FORMULARY FORUM
FLUCONAZOLE: A NEW TRIAZOLE ANTIFUNGAL AGENT Mary T. Pasko, Stephen C. Piscitelli, and Andrea D. Van Slooten
ABSTRACf: Fluconazoleis a fluorine-substituted, bis-triazole antifungal agent. Its mechanismof action, like that of other azoles, involves interruptionof the conversion of lanosterol to ergosterolvia binding to fungalcytochromeP-450and subsequentdisruptionof fungal membranes. ActivityagainstAspergillusspp., Blastomyces dermatitidis, Candida spp., Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, and Paracoccidioides brasiliensis has beendemonstrated in severalanimal models. Fluconazole can be admininstered both orally and intravenously. Mean peak serum concentrations achievedin human volunteersafter 50 and 100mg (oral)are 3.1 and 7.0 ILmollL respectively. Protein bindingis low (11 percent)and cerebrospinal fluid to serum ratio is 0.58 to 0.89. Serum half-lifeis long (22-32 hours)and eliminationis via renal clearanceof unchangeddrug. Clinicaltrials and reports support the use of fluconazole in treatment of candidiasis,particularlyoropharyngeal and esophagealinfectionsin immunocompromised hosts. Fluconazole is also approved for initialand suppresivetherapyof cryptococcal meningitis. Its role in management of systemicfungal infections will be furtherdefinedonce resultsof othercomparativetrials become available. Fluconazole is well toleratedand its effectson steroidogenesisare markedlyless than thoseofketoconazole. Antipyrine clearanceis not alteredat low doses (50 mg) of fluconazole; however, drug interactions with the use of largerdoses can be anticipatedwith agentssuch as cyclosporin, phenytoin,oral hypoglycemics, and warfarin. Rifarnpin appearsto decreasemetabolic clearanceof fluconazole. Fluconazoleis available as oral and parenteral formulations. Once-dailydoses of 1OQ-4OO mg are recommended. Dosagereductionis advisedfor patientswith impairedrenal function.
DICP Ann Pharmacother 1990;24:860-7.
continue to represent a challenge for the clinician and are often life-threatening, particularly in the immunocompromised patient. Yet relatively few agents have been developed for management of mycoses. Azole antifungal agents, along with amphotericin B, are the major chemotherapeutic modalities available. SYSTEMIC FUNGAL INFECI10NS
MARYT. PASKO, PIwm.D., is a Clinical Assistant Professor, School of Phannacy, State Universityof New YOIIe at Buffalo, and Infectious Diseases Department, Department of VeteransAffairs Medical Center, Buffalo, NY; STEPHEN C. PISCITELLI, B.S.Pharm., and ANDREA D. VANSWOTEN, B.S.Pharm., are Doctor ofPharmacy students, Schoolof Pharmacy,State Universityof NewYorl< at Buffalo. ReprInts: Mary T. Pasko, Pharm.D., Schoolof Phannacy, State University of New Yorl< at Buffalo, 373 Cooke Hall, Buffalo, NY 14260. Fluconazole (Diflucan), PfizerPharmaceuticals.
This article is approvedfor continuingeducationcredit.
860
•
DICP, The Annals of Pharmacotherapy •
N
OH
~"'N-CHI- -CH-N
),d
I
N
I
'\=N
F
Figure I. Graphic formula of fluconazole.
Unfortunately, each compound is associated with its respective toxicities and so there is a definite need for effective, well-tolerated antifungal agents. Recent development of the azole class has expanded the therapeutic choices. 1 In addition to imidazoles (miconazole, c1otrimazole, ketoconazole) the newly developed triazoles (fluconazole, itraconazole) offer promising alternatives. The focus ofthis review is fluconazole, which was approved by the Food and Drug Administration in February 1990. Chemistry
Azoles structurally are comprised of a five-membered azole ring to which other aromatic rings are attached via a carbon-nitrogen bond. Azole rings of imidazoles contain two nitrogen atoms whereas three nitrogen atoms are present in triazole compounds. Fluconazole (Figure I) is a water-soluble bis-triazol-difluorophenyl-2-propanol compound.'
Pharnuu:ology Azole antifungal agents interrupt the conversion of lanosterol to ergosterol, the main sterol of yeast and fungal cell membranes. This interruption occurs via binding ofthe azole to fungal cytochrome P-450 which mediates the demethylation step necessary for the conversion of 14-alphamethylsterols to ergosterol. It is hypothesized that the resultant accumulation of 14-methylsterols and altered membrane fluidity causes decreased activity of membranebound desaturase with a subsequent increase in free fatty
1990 September, Volume 24
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acids. This leads to disturbances in fungal membrane permeability."
