- Email: [email protected]
The search for new triazole antifungal agents
176
The search for new triazole Yigal Koltin* and Christopher The first generation
antifungal
and itraconazole, fungal
infections
agent triazoles,
have revolutionised such as mucosal
However,
fungal
particularly
aspergillosis,
infections,
satisfactory
and thus there
new broad-spectrum generation
triazoles
considerable
agents.
voriconazole
promise
candidiasis of some
is still far from requirement
for
The new second
and SCH-56592
in achieving
of serious
the treatment
is an important
antifungal
The
fluconazole
and invasive
meningitis.
show
this goal in the near future.
Addresses *Millennium Pharmaceuticals Inc, Division of Molecular and Cellular Biology, 640 Memorial Drive, Cambridge, e-mail: [email protected]
MA 02139,
USA;
*Department of Discovery Biology, Pfizer Central Research, Sandwich, Kent CT1 3 9NJ, UK; e-mail: [email protected] Current
Opinion
in Chemical
Biology
1997, 1 :176-l
62
http://biomednet.com/elecref/1367593100100176 0 Current
Biology Ltd ISSN
1367-5931
Abbreviations b.i.d. twice daily dosing i.p.
intraperitoneal(ly) intravenous(ly) minimum inhibitory concentration
i.v. MIC o.d.
once daily dosing oesophageal candidiasis oropharyngeal candidiasis
oc OPC F&t
oral 6~ cytochrome
Introduction: discovery
P-450.dependent
challenges
14asterol
drug
Invasive fungal infections now rank alongside bacterial infections as a major cause of morbidity and mortality in seriously debilitated and immunocompromised patients [l]. Almost any fungus has the potential to cause invasive infections, but the most important pathogens in terms
of incidence and mortality spp., respectively.
are Candida
spp.
precise
incidence
of invasive
and
Aspergihs
Carrdida spp.
are the fourth most common cause of nosocomial (originating in hospitals) blood-stream infections in many hospitals and represent 8 to 11% of
all blood-stream infections [2,3]. The risk factors that are known to predispose patients to invasive candidiasis are intravascular cannulae, indwelling catheters, surgical procedures, prolonged use of broad-spectrum antibacterial antibiotics and immunocompromisation (e.g. AIDS, tissue transplant and cancer patients). The clinical manifestations of candidiasis range from transient and uncomplicated blood-stream infections to those with multiple organ involvement and life-threatening disease.
aspergillosis
is unknown,
due mainly to the paucity of reliable diagnostic methods that can be employed antemortem. However, Aspelgillus fumigatus is the most common species isolated from the environment and at postmortem examinations. It is responsible for approximately 80% of nosocomial infections, most prominently in bone marrow transplant and cancer patients, with the remaining 20% being caused by A. j&zvus, A. niger and A. teveus. The lung is usually the primary site of infection after inhalation of fungal spores, and the most common manifestations of disease are chronic allergy to Aspergi/h spores and saprophytic growth (taking advantage of dead or damaged tissue that has arisen as a consequence of previous infections or injury) in pre-existing cavities, which results in the formation of so-called ‘fungus balls’. In seriously debilitated and immunocompromised patients, the lung is the source of infection for invasive aspergillosis, which is characterised by multiple organ involvement and rapid clinical deterioration in the patient. Invasive aspergillosis is invariably fatal, despite current therapies, and it is one of the most devastating fungal infections found in the hospital setting [4]. This review describes the important role of the first generation triazole derivatives in the management of serious fungal infections. It also highlights their drawbacks and the progress that is being made to address them with the new, second generation triazole derivatives.
Current azole antifungal
demethylase
in antifungal
agents
A Hitchcock
the treatment
and cryptococcal
antifungal
agents
In contrast to the large number of antibacterial antibiotics, there are very few antifungal agents that can be prescribed for life-threatening fungal infections. These are amphotericin B, liposomal formulations of amphotericin B, 5fluorocytosine and the azole (N-substituted imidazole and triazole) derivatives. Liposomal amphotericin B [5*,6] and the first generation triazoles fluconazole [7**] and itraconazole [8,9*] (see Figure la) represent an important advance in the treatment of serious fungal infections. Fluconazole is used widely in the prevention and treatment of superficial candidiasis, including oropharyngeal and oesophageal candidiasis (OPC and OC, respectively), and it is showing encouraging efficacy against invasive candidiasis in both immune normal and immunocompromised patients [lo-121. It is also used widely to treat cryptococcal meningitis and to prevent relapse from that infection [12]. This widespread use not only reflects fluconazole’s antifungal efficacy, but also its proven safety profile. The flexibility of its oral (p.0.) and intravenous (i.v.) dosage forms is also advantageous for patients receiving prolonged antifungal therapy. The N-substituted imidazole ketoconazole is more potent than fluconazole in vitro,
(see Figure la) and is absorbed
The search for new triazole antifungal agents Koltin and Hitchcock
177
Figure 1
(a)
a
Fluconazole
Ketonazole
ltraconazole
(b)
F
P
SCH-56592
Voriconazole
D-0670
0 1997 Current Opinion in Chemical Biology
Agents used against pathogenic
fungi. (a) Azoles currently used. (b) Agents in clinical development.
orally, but the lack of an i.v. formulation and its potential for hepatotoxicity limit its use against OPC and OC in AIDS patients. Itraconazole is an improvement on ketoconazole in terms of having a broader antifungal spectrum and better toleration, but its use is hampered by variable oral absorption and the absence of a commercially available i.v. dosage form [8,9*]. Orally-administered itraconazole, however, dissolved in hydroxypropyl P-cyclodextrin has been shown to be effective against fluconazole-resistant OPC in patients with AIDS [ 131. Although itraconazole has shown some efficacy against invasive infections, including aspergillosis, its role in the treatment in general is poorly defined.
of invasive
disease
The azole antifungal agents work by inhibiting cytochrome P-450-dependent 14a-sterol demethylase (P450~hl), an important enzyme in ergosterol biosynthesis in fungi and cholesterol synthesis in mammalian cells [14*]. At therapeutic concentrations, the efficacy of the azoles is thought to reside in their greater affinity for fungal as opposed to mammalian P-45O~hr. Azole-treated fungi are depleted of ergosterol and accumulate 14a-methylated sterols which is thought to disrupt membrane structure
and function,
thereby
inhibiting
fungal
growth.
All of the
azoles are fungistatic, as opposed to fungicidal (inhibit growth but do not kill), against Candida spp., emphasizing the importance of the host’s immune system for eradicating the infecting organism and achieving a clinical cure. A corollary of this situation is that AIDS patients require indefinite suppressive therapy, and given the widespread use of fluconazole in end-stage who have failed ketoconazole
AIDS (including patients or itraconazole therapy), it
is not unexpected that fluconazole-resistant strains have been isolated from this group of patients. There is also an increasing number of reports of infections due to C. Rnrsei, C. glabrata and Aspergi/us spp. which have inherently low susceptibilities to fluconazole [ 15,16**]. Postulated mechanisms of resistance include changes in cell permeability, overproduction or alteration of P-450Dht and modification of other enzymes involved in ergosterol biosynthesis. Fluconazole and itraconazole are key members of the antifungal armamentarium but they have deficiencies either in antifungal spectrum, pharmacokinetics or the availability of parenteral dosage forms. This situation,
178
Next generation therapeutics
together with the increasing incidence of fungal infections, underlines the need for new broad-spectrum antifungal agents. The second generation triazoles, voriconazole,
pathogens (Blastomyces dematitidis, Coccidioides immitis, Paracoccidioides brasilimsis and Histop fasma capsulatum) and to additional emerging fungal pathogens, including
SCH-56592 and DO870 (see Figure lb) are the most promising agents meeting this challenge and have been the subject of extensive investigation during the past
organisms
couple of years. Consequently, these compounds will form the basis of this review. The latest exploratory triazole derivatives emerging from discovery programmes have already been reviewed elsewhere [17*]; however, in view of the relative paucity of information on them it is difficult to make meaningful comparisons with candidates in the more advanced stages of development such as voriconazole and SCH-56592. Liposomal amphotericin B and the semisynthetic pnuemocandins and echinocandins are also being developed as potential competitors to the new triazoles and they have also been the subject of recent reviews [5’,14’]. The best antifungal compounds emerging from pre-clinical research programmes are selected for clinical development on the basis of their efficacy, pharmacokinetic and toxicology profiles. Clinical development comprises three phases. In Phase I, the candidate’s pharmacokinetics, safety and toleration are determined in a small number (10 to 20) of healthy male volunteers. In Phase II, the candidate is tested for efficacy, safety and toleration in approximately 100 to 200 patients with various fungal infections. The aim of Phase III clinical trials is to confirm the efficacy, safety and toleration of the candidate in comparison with standard, marketed agents in studies with large numbers of patients (1000s). The results of such trials will determine whether or not the candidate offers significant advantages over current marketed agents in terms of efficacy and/or safety. Finally, approval by the regulatory authorities is required before the candidate can be marketed for clinical use.
