirubin, and/or alkaline phosphatase concentrations to at least two times above baseline values. Thiriy-four episodes of candidiasis in 24 patients, 12 males and 12 females, were treated. The age range of the patients was 13 days to 14 years (median, 6 years). Underlying conditions were human immunodeficiency virus infection (P2; 4) in eight patients, organ or bone marrow transplantation in seven patients, cancer in five patients, obstructive uropathy in three patients, and severe malnutrition in one patient (an underweight infant). Eighteen patients received one treathent course for one episode of candidiasis each, while the other six patients were treated for two episodes (three patients), three episodes (two patients), and four episodes (one patient). Fluconazole was administered intravenously in 15 of 34 episodes of candidiasis (44%); in three cases, treatment was continued orally, after 2 days for one patient and after 2 weeks for the other two patients. In the remaining 19 episodes, the drug was administered orally from the beginning. Overall, the patients received flucona-
zole for a median of 12 days (range, 8 to 50 days). In 30 of 34 cases, other drugs, including antibacterial agents, antiviral agents, anticonvulsants, and immunosuppressive and antineoplastic drugs, were administered concomitantly. Infectious localization, etiology, and response to treatment are summarized in Table 1. A total of 34 treatment courses in 24 patients resulted in 30 clinical and microbiological cures (88%). In two episodes of fungemia due to Candida parapsilosis, persistence of fever and positive blood cultures (in one patient despite removal of the source of infection [central intravenous catheter]) prompted us to increase the dosage to 12 mg/kg/day. Both patients responded to this increased dosage. Four episodes (12%) did not respond to treatment and improvement was obtained with amphotericin B, in one case in combination with flucytosine (Table 2). One of these patients had a subhepatic abscess due to C. krusei, which is considered to be resistant to fluconazole. Treatment was started when the laboratory reported the presence of yeast cells on direct examination and was modified 12 days later due to lack of clinical response and identification of the infecting pathogen as a potentially resistant strain. In the other three cases, failure was due to lack of clinical response and persistence of positive cultures. Relapse occurred in 10 of the 30 responding episodes (33%) after discontinuation of treatment. Relapses were due to persistence of the predisposing conditions (human immunodeficiency virus infection in five patients, urinary tract obstruction in three patients, and cancer in two patients). Concerning adverse effects, abnormalities ofliver function were observed in eight treatment courses. However, such adverse effects were considered to be definitely related to fluconazole in only two of the episodes (6%). In one case, that of an underweight infant with multiple Candida colonization who responded to fluconazole, the dosage was decreased to 3 mg/kg (18). In the other case, that of a bone marrow transplant patient with oral thrush, fluconazole was discontinued because of clinical and microbiological failure. In both cases, liver function returned to normal after discontinuation of treatment. In the other six episodes, hepatotoxicity was more likely multifactorial in origin. In this noncomparative clinical study, fluconazole was shown to be effective in the treatment of candidiasis in immunocompromised children. Of the 34 episodes treated, only 4 (12%) failed to respond to treatment. In 10o of the episodes, relapses occurred within 15 days from discontinuation of fluconazole, probably reflecting persistence of the predisposing condition. Only two patients (6%) treated with standard dosages developed mild hepatotoxicity, which was categorized as being definitely related to fluconazole. Studies of fluconazole in the treatment of candidiasis in adult patients showed results that were comparable to those reported in the present study. Response rates ranged from
TABLE 2. Analysis of treatment failures Diagnosis
Underlying disease
Etiology
Time to failure
Subhepatic abscess Urinary tract infection
Cancer Obstructive uropathy Autologous bone marrow transplantation Autologous bone marrow transplantation
C. krusei C. albicans Candida spp.
12 11
Amphotericin B
Candida spp.
9
Amphotericin B
Oral thrush
Multiple colonization
(days)
i5
Subsequent treatment
Amphotericin B
Amphotericin B + flucytosine
VOL. 35, 1991
100% (6) to 78% (14) or 71% (15). Relapse rates ranged from 46% (6) to 27% (14). Liver function abnormalities were observed with incidences of 6% (6) and 5% (15). Until the advent of the imidazoles, amphotericin B was the only antifungal agent that was generally effective against Candida spp. However, serious side effects frequently associated with its use, particularly nephrotoxicity, caused considerable concern (9). Renal toxicity is reported with various incidences and degrees of severity in children receiving amphotericin B (13, 16, 17). Fluconazole may represent an attractive therapeutic alternative to amphotericin B in the treatment of candidiasis in immunocompromised children. However, its poor in vitro activity against C. krusei and C. glabrata requires some caution because of the possibility of colonization and superinfection. Further experience is needed to assess optimal dosages and possible pharmacologic interactions and to confirm these results in comparative trials.