Antifungal Activity The antifungal spectrum of fluconazole includes Aspergillus spp., Blastomyces dermatitidis, Candida spp., Coccidioidesimmitis, Cryptococcus neoformans, Histoplasma capsulatum, and Paracoccidioides brasiliensis. 1 Fluconazole':" as well as ketoconazole! are fungistatic in contrast to amphotericin B which has fungicidal activity. In vitro susceptibility testing of antifungal agents is highly dependent upon such test conditions as the size of starting inoculum, medium components, medium pH, incubation time, and time of reading results. S Although intralaboratory results may be reproducible, interlaboratory results have been found to vary markedly." Two reports of improved methodology for determination of minimum inhibitory concentrations (MICs) use a semisolid medium with controlled pH and standard inoculum' and antibiotic addition to the test medium. 8 However, until standardization is adopted, comparative MIC data may not be the most optimal means of assessing relative antifungal activity. Although some studies have shown good correlation between in vitro and in vivo antifungal activity," numerous investigators have found discrepant results between the in vitro activity of fluconazole and in vivo efficacy in animal models using the same organisms.P'" Clinical outcome in humans also is poorly correlated with MIC results. Data collected by the National Institute of Allergy and Infectious Disease (NIAID) Mycoses Study Group compared MICs and clinical response to ketoconazole in treatment of various fungal infections and found no correlation. 14 It has been suggested that assessment of relative antifungal activity among agents is best accomplished by comparison of efficacy achieved in animal models. S The outcome of several representative animal studies is presented in Table I. Models assessing activity against Candida albicans in either immunocornpetentv-":" or immunocomprised'vv-" animals have found increased survival, lower median effective doses, and lower doses required to cure 50 percent of animals for fluconazole as compared with ketoconazole. However, activity was less than that of amphotericin B. 11.16 Several other Candida spp., (tropicalis, glabrata, krusei) were studied in an immunocompetent rat model. fluconazole activity, as assessed by reduction in colony-forming units (CFUs) of fungi in organ tissue, was found to be equal to or less than that of amphotericin B for C. tropicalis and C. glabrata. Both agents failed to reduce CFUs of C. krusei in kidney tissue and fluconazole's activity was marginal in liver tissue!' Outcomes in models of systemic Aspergillusflavus and A. fumigatus." and coccidioidal meningitis" favor fluconazole rather than ketoconazole; however, once again, amphotericin B was superior to either agent. Although histoplasmosis was not cured with either fluconazole given twice daily or amphotericin B, the protective dose for 50 percent of animals for fluconazole was similar in the normal" and immunosuppressed murine model." However, with once-daily dosing in similar models of murine histoplasmosis, fluconazole was much less active than amphotericin B.20 Fluconazole and itraconazole demonstrated equal efficacy in a rabbit model of cryptoccocal meningitis
despite poor penetration of itraconazole into cerebrospinal fluid (CSF). In the same report, similar efficacy between the two agents was found in the treatment of candidal pyelonephritis. 22 In data published in abstracts, fluconazole has been further compared with SCH 39304, a new triazole under investigation. In murine models of pulmonary aspergillosis," systemic coccidioidomycosis.P' and coccidioidal meningitis," SCH 39304 was associated with increased survival rates at lower doses and greater reductions in fungal CFUs in target organs as compared with fluconazole and/or itraconazole. Survival in a murine model of pulmonary blastomycosis was 10-30 percent for fluconazoletreated animals compared with 30-100 percent for SCH 39304 and 80 percent for amphotericin B. 21 Fluconazole activity against ketoconazole-resistant strains of C. albicans has been assessed in vitro and in animal models. With doses up to 20 mg/kg/d in rabbir· 22 and rat models,IO.26 fluconazole did not demonstrate activity against the resistant strains. However, fungistatic activity was achieved with a regimen of fluconazole 80 mg/kg/d in a neutropenic-site rabbit model while ketoconazole 67 mg/kg/d remained inactive."