New triazole
antifungal
agents
Voriconazole Voriconazole
(UK-109,496,
Pfizer,
Sandwich,
the newest of the second generation triazole and is the result of a synthetic programme
Kent,
that are resistant
to amphotericin
Consistent with its potency highly effective against various
B [24-27,28*].
in &r-o, voriconazole is fungal infections in guinea
pigs, when assessed on the basis of animal survivors and reductions in the fungal burden on tissues. The guinea pig was chosen for evaluating voriconazole’s efficacy against infections because in this species the drug achieves prolonged systemic exposures that are comparable to those observed in man [29]. When tested against invasive and pulmonary aspergillosis, voriconazole (lOmg/kg orally, twice a day (p.0. b.i.d.) and 8mg/kg p.o. b.i.d., respectively) was curative (i.e. sterilised tissues) and was significantly more efficacious than itraconazole at the same dose levels and amphotericin B (4mg/kg intraperitoneally (i.p.) on alternate days), regardless of the immune spatus of the animals [30]. Voriconazole (10 me/kg p.o. b.i.d.) was also curative and more active than the same dose of itraconazole against Aspe@//us endocarditis [31*‘]. When tested against invasive candidiasis (C. alhiram) in immune normal and immunocompromised animals, voriconazole produced fluconazole-like efficacy (5 mg/kg p.o. b.i.d.) [32]. hloreover, it was significantly more efficacious than fluconazole against invasive infections caused by fluconazole-resistant C. albicans, C. krusei and C. glabmta, reflecting the greater potency of voriconazole compared to that of fluconazole against these organisms in vitro. \Toriconazole also produced fluconazole-like efficacy against pulmonary and intracranial cryptococcosis (2.5 to 20mg/kg p.o. b.i.d.) [33]. hlore recently, voriconazole has shown activity comparable to that of amphotericin B against rdt pulmonary aspergillosis (30 mg/kg/day p.o. versus 4mg/kg/day i.p.) (221 and rabbit invasive aspergillosis (45 mg/kg/day p.o. versus 1 mg/kg/day i.v.) [34-l, despite suboptimal pharmacokinetics as a consequence of voriconazole being rapidly metabolised in these species.
UK) is
derivatives, aimed at
improving the potency and spectrum of fluconazole [18’]. Several investigators have shown voriconazole to be lo- to SOO-fold more potent than fluconazole (similar to itraconazole) against the primary opportunistic pathogens, Aspcrgillus spp., C~ptoroccu~ spp. and Candida spp., including organisms that are resistant to fluconazole such as C. krusei and C. glabmta (minimum inhibitory concentration (RIIC)) range across the species, 0.001 to 0.5 g/ml) [19,20,21*,22,23’]. This reflects the fact that voriconazole is more potent than fluconazole against fungal P-4501>hl and more effective than fluconazole in penetrating fungal cells. Furthermore, voriconazole is fungicidal for Aspe~~//~~s spp., where the minimum fungicidal concentration (hlFC) is approximately twice the hlIC [19]. The potent in vitro activity of voriconazole also extends to the endemic fungal
The pharmacokinetics of voriconazole have been invcstigated in approximately 300 male volunteers following p.0. and i.v. administration [35]. Systemic exposure increased in a disproportional manner (dose-dependent and time-dependent), due possibly to partial saturation of hepatic metabolism and systemic clearance with increased dose and increased duration of dosing. Elimination was characteristic of metabolic clearance, with only 1% of voriconazole being excreted in the urine as unchanged drug. The apparent oral absorption was 90% and the volume of distribution was approximately 2 L/kg, consistent with the drug being widely distributed in body tissues and fluids. In Phase II clinical trials, voriconazole has shown encouraging results in the treatment of OPC and acute- and chronicinvasive aspergillosis [32,36,37]. In a blinded.
The search
dose-comparative study (50 mg once daily (0.d.) or 200 mg o.d. or 200mg b.i.d.) in AIDS patients with OPC, voriconazole demonstrated clinical efficacy of 97% to 100% (there were 90 evaluable patients in this study) with both 200mg dosing regimens; it was less efficacious (80%) at the once daily dose of 50mg. There were no serious adverse events. There were 32 possible treatment-related adverse events, six of which resulted in patients being discontinued from the study. There was a dose-related incidence of visual disturbance (three patients at 50mg o.d. and 10 at 200 mg b.i.d.) and o.d., four at 200mg two patients discontinued treatment as a result. Generally patients described enhanced brightness of light or blurred vision; the effects were transient and fully reversible, sometimes while still receiving the drug [32].
Voriconazole’s activity against acute invasive aspergillosis has been evaluated in an open, noncomparative study in immunocompromised patients, many of whom had failed treatment with amphotericin B or itraconazole. The dosing regimen was 6mg/kg 12 hourly i.v. x 2 doses (2 doses 12 hours apart), then 3mg/kg 12 hourly i.v. for 6-27 days, followed by 200mg p.o. b.i.d. for 4 to 24 weeks. At an interim analysis of 53/71 evaluable patients, voriconazole produced a favourable clinical response in 74% (39/53) patients (8 complete; 17 partial; and 14 stable), whereas 26% (14/53) failed treatment. Mild to moderate visual disturbance was experienced in 8% (6/71) of patients but this did not lead to withdrawal of drug. Six percent (4/71) of patients were withdrawn from the study due to adverse events: one due to skin rash and three due to raised liver function enzymes.
Voriconazole has also been evaluated against chronic invasive aspergillosis in non-neutropenic patients in an open, non-comparative study [37]. Similar to the acute invasive aspergillosis study, many of the patients enrolled in the chronic invasive aspergillosis trial had failed treatment with amphotericin B and itraconazole. Patients received voriconazole 200mg p.o. b.i.d. for 4 to 24 weeks. At an interim analysis of 13/25 evaluable patients, voriconazole demonstrated a favourable clinical response in 69% (9/13) patients, with 31% (4/13) failing treatment. Mild to moderate visual disturbance was reported (1 l/25) patients but this did not lead to withdrawal Eight study
in 44% of drug.
percent (Z/25) of patients were withdrawn from the due to raised levels of liver function enzymes.
Voriconazole combines potent broad-spectrum antifungal activity irz vitro with pharmacokinetics in man that produce sustained high levels in blood and tissue following p.o. and i.v, administration. This is reflected in the encouraging results obtained from the Phase II clinical trials mentioned above. In view of this, voriconazole has rapidly progressed to Phase III trials in comparison with established agents, in order to explore fully its potential in the treatment
for new triazole antifungal agents Koltin and Hitchcock
of invasive
aspergillosis
and other
life-threatening
179
fungal
infections.
SCH-56592 SCH-56592 (Schering-Plough, Kennilworth, New Jersey, USA) is a structural analogue of itraconazole (tetrahydrofuran skeleton in itraconazole versus 1,3-dioxolone in SCH-56592) and has superseded the previous structurally related development candidate, SCH-51048 [38*]. When tested in a number of mycological media, SCH-56592 showed potent, broad-spectrum activity against the primary opportunistic pathogens Aspqihs spp., Candida spp. and C. neoformans (MIC range across the species, 0.003 to 0.2 pg/ml) [3941,42*]. Like itraconazole, SCH-56592 was also fungicidal against Aspe+‘/us spp. [41] and significantly more potent than fluconazole against Candida non-albicans spp. such as C. krusei and C. giabrata [43’]. Both itraconazole and SCH-56592 also showed a wide range of activities against fluconazole-resistant C. a&cam strains; thus some organisms were relatively sensitive whereas others remained frankly resistant, even at high concentrations of the drug [44*]. As expected from its potency against the primary opportunistic pathogens, SCH-56592 was also active against the endemic fungal pathogens B. dermatitidis and H. cnpsufatum, and a wide range of less common, emerging fungal pathogens [45]. SCH-56592 has been evaluated in several animal models of pulmonary and invasive aspergillosis, invasive candidiasis and cryptococcal meningitis, where efficacy was assessed on the basis of animal survivors and, in the case of some experiments, by reductions of the fungal burden of tissues. Against murine invasive aspergillosis caused by A. fumigatus, SCH-56592 (5 to 25 mg/kg p.o./day) was superior to itraconazole (at the same dose levels) and amphotericin B (5 mdkg i.p./day) in prolonging survival and reducing the AspergiL’us content of tissues [46]. Similar results were obtained in a neutropenic (reduced number of neutrophils) rabbit model of invasive aspergillosis [47]. Thus, SCH-56592 (10 mg/kg p.o./day) was more effective than the same dose of itraconazole and was comparable to amphotericin B (1 mg/kg i.v./day) in prolonging the survival of animals and reducing the Aspeq$/us tissue burden. In a murine model of pulmonary aspergillosis A. fumigatus, SCH-56592 at 10 to 50mg/kg p.o./day superior to amphotericin B (3-6 mg/kg i.v./day) the lung fungal load [48].