NOTES
8.
9. 10. 11. 12.
367
Group. 1987. Ceftazidime combined with short or long course of amikacin for empirical therapy of Gram-negative bacteremia in cancer patients with granulocytopenia. N. Engl. J. Med. 317: 1692-1698. Fisher, M. A., S.-H. Shen, J. Haddad, and W. F. Tarry. 1989. Comparison of in vivo activity of fluconazole with that of amphotericin B against Candida tropicalis, Candida glabrata, and Candida krusei. Antimicrob. Agents Chemother. 33:14431446. Gallis, H. A., R. H. Drew, and W. W. Pickard. 1990. Amphotericin B: 30 years of clinical experience. Rev. Infect. Dis. 12:308-329. Graybill, J. R. 1989. New antifungal agents. Eur. J. Clin. Microbiol. Infect. Dis. 8:402-412. Hanger, D. P., S. Jevons, and J. T. B. Shaw. 1988. Fluconazole and testosterone: in vivo and in vitro studies. Antimicrob. Agents Chemother. 32:646-648. Humphrey, M. J., S. Jevons, and M. H. Tarbit. 1985. Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal drug, in animal and humans. Antimicrob. Agents
Chemother. 28:648-653. 1. 2.
3. 4.
5.
6. 7.
REFERENCES Bennett, J. E. 1990. Fluconazole: a novel advance in therapy for systemic fungal infections. Overview of the symposium. Rev. Infect. Dis. 12(Suppl. 3):S263-S266. Brammer, K. W., and M. H. Tarbit. 1987. A review of the pharmacokinetics of fluconazole (UK-49,858) in laboratory animals and man, p. 141-149. In R. A. Fromtling (ed.), Recent trends in discovery, development and evaluation of antifungal agents. J. R. Prous Science, Paris. Bunin, N. 1989. Oral fluconazole for treatment of disseminated fungal infection. Pediatr. Infect. Dis. J. 8:62. Centers for Disease Control. 1987. CDC classification system for human immunodeficiency virus (HIV) infection in children under 13 years of age. Morbid. Mortal. Weekly Rep. 36:225236. Crislip, M. A., and J. E. Edwards, Jr. 1989. Candidiasis. Infect. Dis. Clin. North Am. 3:103-133. De Wit, S., H. Goossens, D. Weerts, and N. Clumeck. 1989. Comparison of fluconazole and ketoconazole for oropharyngeal candidiasis in AIDS. Lancet i:746-748. EORTC International Antimicrobial Therapy Cooperative
13. Koren, G., A. Lau, J. Klein, C. Golas, M. Bologa-Campeanu, S. Soldin, S. M. MacLeod, and C. Prober. 1988. Pharmacokinetics and adverse effects of amphotericin B in infants and children. J.
Pediatr. 113:559-563. 14. Meunier, F., M. Aoun, and M. Gerard. 1990. Therapy for oropharyngeal candidiasis in the immunocompromised host: a randomized double-blind study of fluconazole vs. ketoconazole. Rev. Infect. Dis. 12(Suppl. 3):S364-S368. 15. Robinson, P. A., A. K. Knirsch, and J. A. Joseph. 1990. Fluconazole for life-threatening fungal infections in patients who cannot be treated with conventional antifungal agents. Rev.
Infect. Dis. 12(Suppl. 3):S349-S363. 16. Starke, J. R., E. 0. Mason, Jr., W. G. Kramer, and S. L. Kaplan. 1987. Pharmacokinetics of amphotericin B in infants
and children. J. Infect. Dis. 155:766-774. 17. Turner, R. B., L. G. Donowitz, and 0. J. Hendley. 1985. Consequences of candidemia for pediatric patients. Am. J. Dis.
Child. 139:178-180. 18. Viscoli, C., E. Castagnola, M. Corsini, R. Gastaldi, M. Soliani, and A. Terragna. 1989. Fluconazole therapy in an underweight infant. Eur. J. Clin. Microbiol. Infect. Dis. 8:925-926.