Pharmacokinetics The pharmacokinetic profile of fluconazole is summarized in Table 2 and a comparison with other azoles is presented in Table 3. The bioavailability of the oral preparation is estimated to be high based on recovery of unchanged drug (64 percent) in the urine.F Fluconazole can be characterized by a two-compartment model. After a daily 30-minute intravenous infusion of 50 or 100 mg to volunteers, peak serum concentrations were 3.1 and 7.0 umol/L on day I, and 7.0 and 15.3 umol/l, on day 7. 24 In patients treated with oral fluconazole for coccidioidal meningitis, peak serum concentrations two to six hours after doses of 50 and 100 mg suggest a linear relationship between dose and serum concentration. fluconazole penetrates well into the CSF of normal volunteers:" and patients with meningitis.P:" Peak CSF concentrations occur between four and eight hours after dosing in patients and reported mean CSF:serum ratios after 100 mg po range from 0.58 to 0.89. 29 Elimination half-life has been reported to be 22-32 hours in normal volunteers.F-" Renal clearance of unchanged drug accounts for approximately 70 percent of total clearance, and renal clearance values were 10-15 percent of those for glomerular filtration rate, suggesting tubular reabsorption. 27
ClinicalStudies Much of the clinical experience with fluconazole published to date is in the form of case reports and open trials. Few comparative studies are available for review at the present time; however, data from these studies are forthcoming. Fluconazole has been evaluated in the treatment of oropharyngeal and esophageal candidiasis in populations consisting largely of immunocompromised patients. 32-34 Dupont and Drouhet studied a group of 61 human immunodeficiency virus (HIV)-positive and 10 HIV-negative patients with oropharyngeal candidiasis. Forty-two of the
DICP, The Annals of Pharmacotherapy • 1990 September, Volume 24 • 861 Downloaded from aop.sagepub.com at MICHIGAN STATE UNIV LIBRARIES on June 8, 2015
In this group, ten recurrences were noted at a median of 18 days after treatment." A randomized, double-blind trial compared oral fluconazole 50 mg/d and ketoconazole 200 mg/d for a 28-day treatment course of oropharyngeal candidiasis in 37 AIDS and AIDS-related-complex patients. Clinical cure was achieved in all patients receiving fluconazole and in 75 percent of those treated with ketoconazole (p =0.044). Culture negativity rates posttreatment were similar for fluconazole and ketoconazole groups (87 and 69 percent, respectively). Relapse rates were lower for ketoconazole (II percent) than fluconazole (46 percent); however, patient numbers were small due to loss to follow-up. 33 In another report, eight patients with chronic mucocutaneous candidiasis who received prior ketoconazole
71 patients were symptomatic, and all 42 patients achieved a clinical cure within seven days of initiating fluconazole. Mycologic response was assessed in 67 of the 71 patients treated and 79.1 percent experienced a significant reduction in candidal colonies at the end of treatment. Fluconazole 50 mg/d po was given to 18 patients for 5-20 days, then 50 mg every other day for 6-49 days. The remaining 53 patients received 50 mg/d for five days, then 50 mg every 48 hours for ten days. Individuals who remained immunocompromised relapsed mycologically and/or clinically within 30 days of the end of treatment. 34 The use of fluconazole as a single oral dose (I50 mg) for treatment of oral candidiasis was reported to induce clinical response among 22 of 23 AIDS patients on day 7 postdose.
Table I. Representative Animal Studies Comparing Antifungal Activity of Fluconazole and Other Agents DOSE (mg/kg)!
REF.
ORGANISM
FLZ
MODEL'
KTZ
rrz
AMB
10
Candida albicans
rat (8)
0.1-0.5
2,10
15
C. albicans
mouse (8) mouser (8)
0.1-2.0 2.5-10
20-100 50
mouser (01)
2.5
10
20
mouse/rat (8) mouser (8) mouse (V) guinea pig (D)
0.01-2.0 po, iv 0.01-2.0 po, iv 0.6-20.0 2.5,5, 10
1-20 1-20 12.5-100 10,20,40
0.01-0.5 iv 0.01-0.5 iv
mouse (8)
2.5, 10, 20 bid
0.1-1.0 ip
10-40 bid
mouser (8)
2.5, 10, 20 bid
0.1-1.0 ip
10-40 bid
C. tropicalis
rat (8)
20,80
1.0 ip
C. glabrata
rat (8)
20,80
1.0 ip
C. krusei
rat (8)
20, 80
1.0 ip
C. albicans Cryptococcus neoformans Aspergillus spp. Cr. neoformans
rabbit (PN) rabbit (M)
10,20,80 iv 10,20,80 iv
200 rng/d
mouse mouse mouse mouse mouse
0.1-100 0.25-10 5 10-50 0.7-483 bid
25-100 25-100 50 50,100
16
C. albicans
II
Trichophyton mentagrophytes C. albicans
17
19
18
19
Histoplasma capsulatum H. capsulatum
20
H. capsulatum
13
Coccidioides immitis Blastomyces dermatitidis
12
21
(8) (8) (IC) (P) (8)
50,200 mg/d 50,200 mg/d 0.1-3.0 ip 0.1-3.0 ip 3 ip 3 ip 1-14
mouser (8)
1.4-90 bid
0.8-2.7§
mouse (8) mouser (8) mouse (M)
1.25-20
0.62-10 ip
20,60
mouse (P)
25,50,100
60
6 ip I ipll
RESULTS
survival: FLZ 0.5 mg/kg >KTZ 10 mg/kg survival: FLZ>KTZ (p=0.05) survival: FLZ 10 mg/kg>KTZ (pFLZ no culture negative, t CFU (kidney): both ineffective; t CFU (liver): AMB>FLZ equal efficacy equal efficacy ED 50 : AMBKTZ therapeutic:toxic ratio AMBFLZ 60 mg/kg/d >KTZ survival: AMB 80%, FLZ 10-30%
'Infections: D = dermal; 01 = gastrointestinal; M = meningitis; P = pulmonary; PN = pyelonephritis; 8 = systemic; V = vaginal. .tDose administered orally once daily unless otherwise indicated: ip = intraperitoneal; iv = intravenous; bid = twice daily. :!:Immunosuppressed animal model. §Dosed every other day. [Dosed five days per week. AMB = amphotericin B; CD 50 = dose curing 50 percent; t CFU = reduction in colony-forming units per gram of tissue; ED 50 = 50 percent effective dose; FLZ = fluconazole; ITZ = itraconazole; KTZ = ketoconazole; PD.., = protective dose for 90 percent.