with was
in reducing
In immunocompromised mice with invasive candidiasis caused by C. albicans, SCH-56592 (50% effective dose range, 0.2 to Smg/kg p.o./day) was more active than fluconazole (50% effective dose range, 2.5 to 27mgjkg p.o./day), when measured on the basis of survivors [49]. SCH-56592 (50 to lOOmg/kg p.0.) was also effective in protecting mice from infections with A fumigatus or C. a&cam when it was administered l-72 hours prior to infection, thereby demonstrating its prophylactic
180
Next generation
therapeutics
potential [SO]. SCH-56592 has also been rabbit model of cryptococcal meningitis with fluconazole-[42*]. Both compounds p.o./day significantly reduced the brain and were equally efficacious
evaluated in a in comparison at 20 mglkg
Cryptococcus content
of
in this respect.
Pharmacokinetic studies in a number of laboratory species have demonstrated dose-related increases in the serum concentration of SCH-56592 [Sl]. In dogs and monkeys the oral bioavailability of SCH-56592 was approximately 20% and the plasma elimination half-life values were 18 and 22 hours, respectively. These pharmacokinetics predict that once-daily dosing in man should provide serum concentrations of SCH-56592 above the MICs for all of the key fungal pathogens. SCH-56592 demonstrates potent broad-spectrum antifungal activity in vitro which translates to good efficacy in the usual laboratory models of fungal infections. In addition, the pharmacokinetics of this drug in dog and monkey predict that once-daily dosing in man should be sufficient to treat serious fungal infections. This encouraging profile supports the continued development of SCH-56592, which is currently in Phase I/II studies designed to investigate its safety, pharmacokinetics and antifungal efficacy. DO870 The triazolestyryl derivative DO870 (Zeneca, Macclesfield, UK) is highly potent in vitro against Candida spp., including the fluconazole-resistant organisms, Cryptococcus spp., Ttichosporon spp. and H. capsulatum (MIC range across the species, 0.001 to 0.25 g/ml) ([ 14.1 and references therein). By contrast, it is relatively weak against Aspergihs spp. in vitro (5 dml), which is an important drawback when compared with the potent activities of itraconazole, voriconazole and SCH-56592 against this key pathogen. Consistent with its potency in vitro, DO870 is superior to fluconazole in various rodent infection models with the aforementioned pathogens (effective dose range, one to lOmg/kg/day) ([14*] and references therein). However, its efficacy against aspergillosis is somewhat unexpected given the relatively weak potency against Aspqihs in
in
77% (27/35) of patients, clinical improvement was recorded for 17% (6/35) and 6% (Z/35) failed at the lowest dose. Thirty seven percent of patients relapsed within two weeks
DO870 has progressed to clinical studies in volunteers and in AIDS patients with OPC [52]. In both groups, DO870 had long plasma elimination halflife values of one to 10 days, with a median value of three days. The treatment studies in AIDS patients employed three dosing regimens in two phases. In the first phase, a single 50mg dose on day 1 was followed by lOmg/day for four days. In the second phase, a single 100mg dose on day 1 was followed either by 25 mgjday for four days or 10 mg/day for five days. On completion of the study, clinical cures were obtained
tieatment.
Mild adverse
events,
Conclusions Fungal infections are assuming greater importance as the cause of morbidity and mortality in hospitalised patients. The first generation triazoles, fluconazole and itraconazole have had a significant impact in the prevention and treatment of some of these infections. Fluconazole is now the triazole of choice for prophylaxis and treatment of candidiasis caused by C. a/&am and for cryptococcal meningitis. Deficiencies in the antifungal spectrum of fluconazole and pharmacokinetics of itraconazole limit their use against fluconazole-resistant Candida infections and aspergillosis. The new second generation triazoles, voriconazole and SCH-56592, show considerable promise in addressing these shortcomings on the basis of comprehensive preclinical studies and, in the case of voriconazole, clinical data generated from Phase I/II trials. Further development of both compounds is warranted and Phase III trials in comparison with established agents are the next important step towards defining the roles of voriconazole and SCH-56592 in the management of life-threatening fungal infections.
References
and recommended
reading
Papers of particular interest, published within the annual period of review, have been highlighted as: . l
*
of special interest of outstanding interest
1.
Bennett JE: Antimicrobial agents: antifungal agents. In Goodman and Gilman’s, The Pharmacological Basis of Therapeutics, edn 9. Edited bv Hardman JG. Limbird LE, Molinoff PB, Ruddon RW, Gilman AG: New York: McGraw-Hill Inc; 1995:1175-l 190.
2.
Banerjee SN, Emori G, Culver DH, Gaynes RP, Jarvis WR, Horan T, Edwards JR, Tolson J, Henderson T, Martone WJ and The National Nosocomial Infections Surveillance Svstem: National nosocomial infections surveillance: seculaitrends in nosocomial primary blood stream infections in the United States, 1980-I 989. Am I Med 1991, 91 (suppl36):86-89.
3.
Fraser VJ, Jones M, Dunkel J, Storfer S, Medoff G, Dunagan WC: Candidemia in a tertiary care hospital: epidemiology, risk factors and predictors of mortality. C/in infect Dis 1992. 14:414-421.
4.
Denning DW, Stevens DA: Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases. Rev infect Dis 1990, 12:1147-l 201.
5. .
Hiemenz JW, Walsh TJ: Lipid formulations of amphotericin B: recent progress and future directions. C/in infect Dis 1996, 22(suppl 2):133-l 44.
vitro. A possible
explanation for this phenomenon is the long plasma elimination half-life of DO870 in laboratory species (>30 hours), which results in accumulation of DO870 in animals after multiple dosing.
after stopping
possibly related to treatment with D0870, occurred in 14% (5/35) of patients. Higher doses and longer treatment times with DO870 have been suggested in an attempt to further improve efficacy and reduce the rate of relapses. However, the 1996 annual Zeneca report suggests that these studies will not be undertaken and that DO870 has been discontinued from development, possibly due to its relatively weak in vitro potency against Aspergihs spp.
The search
A useful vignette of current and emerging liposomal formulations of amphotericin B and the development issues that require to be addressed before they can replace raw amphotericin B as first line therapy. 6.
20.
Hartsel S, Bolard J: Amphotericin 8: new life for an old drug. Trends Pharmacol Sci 1996, 17:445-449.
antifungal
agents
Barry AL, Brown SD: In vitro studies agents (voriconazole [UK-109.4961 Candid8 species. Antimicrob Agents 40:1948-l 949. This paper emphasises the potent activity of fluconazole against a wide range of Candida
8.
22.
Grant SM, Clissold SP: Itraconazole: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses. Drugs 1989, 3731 o-344.
9. .
Haria M, Bryson HM, Goa KL. Itraconazole: a reappraisal of its pharmacological properties and therapeutic use in the management of superficial infections. Drugs 1996, 51:585-620. A thorough review of itraconazole underlining its growing importance in the treatment of superficial, as opposed to invasive, fungal infections. 10.
Rex JH, Bennett JE, Sugar AM, Pappas PG, Van Der Horst CM, Edwards JE, Washburn RG, Scheld WM, Karchmer AW, Dine AP et a/.: A randomised trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. N fngl J Med 1994, 331 :1325-l 330.
11.
Anaissie EJ, Vartivarian SE, Abi-Said D, Uzun 0, Pinczowski H, Kontoyiannis DP, Khoury P, Papadakis K, Gardner A, Raad II et al.: Fluconazole versus amphotericin B in the treatment of hematogenous candidiasis: a matched cohort study. Am J Med 1996, 101 :170-l 76.
12.
Menichetti F, Fiorio M, Tosti A, Gatti G, Pasticci MB, Miletich MM, Bassetti D, Pauluzzi S: High-dose fluconazole therapy for cryptococcal meningitis in patients with AIDS. C/in infect Dis 1996, 22:838-840.
13.
Cartledge JD, Midgley J, Gazzard BG: ltraconazole cyclodextrin solution; the role in in vitro susceptibility testing in predicting successful treatment of HIV-related fluconazole-resistant and fluconazole-susceptible oral candidiasis. AlDS 1997, 11 :163-l 68.
15.
181
of two triazole antifungal and fluconazole) against Chemother 1996, voriconazole relative to that of spp.
Murphy M, Bernard EM, lshimaru T, Armstrong D: Activity of voriconazole (UK-109,496) against clinical isolates of Aspergillus species and its effectiveness in an experimental model of invasive aspergillosis. Antimicrob Agents Chemother 1997, 41:696-698.
23. .
Ruhnke M, Schmidt-Westhausen A, Trautmann M: In vitro activities of voriconazole (UK-109,496) against fluconazolesusceptible and -resistant C8ndid8 elbicans isolates from oral cavities of patients with human immunodeficiency virus infection. Antimicrob Agents Chemother 1997, 41:575-577. This paper emphasises that the potency advantage of voriconazole over fluconazole against Candida in vitro, translates to a clinical response to voriconazole in HIV patients with OPC refractory to fluconazole. 24.
McGinnis MR, Pasarell L, Cooper CR: In vitro susceptibility of clinical mould isolates to UK-109,496, amphotericin B. fluconazole and itraconazole [abstract E761. In Proceedings and Abstracts of the 35th fntersciences Conference on Anfimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:99.
25.
Espinel-lngroff A, Flynn T: Antifungal activity of the new triazole voriconazole against established, new and emerging yeast pathogens [abstract F631. In Proceedings and Abstracts of the 36th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington DC: American Society for Microbiology; 1996:114.
26.
Espinel-lnaroff A: Evaluation of the in vitro activitv of the new triaz;le voriconazole against opportunistic filamentous fungi [abstract F841. In Proceedings and Abstracts of the 36th Intersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1994:l 14.
27.
Sutton DA, Fothergill AW, Barchiesi FJ, Rinaldi MG: In vitro activity of voriconazole against dimorphic fungi [abstract F651. In Proceedings and Abstracts of the 36th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1996:114.
14. .
Georaooaoadakou NH. Walsh TJ: Antifunaal agents: chekoiherapeutic targets and immunologic itrategies. Antimicrob Agents Chemother 1996, 40:279-291. ._ I A usetul summary 01 current ana emergtng antltungal targets and lnhlbltors and of immunological approaches to treating fungal infections.
Koltin and Hitchcock
Barchesi F, Restrepo M, McGough DA, Rinaldi MG: In vitro activity of a new antifungal triazole: UK-109,496 [abstract F711. In Proceedings and Abstracts of the 35th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology: 1995:125.
Goa KL, Barradell LB: Fluconazole: an update on its pharmacodynamic and pharmacokinetic properties and therapeutic use in major superficial and systemic mycoses in immunocompromised patients. Drugs 1996, 50:658-690. A comprehensive and well written review of fluconazole’s role in the management of invasive and superficial fungal infections.
7. ..
21. .
for new triazole
Rex JH, Rinaldi MG, Pfaller MA: Resistance of Candida species to fluconazole. Antimicrob Agents Chemother 1995, 39:1-6. 28. .
Rex JH, Pfaller MA, Galgiani JN, Bartlett MS, Espinel-lngroff A, Ghannoum MA, Lancaster M, Odds FC, Rinaldi MG, Walsh TJ, Barry AL for the Subcommittee on Antifungal Susceptibility Testing of the National Committee for Clinical Laboratory Standards: Development of interpretative breakpoints for antifungal susceptibility testing: conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole and Candida infections. C/in Infect Dis 1997, 24:235-247. An excellent analysis of the relationship between in vitro susceptibility testing and clinical outcome for fluconazole and itraconazole against C. albicans. It draws on data that have accrued during the past decade and represents the benchmark for further in vitro-in viva correlation studies in the antifungal area.
Radford SA, Johnson EM, Warnock DW: In vitro studies of activity of voriconazole (UK-109,496), a new triazole antifungal agent, against emerging and less common mould pathogens. Antimicrob Agents Chemother 1997, 41:841-843. . This paper turther hIghlIghts the broad-spectrum antifungal potency of voriconazole. 29.
Jezequel SG, Clark M, Cole S, Evans KE. Wastall P: UK- 109,496, a novel, wide-SDectrum triazole derivative for the treatment of fungal infections: pre-clinical pharmacokinetics tabstraci F761. In Proceedings and Abstracts of the 35th intersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:126.
1z
30.
Hitchcock CA, Andrews FU, Lewis BGH, Troke PF: UK- 109,496, a novel, wide-spectrum triazole for the treatment of fungal infections: antifungal activity in experimental infections with Aspergillus [abstract F741. In Proceedings and Abstracts of the 35th Intersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:126.
16. ..
Takashima K, Oki T: Azole antifungal agents. Ewp Opin Ther Patents 1996, 6:645-654. i useful, concise review of current and emerging triazole derivatives. 18. .
Dickinson RP, Bell AS, Hitchcock CA, Narayanaswami S, Ray SJ, Richardson K, Troke PF: Novel antiungal 2-aryl-l(1H-l ,2,4-triazol-1 -yl)butan-l-01 derivatives with high activity against Aspergillus fumigatus. Bioorg Med Chem Leti 1996, 6:2031-2036. This paper describes the key structure-activity relationships of exploratory triazoles. leading to the discovery of voriconazole and its potent antifungal activity in vitro and in t&o. 19.
Hitchcock CA, Pye GW, Oliver GP, Troke PF: UK-109,496. a novel wide-spectrum triazole derivative for the treatment of fungal infections: antifungal activity and selectivity in vitro [abstract F721. In Proceedings and Abstracts of the 35th Intersciences Conference on Antimicrobial Agents and Chemotherapy. Washington DC: American Society for Microbiology: 1995:125.
31. ..
Martin MV, Yates J, Hitchcock CA: Comparison of voriconazole (UK-109,496) and itraconazole in prevention 8nd treatment of Aspergillus timigatus endocarditis in guinea pigs. Anrimicrob Agents Chemother 1997, 41 :13-l 6. . .. This paper IS a good lllustratlon ot how vonconazole’s fungicidal mechanism of action against Aspergillus in vitro translates to cures in a guinea pig model of Aspergillus endocarditis. 32.
Troke PF, Brammer KW, Hitchcock CA, Yonren S, Sarantis N: UK-1 09,496, a novel, wide-spectrum triazole derivative for the treatment of fungal infections: activity in systemic candidiasis models and early clinical efficacy in oropharyngeal
182
Next generation therapeutics
candidiasis [abstract F731. In Proceedings
and Abstracts of the 35th Mersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:125.
33.
Hitchcock CA, Andrews RJ, Lewis BGH, Troke PF: UK-109,496, a novel, wide-spectrum triazole derivative for the treatment of fungal infections: antifungal activity in experimental infections with Crv~tococcus [abstract F751. In Proceedinos and Abstracts -. of the 35th lnrersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 19%:126 .z
34. .
George D, Miniter P, Andriole VT: Efficacy of UK-109,496. a new azole antifungal agent in an experimental model of invasive aspergillosis. Antimicrob Agents Cbemotber 1996, 40:86-91. This paper shows that although vonconazole IS eftectlve against lnvaslve aspergillosis in rabbits, it is not as active as would be predicted from its potency in vitro. This reflects the rapid metabolism of voriconazole in this species, in contrast to guinea pigs and man. 35.
Patterson BE, Coates PE: UK-109,496, a novel, wide-spectrum triazole derivative for the treatment of fungal infections: pharmacokinetics in man [abstract F781. In Proceedings and Abstracts of the 35th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:126.
36.
Denning D, del Favero A, Gluckman E, Norfolk D, Ruhnke M, Yonren S, Troke PF, Sarantis N: UK-109.496, a novel, widespectrum triazole derivative for the treatment of fungal infections: clinical efficacy in acute invasive aspergillosis [abstract F901. In Proceedings and Abstracts of the 35th Intersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:126.
37.
DuPont 8, Denning D, Lode H, Yonren S, Troke PF, Sarantis N: UK-109,496, a novel, wide-spectrum triazole derivative for the treatment of fungal infections: clinical efficacy in chronic invasive aspergillosis [abstract Fall. In Proceedings and Abstracts of the 35th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:127.
36. Fromtling RA, Castaner J: SCH-56592. Drugs future 1996, . 21:160-166. A useful review of the pre-clinical profile of SCH 56592, drawing on data that have been published in abstracts or full papers during the past two years. 39.