862
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Fluconazole
therapy were noted to respond favorably to fluconazole 50 mg/d when treated for up to four weeks. Four relapses occurred within four months among the eight patients. 35 A variety of fungal infections due to Candida spp. (esophagitis, pneumonia, pyelonephritis, ophthalmitis, abscess, fungemia), Cryptococcus neoformans (meningitis), Aspergillus fumigatus (pneumonia), and Exophiala spp. (tenosynovitis) were treated with fluconazole for a mean of 33 days. Of 17 evaluable cases, treatment failure occurred in the cases of tenosynovitis (Exophiala spp.), fungemia (C. glabrata), and pyelonephritis (C. albicans). Cure or improvement occurred in the remaining 14 cases. Low daily doses (50 mg) were administered to all patients except those with meningitis or ophthalmitis who received 100 rug/d." Rubin et al. reported the results of an open trial in which fluconazole was given to 43 patients with candidal infections who had not responded to amphotericin B or had developed adverse reactions, or for whom standard therapy was contraindicated. Overall, 74 percent of patients improved or were cured (8 of 14 refractory esophagitis; 8 of 10 disseminated candidiasis; 10 of 10 urinary tract candidiasis). Among immunocompromised patients, 18 of 27 (66.7 percent) were cured or improved (10 of 16 AIDS patients, 3 of 4 patients with leukemia, 5 of 7 transplant patients). Mean daily dose was 180 mg administered for a mean of 72 days." Experience in the treatment of meningitis includes case reports of patients with cryptococcal disease38-41 and coccidioidal meningitis;" the majority of whom had AIDS or had undergone renal transplantation. Two open-label studies describe response in AIDS patients with cryptococcal infections. 31.43 Additional studies published in abstract form compare fluconazole and amphotericin B in treatment of cryptococcal meningitis. 44,45 Stern et al. treated 22 AIDS patients including 7 with
Table 2. Pharmacokinetics of Fluconazole in Humans NORMAL VOLUNTEERS REF. 27 REF. 28
Subjects (n) Age (y) Dose (once daily) Peak serum concentration
INFECTED PATIENTS' REF. 29
4 10 3 5 18-45 32-71 32-71 ND I mglkg po 50 mg iv 50 mg po 100 mg po 8.2-11.4 14.7-26.1 4.6 7.0
(umol/L)
CSF Concentration
ND
4.2t
6.5-7.5
11.1-20.2
0.62t 0.78 ND 32 ND 18.111 37.6 GC
0.74§ ND ND ND ND ND ND BIO
0.89§ ND ND ND ND ND ND BIO
(umol/L)
CSF:serum ratio ND Vd (Ukg) 0.7±0.06 Protein binding 11% Serum tV2 (h) 22±3.5 CI plasma (mUminlkg) 0.4 ± 0.04 CI renal (mUminlkg) 0.27±0.07 43±2 AUC (/Lg"hlmL) Assay method GC
'Coccidioidal meningitis. tOne hour after six daily 50-mg doses in three subjects. tOne hour after 100 mg iv in three subjects. §Determined at 4-12 hours after dose. IIExpressed in mUmin. AUC = area under the serum concentration-time curve; BIO = bioassay; CI = clearance; CSF = cerebrospinal fluid; GC = gas chromatography; ND = not determined; tV2 = half-life; Vd = volume of distribution.