Parmegiani R, Cacciapuoti A, Loebenberg D, Antonacci B, Norris C, Yarosh-Tomaine T, Michalski M, Hare RS, Miller GH: fn vitro activity of sch 56592. an orally active broad-spectrum antifungal agent [abstract F621. In Proceedings and Abstracts of the 35th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:123.
40.
Law D, Denning DW: In vitro activity of Schering 56592 compared with fluconazole and itraconazole against Candida spp. [abstract F881. In Proceedings and Abstracts of the 36th Intersciences Conference on Anrimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:l 15.
41.
DuPont 8, lmprovisi L, Dromer F: In vitro and in vivo activity of a new antifunoal aaent SCH 58592 [abstract F931. In Proceedings andlbst&ts of the 36th ~lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1996:116.
43. .
Galgiani JN, Lewis ML: In vitro studies of activities of the antifungal triazoles SCH56592 and itraconazole against Candid8 albicans, Cryptococcos neoformans, and other pathogenic yeasts. Antimicrob Agents Cbemotber 1997, 41 :180-l 63. This paper shows that SCH-56592 has potent, itraconazole-like activity against a wide range of yeasts. It also highlights that the results of susceptibility tests in standard media may be influenced by the method used to solubilise SCH-56592 and itraconazole. 44. .
Pfaller MA, Messer S, Jones RN: Activity of a new triazole, Sch 56592, compared with those of four other antifungal agents tested against clinical isolates of Candida spp.8nd Saccharomyces cerevisiae. Anfimicrob Agents Cbemotber 1997, 411233-235. This paper demonstrates that SCH.56592 is at least equivalent to itraconazole and significantly more potent than fluconazole against a wide range of clinically important yeasts. 45.
Fothergill AW, Sutton DA, Rinaldi MG: An in vitro headto-head comparison of Schering 56592, amphotericin B, fluconazole and itraconazole against a spectrum of filamentous fungi [abstract F891. In Proceedings and Abskacfs of the 36th Mersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1996:115.
46.
Oakley KL, Morrissey G, Denning DW: Efficacy of SCH56592 in 2 immunocompromised murine models of invasive aspergillosis [abstract F971. In Proceedings and Abstracts of the 36th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1996:116.
47.
Patterson TF, Kirkpatrick WR, Mcattee RK, Loebenberg D: Efficacy of SCH 56592 in a rabbit model of invasive asoeraillosis [abstract F981. In froceedinos and Abstracts . of the 36th lntersciences Conference on Akimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1996:l 16.
48.
Graybill J, Najvar L, Bocanegra R, Fothergill A, Luther M: Treatment of murine pulmonary aspergillosis with SCH 56592 [abstract F991. In Proceedings and Abstracts of the 36th lntersciences Conference on Antimicrobial Aaents and Chemotherapy. Washington, DC: American Society for Microbiology; 1996:l 1 7.
49.
Cacciapuoti A, Parmegiani A, Loebenberg D, Antonacci B, Moss EL, Menzel F, Norris C, Hare RS, Miller GH: Efficacy of SCH 56592 in pulmonary aspergillosis and candidiaiis in mice [abstract F671. In Proceedings and Absrracts of the 35th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:123.
50.
Cacciapuoti A, Loebenberg D, Frank D, Moss EL, Menzel F, Michalski M, Norris C. Yaremko B, Hare RS, Miller GH: Effect of delayed or extended treatment with SCH 56592 or concomitant treatment with amphotericin B in murine models of pulmonary aspergillosis and systemic candidiasis [abstract F961. In Proceedings and Abstracts of the 36th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1996:116.
51.
Nomeir A, Kumari P, Hilberi MJ, Loebenberg D, Cacciapuoti A, Menzel I. Moss E. Hare R. Miller GH. Caven N. Lin CC: Comparative pharmacokinetics of a new triazole antifungal agent Sch 56592 in mice, rats, rabbits, dogs and cynomolgus monkeys [abstract F681. In Proceedings and Abstracts of the 35th Intersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:124.
52.
De Wit S, DuPont B, Cartledge JD, Hawkins DA, Gezzard BG, Clumeck N, Denning DW: A dose-comparison study of a new triazole antifungal (D0870) in HIV-positive patients with oral candidiasis. ADS 1997, 11:759-763
42. .
Perfect JR. Cox GM. Dodae RK. Schell WA: In vitro and in vivb efficacies of ihe a;ole SCH-56592 against Cryptococcus neoformans. Antimicrob Agents Cbemotber 1996, 40:1910-1913 This paper shows that the potent activity of SCH.56592 against Crypfococcus in vitro translates to good efficacy in a rabbit model of cryptococcal meningitis.
The search for new triazole Yigal Koltin* and Christopher The first generation
antifungal
and itraconazole, fungal
infections
agent triazoles,
have revolutionised such as mucosal
However,
fungal
particularly
aspergillosis,
infections,
satisfactory
and thus there
new broad-spectrum generation
triazoles
considerable
agents.
voriconazole
promise
candidiasis of some
is still far from requirement
for
The new second
and SCH-56592
in achieving
of serious
the treatment
is an important
antifungal
The
fluconazole
and invasive
meningitis.
show
this goal in the near future.
Addresses *Millennium Pharmaceuticals Inc, Division of Molecular and Cellular Biology, 640 Memorial Drive, Cambridge, e-mail: [email protected]
MA 02139,
USA;
*Department of Discovery Biology, Pfizer Central Research, Sandwich, Kent CT1 3 9NJ, UK; e-mail: [email protected] Current
Opinion
in Chemical
Biology
1997, 1 :176-l
62
http://biomednet.com/elecref/1367593100100176 0 Current
Biology Ltd ISSN
1367-5931
Abbreviations b.i.d. twice daily dosing i.p.
intraperitoneal(ly) intravenous(ly) minimum inhibitory concentration
i.v. MIC o.d.
once daily dosing oesophageal candidiasis oropharyngeal candidiasis
oc OPC F&t
oral 6~ cytochrome
Introduction: discovery
P-450.dependent
challenges
14asterol
drug
Invasive fungal infections now rank alongside bacterial infections as a major cause of morbidity and mortality in seriously debilitated and immunocompromised patients [l]. Almost any fungus has the potential to cause invasive infections, but the most important pathogens in terms
of incidence and mortality spp., respectively.
are Candida
spp.
precise
incidence
of invasive
and
Aspergihs
Carrdida spp.
are the fourth most common cause of nosocomial (originating in hospitals) blood-stream infections in many hospitals and represent 8 to 11% of
all blood-stream infections [2,3]. The risk factors that are known to predispose patients to invasive candidiasis are intravascular cannulae, indwelling catheters, surgical procedures, prolonged use of broad-spectrum antibacterial antibiotics and immunocompromisation (e.g. AIDS, tissue transplant and cancer patients). The clinical manifestations of candidiasis range from transient and uncomplicated blood-stream infections to those with multiple organ involvement and life-threatening disease.
aspergillosis
is unknown,
due mainly to the paucity of reliable diagnostic methods that can be employed antemortem. However, Aspelgillus fumigatus is the most common species isolated from the environment and at postmortem examinations. It is responsible for approximately 80% of nosocomial infections, most prominently in bone marrow transplant and cancer patients, with the remaining 20% being caused by A. j&zvus, A. niger and A. teveus. The lung is usually the primary site of infection after inhalation of fungal spores, and the most common manifestations of disease are chronic allergy to Aspergi/h spores and saprophytic growth (taking advantage of dead or damaged tissue that has arisen as a consequence of previous infections or injury) in pre-existing cavities, which results in the formation of so-called ‘fungus balls’. In seriously debilitated and immunocompromised patients, the lung is the source of infection for invasive aspergillosis, which is characterised by multiple organ involvement and rapid clinical deterioration in the patient. Invasive aspergillosis is invariably fatal, despite current therapies, and it is one of the most devastating fungal infections found in the hospital setting [4]. This review describes the important role of the first generation triazole derivatives in the management of serious fungal infections. It also highlights their drawbacks and the progress that is being made to address them with the new, second generation triazole derivatives.
Current azole antifungal
demethylase
in antifungal
agents
A Hitchcock
the treatment
and cryptococcal
antifungal
agents
In contrast to the large number of antibacterial antibiotics, there are very few antifungal agents that can be prescribed for life-threatening fungal infections. These are amphotericin B, liposomal formulations of amphotericin B, 5fluorocytosine and the azole (N-substituted imidazole and triazole) derivatives. Liposomal amphotericin B [5*,6] and the first generation triazoles fluconazole [7**] and itraconazole [8,9*] (see Figure la) represent an important advance in the treatment of serious fungal infections. Fluconazole is used widely in the prevention and treatment of superficial candidiasis, including oropharyngeal and oesophageal candidiasis (OPC and OC, respectively), and it is showing encouraging efficacy against invasive candidiasis in both immune normal and immunocompromised patients [lo-121. It is also used widely to treat cryptococcal meningitis and to prevent relapse from that infection [12]. This widespread use not only reflects fluconazole’s antifungal efficacy, but also its proven safety profile. The flexibility of its oral (p.0.) and intravenous (i.v.) dosage forms is also advantageous for patients receiving prolonged antifungal therapy. The N-substituted imidazole ketoconazole is more potent than fluconazole in vitro,
(see Figure la) and is absorbed
The search for new triazole antifungal agents Koltin and Hitchcock
177
Figure 1
(a)
a
Fluconazole
Ketonazole
ltraconazole
(b)
F
P
SCH-56592
Voriconazole
D-0670
0 1997 Current Opinion in Chemical Biology
Agents used against pathogenic
fungi. (a) Azoles currently used. (b) Agents in clinical development.
orally, but the lack of an i.v. formulation and its potential for hepatotoxicity limit its use against OPC and OC in AIDS patients. Itraconazole is an improvement on ketoconazole in terms of having a broader antifungal spectrum and better toleration, but its use is hampered by variable oral absorption and the absence of a commercially available i.v. dosage form [8,9*]. Orally-administered itraconazole, however, dissolved in hydroxypropyl P-cyclodextrin has been shown to be effective against fluconazole-resistant OPC in patients with AIDS [ 131. Although itraconazole has shown some efficacy against invasive infections, including aspergillosis, its role in the treatment in general is poorly defined.
of invasive
disease
The azole antifungal agents work by inhibiting cytochrome P-450-dependent 14a-sterol demethylase (P450~hl), an important enzyme in ergosterol biosynthesis in fungi and cholesterol synthesis in mammalian cells [14*]. At therapeutic concentrations, the efficacy of the azoles is thought to reside in their greater affinity for fungal as opposed to mammalian P-45O~hr. Azole-treated fungi are depleted of ergosterol and accumulate 14a-methylated sterols which is thought to disrupt membrane structure
and function,
thereby
inhibiting
fungal
growth.
All of the
azoles are fungistatic, as opposed to fungicidal (inhibit growth but do not kill), against Candida spp., emphasizing the importance of the host’s immune system for eradicating the infecting organism and achieving a clinical cure. A corollary of this situation is that AIDS patients require indefinite suppressive therapy, and given the widespread use of fluconazole in end-stage who have failed ketoconazole
AIDS (including patients or itraconazole therapy), it
is not unexpected that fluconazole-resistant strains have been isolated from this group of patients. There is also an increasing number of reports of infections due to C. Rnrsei, C. glabrata and Aspergi/us spp. which have inherently low susceptibilities to fluconazole [ 15,16**]. Postulated mechanisms of resistance include changes in cell permeability, overproduction or alteration of P-450Dht and modification of other enzymes involved in ergosterol biosynthesis. Fluconazole and itraconazole are key members of the antifungal armamentarium but they have deficiencies either in antifungal spectrum, pharmacokinetics or the availability of parenteral dosage forms. This situation,
178
Next generation therapeutics
together with the increasing incidence of fungal infections, underlines the need for new broad-spectrum antifungal agents. The second generation triazoles, voriconazole,
pathogens (Blastomyces dematitidis, Coccidioides immitis, Paracoccidioides brasilimsis and Histop fasma capsulatum) and to additional emerging fungal pathogens, including
SCH-56592 and DO870 (see Figure lb) are the most promising agents meeting this challenge and have been the subject of extensive investigation during the past
organisms
couple of years. Consequently, these compounds will form the basis of this review. The latest exploratory triazole derivatives emerging from discovery programmes have already been reviewed elsewhere [17*]; however, in view of the relative paucity of information on them it is difficult to make meaningful comparisons with candidates in the more advanced stages of development such as voriconazole and SCH-56592. Liposomal amphotericin B and the semisynthetic pnuemocandins and echinocandins are also being developed as potential competitors to the new triazoles and they have also been the subject of recent reviews [5’,14’]. The best antifungal compounds emerging from pre-clinical research programmes are selected for clinical development on the basis of their efficacy, pharmacokinetic and toxicology profiles. Clinical development comprises three phases. In Phase I, the candidate’s pharmacokinetics, safety and toleration are determined in a small number (10 to 20) of healthy male volunteers. In Phase II, the candidate is tested for efficacy, safety and toleration in approximately 100 to 200 patients with various fungal infections. The aim of Phase III clinical trials is to confirm the efficacy, safety and toleration of the candidate in comparison with standard, marketed agents in studies with large numbers of patients (1000s). The results of such trials will determine whether or not the candidate offers significant advantages over current marketed agents in terms of efficacy and/or safety. Finally, approval by the regulatory authorities is required before the candidate can be marketed for clinical use.
New triazole
antifungal
agents
Voriconazole Voriconazole
(UK-109,496,
Pfizer,
Sandwich,
the newest of the second generation triazole and is the result of a synthetic programme
Kent,
that are resistant
to amphotericin
Consistent with its potency highly effective against various
B [24-27,28*].
in &r-o, voriconazole is fungal infections in guinea
pigs, when assessed on the basis of animal survivors and reductions in the fungal burden on tissues. The guinea pig was chosen for evaluating voriconazole’s efficacy against infections because in this species the drug achieves prolonged systemic exposures that are comparable to those observed in man [29]. When tested against invasive and pulmonary aspergillosis, voriconazole (lOmg/kg orally, twice a day (p.0. b.i.d.) and 8mg/kg p.o. b.i.d., respectively) was curative (i.e. sterilised tissues) and was significantly more efficacious than itraconazole at the same dose levels and amphotericin B (4mg/kg intraperitoneally (i.p.) on alternate days), regardless of the immune spatus of the animals [30]. Voriconazole (10 me/kg p.o. b.i.d.) was also curative and more active than the same dose of itraconazole against Aspe@//us endocarditis [31*‘]. When tested against invasive candidiasis (C. alhiram) in immune normal and immunocompromised animals, voriconazole produced fluconazole-like efficacy (5 mg/kg p.o. b.i.d.) [32]. hloreover, it was significantly more efficacious than fluconazole against invasive infections caused by fluconazole-resistant C. albicans, C. krusei and C. glabmta, reflecting the greater potency of voriconazole compared to that of fluconazole against these organisms in vitro. \Toriconazole also produced fluconazole-like efficacy against pulmonary and intracranial cryptococcosis (2.5 to 20mg/kg p.o. b.i.d.) [33]. hlore recently, voriconazole has shown activity comparable to that of amphotericin B against rdt pulmonary aspergillosis (30 mg/kg/day p.o. versus 4mg/kg/day i.p.) (221 and rabbit invasive aspergillosis (45 mg/kg/day p.o. versus 1 mg/kg/day i.v.) [34-l, despite suboptimal pharmacokinetics as a consequence of voriconazole being rapidly metabolised in these species.
UK) is
derivatives, aimed at
improving the potency and spectrum of fluconazole [18’]. Several investigators have shown voriconazole to be lo- to SOO-fold more potent than fluconazole (similar to itraconazole) against the primary opportunistic pathogens, Aspcrgillus spp., C~ptoroccu~ spp. and Candida spp., including organisms that are resistant to fluconazole such as C. krusei and C. glabmta (minimum inhibitory concentration (RIIC)) range across the species, 0.001 to 0.5 g/ml) [19,20,21*,22,23’]. This reflects the fact that voriconazole is more potent than fluconazole against fungal P-4501>hl and more effective than fluconazole in penetrating fungal cells. Furthermore, voriconazole is fungicidal for Aspe~~//~~s spp., where the minimum fungicidal concentration (hlFC) is approximately twice the hlIC [19]. The potent in vitro activity of voriconazole also extends to the endemic fungal
The pharmacokinetics of voriconazole have been invcstigated in approximately 300 male volunteers following p.0. and i.v. administration [35]. Systemic exposure increased in a disproportional manner (dose-dependent and time-dependent), due possibly to partial saturation of hepatic metabolism and systemic clearance with increased dose and increased duration of dosing. Elimination was characteristic of metabolic clearance, with only 1% of voriconazole being excreted in the urine as unchanged drug. The apparent oral absorption was 90% and the volume of distribution was approximately 2 L/kg, consistent with the drug being widely distributed in body tissues and fluids. In Phase II clinical trials, voriconazole has shown encouraging results in the treatment of OPC and acute- and chronicinvasive aspergillosis [32,36,37]. In a blinded.