Table 3. Comparison of Triazole Antifungal Agents l,27-30
Molecular weight (Da) Water solubility % Protein bound Half-life (h) % Urinary excretiont CSF:serum ratio (%) Formulations
MCZ
KTZ
ITZ
A.Z
416
531
706
306
poor 95 15-36*
FLUCONAZOLE: A NEW TRIAZOLE ANTIFUNGAL AGENT Mary T. Pasko, Stephen C. Piscitelli, and Andrea D. Van Slooten
ABSTRACf: Fluconazoleis a fluorine-substituted, bis-triazole antifungal agent. Its mechanismof action, like that of other azoles, involves interruptionof the conversion of lanosterol to ergosterolvia binding to fungalcytochromeP-450and subsequentdisruptionof fungal membranes. ActivityagainstAspergillusspp., Blastomyces dermatitidis, Candida spp., Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, and Paracoccidioides brasiliensis has beendemonstrated in severalanimal models. Fluconazole can be admininstered both orally and intravenously. Mean peak serum concentrations achievedin human volunteersafter 50 and 100mg (oral)are 3.1 and 7.0 ILmollL respectively. Protein bindingis low (11 percent)and cerebrospinal fluid to serum ratio is 0.58 to 0.89. Serum half-lifeis long (22-32 hours)and eliminationis via renal clearanceof unchangeddrug. Clinicaltrials and reports support the use of fluconazole in treatment of candidiasis,particularlyoropharyngeal and esophagealinfectionsin immunocompromised hosts. Fluconazole is also approved for initialand suppresivetherapyof cryptococcal meningitis. Its role in management of systemicfungal infections will be furtherdefinedonce resultsof othercomparativetrials become available. Fluconazole is well toleratedand its effectson steroidogenesisare markedlyless than thoseofketoconazole. Antipyrine clearanceis not alteredat low doses (50 mg) of fluconazole; however, drug interactions with the use of largerdoses can be anticipatedwith agentssuch as cyclosporin, phenytoin,oral hypoglycemics, and warfarin. Rifarnpin appearsto decreasemetabolic clearanceof fluconazole. Fluconazoleis available as oral and parenteral formulations. Once-dailydoses of 1OQ-4OO mg are recommended. Dosagereductionis advisedfor patientswith impairedrenal function.
DICP Ann Pharmacother 1990;24:860-7.
continue to represent a challenge for the clinician and are often life-threatening, particularly in the immunocompromised patient. Yet relatively few agents have been developed for management of mycoses. Azole antifungal agents, along with amphotericin B, are the major chemotherapeutic modalities available. SYSTEMIC FUNGAL INFECI10NS
MARYT. PASKO, PIwm.D., is a Clinical Assistant Professor, School of Phannacy, State Universityof New YOIIe at Buffalo, and Infectious Diseases Department, Department of VeteransAffairs Medical Center, Buffalo, NY; STEPHEN C. PISCITELLI, B.S.Pharm., and ANDREA D. VANSWOTEN, B.S.Pharm., are Doctor ofPharmacy students, Schoolof Pharmacy,State Universityof NewYorl< at Buffalo. ReprInts: Mary T. Pasko, Pharm.D., Schoolof Phannacy, State University of New Yorl< at Buffalo, 373 Cooke Hall, Buffalo, NY 14260. Fluconazole (Diflucan), PfizerPharmaceuticals.
This article is approvedfor continuingeducationcredit.
860
•
DICP, The Annals of Pharmacotherapy •
N
OH
~"'N-CHI- -CH-N
),d
I
N
I
'\=N
F
Figure I. Graphic formula of fluconazole.
Unfortunately, each compound is associated with its respective toxicities and so there is a definite need for effective, well-tolerated antifungal agents. Recent development of the azole class has expanded the therapeutic choices. 1 In addition to imidazoles (miconazole, c1otrimazole, ketoconazole) the newly developed triazoles (fluconazole, itraconazole) offer promising alternatives. The focus ofthis review is fluconazole, which was approved by the Food and Drug Administration in February 1990. Chemistry
Azoles structurally are comprised of a five-membered azole ring to which other aromatic rings are attached via a carbon-nitrogen bond. Azole rings of imidazoles contain two nitrogen atoms whereas three nitrogen atoms are present in triazole compounds. Fluconazole (Figure I) is a water-soluble bis-triazol-difluorophenyl-2-propanol compound.'
Pharnuu:ology Azole antifungal agents interrupt the conversion of lanosterol to ergosterol, the main sterol of yeast and fungal cell membranes. This interruption occurs via binding ofthe azole to fungal cytochrome P-450 which mediates the demethylation step necessary for the conversion of 14-alphamethylsterols to ergosterol. It is hypothesized that the resultant accumulation of 14-methylsterols and altered membrane fluidity causes decreased activity of membranebound desaturase with a subsequent increase in free fatty
1990 September, Volume 24
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acids. This leads to disturbances in fungal membrane permeability."
Antifungal Activity The antifungal spectrum of fluconazole includes Aspergillus spp., Blastomyces dermatitidis, Candida spp., Coccidioidesimmitis, Cryptococcus neoformans, Histoplasma capsulatum, and Paracoccidioides brasiliensis. 1 Fluconazole':" as well as ketoconazole! are fungistatic in contrast to amphotericin B which has fungicidal activity. In vitro susceptibility testing of antifungal agents is highly dependent upon such test conditions as the size of starting inoculum, medium components, medium pH, incubation time, and time of reading results. S Although intralaboratory results may be reproducible, interlaboratory results have been found to vary markedly." Two reports of improved methodology for determination of minimum inhibitory concentrations (MICs) use a semisolid medium with controlled pH and standard inoculum' and antibiotic addition to the test medium. 8 However, until standardization is adopted, comparative MIC data may not be the most optimal means of assessing relative antifungal activity. Although some studies have shown good correlation between in vitro and in vivo antifungal activity," numerous investigators have found discrepant results between the in vitro activity of fluconazole and in vivo efficacy in animal models using the same organisms.P'" Clinical outcome in humans also is poorly correlated with MIC results. Data collected by the National Institute of Allergy and Infectious Disease (NIAID) Mycoses Study Group compared MICs and clinical response to ketoconazole in treatment of various fungal infections and found no correlation. 14 It has been suggested that assessment of relative antifungal activity among agents is best accomplished by comparison of efficacy achieved in animal models. S The outcome of several representative animal studies is presented in Table I. Models assessing activity against Candida albicans in either immunocornpetentv-":" or immunocomprised'vv-" animals have found increased survival, lower median effective doses, and lower doses required to cure 50 percent of animals for fluconazole as compared with ketoconazole. However, activity was less than that of amphotericin B. 11.16 Several other Candida spp., (tropicalis, glabrata, krusei) were studied in an immunocompetent rat model. fluconazole activity, as assessed by reduction in colony-forming units (CFUs) of fungi in organ tissue, was found to be equal to or less than that of amphotericin B for C. tropicalis and C. glabrata. Both agents failed to reduce CFUs of C. krusei in kidney tissue and fluconazole's activity was marginal in liver tissue!' Outcomes in models of systemic Aspergillusflavus and A. fumigatus." and coccidioidal meningitis" favor fluconazole rather than ketoconazole; however, once again, amphotericin B was superior to either agent. Although histoplasmosis was not cured with either fluconazole given twice daily or amphotericin B, the protective dose for 50 percent of animals for fluconazole was similar in the normal" and immunosuppressed murine model." However, with once-daily dosing in similar models of murine histoplasmosis, fluconazole was much less active than amphotericin B.20 Fluconazole and itraconazole demonstrated equal efficacy in a rabbit model of cryptoccocal meningitis
despite poor penetration of itraconazole into cerebrospinal fluid (CSF). In the same report, similar efficacy between the two agents was found in the treatment of candidal pyelonephritis. 22 In data published in abstracts, fluconazole has been further compared with SCH 39304, a new triazole under investigation. In murine models of pulmonary aspergillosis," systemic coccidioidomycosis.P' and coccidioidal meningitis," SCH 39304 was associated with increased survival rates at lower doses and greater reductions in fungal CFUs in target organs as compared with fluconazole and/or itraconazole. Survival in a murine model of pulmonary blastomycosis was 10-30 percent for fluconazoletreated animals compared with 30-100 percent for SCH 39304 and 80 percent for amphotericin B. 21 Fluconazole activity against ketoconazole-resistant strains of C. albicans has been assessed in vitro and in animal models. With doses up to 20 mg/kg/d in rabbir· 22 and rat models,IO.26 fluconazole did not demonstrate activity against the resistant strains. However, fungistatic activity was achieved with a regimen of fluconazole 80 mg/kg/d in a neutropenic-site rabbit model while ketoconazole 67 mg/kg/d remained inactive."