The search
dose-comparative study (50 mg once daily (0.d.) or 200 mg o.d. or 200mg b.i.d.) in AIDS patients with OPC, voriconazole demonstrated clinical efficacy of 97% to 100% (there were 90 evaluable patients in this study) with both 200mg dosing regimens; it was less efficacious (80%) at the once daily dose of 50mg. There were no serious adverse events. There were 32 possible treatment-related adverse events, six of which resulted in patients being discontinued from the study. There was a dose-related incidence of visual disturbance (three patients at 50mg o.d. and 10 at 200 mg b.i.d.) and o.d., four at 200mg two patients discontinued treatment as a result. Generally patients described enhanced brightness of light or blurred vision; the effects were transient and fully reversible, sometimes while still receiving the drug [32].
Voriconazole’s activity against acute invasive aspergillosis has been evaluated in an open, noncomparative study in immunocompromised patients, many of whom had failed treatment with amphotericin B or itraconazole. The dosing regimen was 6mg/kg 12 hourly i.v. x 2 doses (2 doses 12 hours apart), then 3mg/kg 12 hourly i.v. for 6-27 days, followed by 200mg p.o. b.i.d. for 4 to 24 weeks. At an interim analysis of 53/71 evaluable patients, voriconazole produced a favourable clinical response in 74% (39/53) patients (8 complete; 17 partial; and 14 stable), whereas 26% (14/53) failed treatment. Mild to moderate visual disturbance was experienced in 8% (6/71) of patients but this did not lead to withdrawal of drug. Six percent (4/71) of patients were withdrawn from the study due to adverse events: one due to skin rash and three due to raised liver function enzymes.
Voriconazole has also been evaluated against chronic invasive aspergillosis in non-neutropenic patients in an open, non-comparative study [37]. Similar to the acute invasive aspergillosis study, many of the patients enrolled in the chronic invasive aspergillosis trial had failed treatment with amphotericin B and itraconazole. Patients received voriconazole 200mg p.o. b.i.d. for 4 to 24 weeks. At an interim analysis of 13/25 evaluable patients, voriconazole demonstrated a favourable clinical response in 69% (9/13) patients, with 31% (4/13) failing treatment. Mild to moderate visual disturbance was reported (1 l/25) patients but this did not lead to withdrawal Eight study
in 44% of drug.
percent (Z/25) of patients were withdrawn from the due to raised levels of liver function enzymes.
Voriconazole combines potent broad-spectrum antifungal activity irz vitro with pharmacokinetics in man that produce sustained high levels in blood and tissue following p.o. and i.v, administration. This is reflected in the encouraging results obtained from the Phase II clinical trials mentioned above. In view of this, voriconazole has rapidly progressed to Phase III trials in comparison with established agents, in order to explore fully its potential in the treatment
for new triazole antifungal agents Koltin and Hitchcock
of invasive
aspergillosis
and other
life-threatening
179
fungal
infections.
SCH-56592 SCH-56592 (Schering-Plough, Kennilworth, New Jersey, USA) is a structural analogue of itraconazole (tetrahydrofuran skeleton in itraconazole versus 1,3-dioxolone in SCH-56592) and has superseded the previous structurally related development candidate, SCH-51048 [38*]. When tested in a number of mycological media, SCH-56592 showed potent, broad-spectrum activity against the primary opportunistic pathogens Aspqihs spp., Candida spp. and C. neoformans (MIC range across the species, 0.003 to 0.2 pg/ml) [3941,42*]. Like itraconazole, SCH-56592 was also fungicidal against Aspe+‘/us spp. [41] and significantly more potent than fluconazole against Candida non-albicans spp. such as C. krusei and C. giabrata [43’]. Both itraconazole and SCH-56592 also showed a wide range of activities against fluconazole-resistant C. a&cam strains; thus some organisms were relatively sensitive whereas others remained frankly resistant, even at high concentrations of the drug [44*]. As expected from its potency against the primary opportunistic pathogens, SCH-56592 was also active against the endemic fungal pathogens B. dermatitidis and H. cnpsufatum, and a wide range of less common, emerging fungal pathogens [45]. SCH-56592 has been evaluated in several animal models of pulmonary and invasive aspergillosis, invasive candidiasis and cryptococcal meningitis, where efficacy was assessed on the basis of animal survivors and, in the case of some experiments, by reductions of the fungal burden of tissues. Against murine invasive aspergillosis caused by A. fumigatus, SCH-56592 (5 to 25 mg/kg p.o./day) was superior to itraconazole (at the same dose levels) and amphotericin B (5 mdkg i.p./day) in prolonging survival and reducing the AspergiL’us content of tissues [46]. Similar results were obtained in a neutropenic (reduced number of neutrophils) rabbit model of invasive aspergillosis [47]. Thus, SCH-56592 (10 mg/kg p.o./day) was more effective than the same dose of itraconazole and was comparable to amphotericin B (1 mg/kg i.v./day) in prolonging the survival of animals and reducing the Aspeq$/us tissue burden. In a murine model of pulmonary aspergillosis A. fumigatus, SCH-56592 at 10 to 50mg/kg p.o./day superior to amphotericin B (3-6 mg/kg i.v./day) the lung fungal load [48].
with was
in reducing
In immunocompromised mice with invasive candidiasis caused by C. albicans, SCH-56592 (50% effective dose range, 0.2 to Smg/kg p.o./day) was more active than fluconazole (50% effective dose range, 2.5 to 27mgjkg p.o./day), when measured on the basis of survivors [49]. SCH-56592 (50 to lOOmg/kg p.0.) was also effective in protecting mice from infections with A fumigatus or C. a&cam when it was administered l-72 hours prior to infection, thereby demonstrating its prophylactic
180
Next generation
therapeutics
potential [SO]. SCH-56592 has also been rabbit model of cryptococcal meningitis with fluconazole-[42*]. Both compounds p.o./day significantly reduced the brain and were equally efficacious
evaluated in a in comparison at 20 mglkg
Cryptococcus content
of
in this respect.
Pharmacokinetic studies in a number of laboratory species have demonstrated dose-related increases in the serum concentration of SCH-56592 [Sl]. In dogs and monkeys the oral bioavailability of SCH-56592 was approximately 20% and the plasma elimination half-life values were 18 and 22 hours, respectively. These pharmacokinetics predict that once-daily dosing in man should provide serum concentrations of SCH-56592 above the MICs for all of the key fungal pathogens. SCH-56592 demonstrates potent broad-spectrum antifungal activity in vitro which translates to good efficacy in the usual laboratory models of fungal infections. In addition, the pharmacokinetics of this drug in dog and monkey predict that once-daily dosing in man should be sufficient to treat serious fungal infections. This encouraging profile supports the continued development of SCH-56592, which is currently in Phase I/II studies designed to investigate its safety, pharmacokinetics and antifungal efficacy. DO870 The triazolestyryl derivative DO870 (Zeneca, Macclesfield, UK) is highly potent in vitro against Candida spp., including the fluconazole-resistant organisms, Cryptococcus spp., Ttichosporon spp. and H. capsulatum (MIC range across the species, 0.001 to 0.25 g/ml) ([ 14.1 and references therein). By contrast, it is relatively weak against Aspergihs spp. in vitro (5 dml), which is an important drawback when compared with the potent activities of itraconazole, voriconazole and SCH-56592 against this key pathogen. Consistent with its potency in vitro, DO870 is superior to fluconazole in various rodent infection models with the aforementioned pathogens (effective dose range, one to lOmg/kg/day) ([14*] and references therein). However, its efficacy against aspergillosis is somewhat unexpected given the relatively weak potency against Aspqihs in
in
77% (27/35) of patients, clinical improvement was recorded for 17% (6/35) and 6% (Z/35) failed at the lowest dose. Thirty seven percent of patients relapsed within two weeks
DO870 has progressed to clinical studies in volunteers and in AIDS patients with OPC [52]. In both groups, DO870 had long plasma elimination halflife values of one to 10 days, with a median value of three days. The treatment studies in AIDS patients employed three dosing regimens in two phases. In the first phase, a single 50mg dose on day 1 was followed by lOmg/day for four days. In the second phase, a single 100mg dose on day 1 was followed either by 25 mgjday for four days or 10 mg/day for five days. On completion of the study, clinical cures were obtained
tieatment.