Pharmacokinetics The pharmacokinetic profile of fluconazole is summarized in Table 2 and a comparison with other azoles is presented in Table 3. The bioavailability of the oral preparation is estimated to be high based on recovery of unchanged drug (64 percent) in the urine.F Fluconazole can be characterized by a two-compartment model. After a daily 30-minute intravenous infusion of 50 or 100 mg to volunteers, peak serum concentrations were 3.1 and 7.0 umol/L on day I, and 7.0 and 15.3 umol/l, on day 7. 24 In patients treated with oral fluconazole for coccidioidal meningitis, peak serum concentrations two to six hours after doses of 50 and 100 mg suggest a linear relationship between dose and serum concentration. fluconazole penetrates well into the CSF of normal volunteers:" and patients with meningitis.P:" Peak CSF concentrations occur between four and eight hours after dosing in patients and reported mean CSF:serum ratios after 100 mg po range from 0.58 to 0.89. 29 Elimination half-life has been reported to be 22-32 hours in normal volunteers.F-" Renal clearance of unchanged drug accounts for approximately 70 percent of total clearance, and renal clearance values were 10-15 percent of those for glomerular filtration rate, suggesting tubular reabsorption. 27
ClinicalStudies Much of the clinical experience with fluconazole published to date is in the form of case reports and open trials. Few comparative studies are available for review at the present time; however, data from these studies are forthcoming. Fluconazole has been evaluated in the treatment of oropharyngeal and esophageal candidiasis in populations consisting largely of immunocompromised patients. 32-34 Dupont and Drouhet studied a group of 61 human immunodeficiency virus (HIV)-positive and 10 HIV-negative patients with oropharyngeal candidiasis. Forty-two of the
DICP, The Annals of Pharmacotherapy • 1990 September, Volume 24 • 861 Downloaded from aop.sagepub.com at MICHIGAN STATE UNIV LIBRARIES on June 8, 2015
In this group, ten recurrences were noted at a median of 18 days after treatment." A randomized, double-blind trial compared oral fluconazole 50 mg/d and ketoconazole 200 mg/d for a 28-day treatment course of oropharyngeal candidiasis in 37 AIDS and AIDS-related-complex patients. Clinical cure was achieved in all patients receiving fluconazole and in 75 percent of those treated with ketoconazole (p =0.044). Culture negativity rates posttreatment were similar for fluconazole and ketoconazole groups (87 and 69 percent, respectively). Relapse rates were lower for ketoconazole (II percent) than fluconazole (46 percent); however, patient numbers were small due to loss to follow-up. 33 In another report, eight patients with chronic mucocutaneous candidiasis who received prior ketoconazole
71 patients were symptomatic, and all 42 patients achieved a clinical cure within seven days of initiating fluconazole. Mycologic response was assessed in 67 of the 71 patients treated and 79.1 percent experienced a significant reduction in candidal colonies at the end of treatment. Fluconazole 50 mg/d po was given to 18 patients for 5-20 days, then 50 mg every other day for 6-49 days. The remaining 53 patients received 50 mg/d for five days, then 50 mg every 48 hours for ten days. Individuals who remained immunocompromised relapsed mycologically and/or clinically within 30 days of the end of treatment. 34 The use of fluconazole as a single oral dose (I50 mg) for treatment of oral candidiasis was reported to induce clinical response among 22 of 23 AIDS patients on day 7 postdose.
Table I. Representative Animal Studies Comparing Antifungal Activity of Fluconazole and Other Agents DOSE (mg/kg)!
REF.
ORGANISM
FLZ
MODEL'
KTZ
rrz
AMB
10
Candida albicans
rat (8)
0.1-0.5
2,10
15
C. albicans
mouse (8) mouser (8)
0.1-2.0 2.5-10
20-100 50
mouser (01)
2.5
10
20
mouse/rat (8) mouser (8) mouse (V) guinea pig (D)
0.01-2.0 po, iv 0.01-2.0 po, iv 0.6-20.0 2.5,5, 10
1-20 1-20 12.5-100 10,20,40
0.01-0.5 iv 0.01-0.5 iv
mouse (8)
2.5, 10, 20 bid
0.1-1.0 ip
10-40 bid
mouser (8)
2.5, 10, 20 bid
0.1-1.0 ip
10-40 bid
C. tropicalis
rat (8)
20,80
1.0 ip
C. glabrata
rat (8)
20,80
1.0 ip
C. krusei
rat (8)
20, 80
1.0 ip
C. albicans Cryptococcus neoformans Aspergillus spp. Cr. neoformans
rabbit (PN) rabbit (M)
10,20,80 iv 10,20,80 iv
200 rng/d
mouse mouse mouse mouse mouse
0.1-100 0.25-10 5 10-50 0.7-483 bid
25-100 25-100 50 50,100
16
C. albicans
II
Trichophyton mentagrophytes C. albicans
17
19
18
19
Histoplasma capsulatum H. capsulatum
20
H. capsulatum
13
Coccidioides immitis Blastomyces dermatitidis
12
21
(8) (8) (IC) (P) (8)
50,200 mg/d 50,200 mg/d 0.1-3.0 ip 0.1-3.0 ip 3 ip 3 ip 1-14
mouser (8)
1.4-90 bid
0.8-2.7§
mouse (8) mouser (8) mouse (M)
1.25-20
0.62-10 ip
20,60
mouse (P)
25,50,100
60
6 ip I ipll
RESULTS
survival: FLZ 0.5 mg/kg >KTZ 10 mg/kg survival: FLZ>KTZ (p=0.05) survival: FLZ 10 mg/kg>KTZ (pFLZ no culture negative, t CFU (kidney): both ineffective; t CFU (liver): AMB>FLZ equal efficacy equal efficacy ED 50 : AMBKTZ therapeutic:toxic ratio AMBFLZ 60 mg/kg/d >KTZ survival: AMB 80%, FLZ 10-30%
'Infections: D = dermal; 01 = gastrointestinal; M = meningitis; P = pulmonary; PN = pyelonephritis; 8 = systemic; V = vaginal. .tDose administered orally once daily unless otherwise indicated: ip = intraperitoneal; iv = intravenous; bid = twice daily. :!:Immunosuppressed animal model. §Dosed every other day. [Dosed five days per week. AMB = amphotericin B; CD 50 = dose curing 50 percent; t CFU = reduction in colony-forming units per gram of tissue; ED 50 = 50 percent effective dose; FLZ = fluconazole; ITZ = itraconazole; KTZ = ketoconazole; PD.., = protective dose for 90 percent.
862
•
DICP, The Annals of Pharmacotherapy •
1990 September, Volume 24
Downloaded from aop.sagepub.com at MICHIGAN STATE UNIV LIBRARIES on June 8, 2015
Fluconazole
therapy were noted to respond favorably to fluconazole 50 mg/d when treated for up to four weeks. Four relapses occurred within four months among the eight patients. 35 A variety of fungal infections due to Candida spp. (esophagitis, pneumonia, pyelonephritis, ophthalmitis, abscess, fungemia), Cryptococcus neoformans (meningitis), Aspergillus fumigatus (pneumonia), and Exophiala spp. (tenosynovitis) were treated with fluconazole for a mean of 33 days. Of 17 evaluable cases, treatment failure occurred in the cases of tenosynovitis (Exophiala spp.), fungemia (C. glabrata), and pyelonephritis (C. albicans). Cure or improvement occurred in the remaining 14 cases. Low daily doses (50 mg) were administered to all patients except those with meningitis or ophthalmitis who received 100 rug/d." Rubin et al. reported the results of an open trial in which fluconazole was given to 43 patients with candidal infections who had not responded to amphotericin B or had developed adverse reactions, or for whom standard therapy was contraindicated. Overall, 74 percent of patients improved or were cured (8 of 14 refractory esophagitis; 8 of 10 disseminated candidiasis; 10 of 10 urinary tract candidiasis). Among immunocompromised patients, 18 of 27 (66.7 percent) were cured or improved (10 of 16 AIDS patients, 3 of 4 patients with leukemia, 5 of 7 transplant patients). Mean daily dose was 180 mg administered for a mean of 72 days." Experience in the treatment of meningitis includes case reports of patients with cryptococcal disease38-41 and coccidioidal meningitis;" the majority of whom had AIDS or had undergone renal transplantation. Two open-label studies describe response in AIDS patients with cryptococcal infections. 31.43 Additional studies published in abstract form compare fluconazole and amphotericin B in treatment of cryptococcal meningitis. 44,45 Stern et al. treated 22 AIDS patients including 7 with
Table 2. Pharmacokinetics of Fluconazole in Humans NORMAL VOLUNTEERS REF. 27 REF. 28
Subjects (n) Age (y) Dose (once daily) Peak serum concentration
INFECTED PATIENTS' REF. 29
4 10 3 5 18-45 32-71 32-71 ND I mglkg po 50 mg iv 50 mg po 100 mg po 8.2-11.4 14.7-26.1 4.6 7.0
(umol/L)
CSF Concentration
ND
4.2t
6.5-7.5
11.1-20.2
0.62t 0.78 ND 32 ND 18.111 37.6 GC
0.74§ ND ND ND ND ND ND BIO
0.89§ ND ND ND ND ND ND BIO
(umol/L)
CSF:serum ratio ND Vd (Ukg) 0.7±0.06 Protein binding 11% Serum tV2 (h) 22±3.5 CI plasma (mUminlkg) 0.4 ± 0.04 CI renal (mUminlkg) 0.27±0.07 43±2 AUC (/Lg"hlmL) Assay method GC
'Coccidioidal meningitis. tOne hour after six daily 50-mg doses in three subjects. tOne hour after 100 mg iv in three subjects. §Determined at 4-12 hours after dose. IIExpressed in mUmin. AUC = area under the serum concentration-time curve; BIO = bioassay; CI = clearance; CSF = cerebrospinal fluid; GC = gas chromatography; ND = not determined; tV2 = half-life; Vd = volume of distribution.
Table 3. Comparison of Triazole Antifungal Agents l,27-30
Molecular weight (Da) Water solubility % Protein bound Half-life (h) % Urinary excretiont CSF:serum ratio (%) Formulations
MCZ
KTZ
ITZ
A.Z
416
531
706
306
poor 95 15-36*