Mild adverse
events,
Conclusions Fungal infections are assuming greater importance as the cause of morbidity and mortality in hospitalised patients. The first generation triazoles, fluconazole and itraconazole have had a significant impact in the prevention and treatment of some of these infections. Fluconazole is now the triazole of choice for prophylaxis and treatment of candidiasis caused by C. a/&am and for cryptococcal meningitis. Deficiencies in the antifungal spectrum of fluconazole and pharmacokinetics of itraconazole limit their use against fluconazole-resistant Candida infections and aspergillosis. The new second generation triazoles, voriconazole and SCH-56592, show considerable promise in addressing these shortcomings on the basis of comprehensive preclinical studies and, in the case of voriconazole, clinical data generated from Phase I/II trials. Further development of both compounds is warranted and Phase III trials in comparison with established agents are the next important step towards defining the roles of voriconazole and SCH-56592 in the management of life-threatening fungal infections.
References
and recommended
reading
Papers of particular interest, published within the annual period of review, have been highlighted as: . l
*
of special interest of outstanding interest
1.
Bennett JE: Antimicrobial agents: antifungal agents. In Goodman and Gilman’s, The Pharmacological Basis of Therapeutics, edn 9. Edited bv Hardman JG. Limbird LE, Molinoff PB, Ruddon RW, Gilman AG: New York: McGraw-Hill Inc; 1995:1175-l 190.
2.
Banerjee SN, Emori G, Culver DH, Gaynes RP, Jarvis WR, Horan T, Edwards JR, Tolson J, Henderson T, Martone WJ and The National Nosocomial Infections Surveillance Svstem: National nosocomial infections surveillance: seculaitrends in nosocomial primary blood stream infections in the United States, 1980-I 989. Am I Med 1991, 91 (suppl36):86-89.
3.
Fraser VJ, Jones M, Dunkel J, Storfer S, Medoff G, Dunagan WC: Candidemia in a tertiary care hospital: epidemiology, risk factors and predictors of mortality. C/in infect Dis 1992. 14:414-421.
4.
Denning DW, Stevens DA: Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases. Rev infect Dis 1990, 12:1147-l 201.
5. .
Hiemenz JW, Walsh TJ: Lipid formulations of amphotericin B: recent progress and future directions. C/in infect Dis 1996, 22(suppl 2):133-l 44.
vitro. A possible
explanation for this phenomenon is the long plasma elimination half-life of DO870 in laboratory species (>30 hours), which results in accumulation of DO870 in animals after multiple dosing.
after stopping
possibly related to treatment with D0870, occurred in 14% (5/35) of patients. Higher doses and longer treatment times with DO870 have been suggested in an attempt to further improve efficacy and reduce the rate of relapses. However, the 1996 annual Zeneca report suggests that these studies will not be undertaken and that DO870 has been discontinued from development, possibly due to its relatively weak in vitro potency against Aspergihs spp.
The search
A useful vignette of current and emerging liposomal formulations of amphotericin B and the development issues that require to be addressed before they can replace raw amphotericin B as first line therapy. 6.
20.
Hartsel S, Bolard J: Amphotericin 8: new life for an old drug. Trends Pharmacol Sci 1996, 17:445-449.
antifungal
agents
Barry AL, Brown SD: In vitro studies agents (voriconazole [UK-109.4961 Candid8 species. Antimicrob Agents 40:1948-l 949. This paper emphasises the potent activity of fluconazole against a wide range of Candida
8.
22.
Grant SM, Clissold SP: Itraconazole: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses. Drugs 1989, 3731 o-344.
9. .
Haria M, Bryson HM, Goa KL. Itraconazole: a reappraisal of its pharmacological properties and therapeutic use in the management of superficial infections. Drugs 1996, 51:585-620. A thorough review of itraconazole underlining its growing importance in the treatment of superficial, as opposed to invasive, fungal infections. 10.
Rex JH, Bennett JE, Sugar AM, Pappas PG, Van Der Horst CM, Edwards JE, Washburn RG, Scheld WM, Karchmer AW, Dine AP et a/.: A randomised trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. N fngl J Med 1994, 331 :1325-l 330.
11.
Anaissie EJ, Vartivarian SE, Abi-Said D, Uzun 0, Pinczowski H, Kontoyiannis DP, Khoury P, Papadakis K, Gardner A, Raad II et al.: Fluconazole versus amphotericin B in the treatment of hematogenous candidiasis: a matched cohort study. Am J Med 1996, 101 :170-l 76.
12.
Menichetti F, Fiorio M, Tosti A, Gatti G, Pasticci MB, Miletich MM, Bassetti D, Pauluzzi S: High-dose fluconazole therapy for cryptococcal meningitis in patients with AIDS. C/in infect Dis 1996, 22:838-840.
13.
Cartledge JD, Midgley J, Gazzard BG: ltraconazole cyclodextrin solution; the role in in vitro susceptibility testing in predicting successful treatment of HIV-related fluconazole-resistant and fluconazole-susceptible oral candidiasis. AlDS 1997, 11 :163-l 68.
15.
181
of two triazole antifungal and fluconazole) against Chemother 1996, voriconazole relative to that of spp.
Murphy M, Bernard EM, lshimaru T, Armstrong D: Activity of voriconazole (UK-109,496) against clinical isolates of Aspergillus species and its effectiveness in an experimental model of invasive aspergillosis. Antimicrob Agents Chemother 1997, 41:696-698.
23. .
Ruhnke M, Schmidt-Westhausen A, Trautmann M: In vitro activities of voriconazole (UK-109,496) against fluconazolesusceptible and -resistant C8ndid8 elbicans isolates from oral cavities of patients with human immunodeficiency virus infection. Antimicrob Agents Chemother 1997, 41:575-577. This paper emphasises that the potency advantage of voriconazole over fluconazole against Candida in vitro, translates to a clinical response to voriconazole in HIV patients with OPC refractory to fluconazole. 24.
McGinnis MR, Pasarell L, Cooper CR: In vitro susceptibility of clinical mould isolates to UK-109,496, amphotericin B. fluconazole and itraconazole [abstract E761. In Proceedings and Abstracts of the 35th fntersciences Conference on Anfimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:99.
25.
Espinel-lngroff A, Flynn T: Antifungal activity of the new triazole voriconazole against established, new and emerging yeast pathogens [abstract F631. In Proceedings and Abstracts of the 36th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington DC: American Society for Microbiology; 1996:114.
26.
Espinel-lnaroff A: Evaluation of the in vitro activitv of the new triaz;le voriconazole against opportunistic filamentous fungi [abstract F841. In Proceedings and Abstracts of the 36th Intersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1994:l 14.
27.
Sutton DA, Fothergill AW, Barchiesi FJ, Rinaldi MG: In vitro activity of voriconazole against dimorphic fungi [abstract F651. In Proceedings and Abstracts of the 36th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1996:114.
14. .
Georaooaoadakou NH. Walsh TJ: Antifunaal agents: chekoiherapeutic targets and immunologic itrategies. Antimicrob Agents Chemother 1996, 40:279-291. ._ I A usetul summary 01 current ana emergtng antltungal targets and lnhlbltors and of immunological approaches to treating fungal infections.
Koltin and Hitchcock
Barchesi F, Restrepo M, McGough DA, Rinaldi MG: In vitro activity of a new antifungal triazole: UK-109,496 [abstract F711. In Proceedings and Abstracts of the 35th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology: 1995:125.
Goa KL, Barradell LB: Fluconazole: an update on its pharmacodynamic and pharmacokinetic properties and therapeutic use in major superficial and systemic mycoses in immunocompromised patients. Drugs 1996, 50:658-690. A comprehensive and well written review of fluconazole’s role in the management of invasive and superficial fungal infections.
7. ..
21. .
for new triazole
Rex JH, Rinaldi MG, Pfaller MA: Resistance of Candida species to fluconazole. Antimicrob Agents Chemother 1995, 39:1-6. 28. .
Rex JH, Pfaller MA, Galgiani JN, Bartlett MS, Espinel-lngroff A, Ghannoum MA, Lancaster M, Odds FC, Rinaldi MG, Walsh TJ, Barry AL for the Subcommittee on Antifungal Susceptibility Testing of the National Committee for Clinical Laboratory Standards: Development of interpretative breakpoints for antifungal susceptibility testing: conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole and Candida infections. C/in Infect Dis 1997, 24:235-247. An excellent analysis of the relationship between in vitro susceptibility testing and clinical outcome for fluconazole and itraconazole against C. albicans. It draws on data that have accrued during the past decade and represents the benchmark for further in vitro-in viva correlation studies in the antifungal area.
Radford SA, Johnson EM, Warnock DW: In vitro studies of activity of voriconazole (UK-109,496), a new triazole antifungal agent, against emerging and less common mould pathogens. Antimicrob Agents Chemother 1997, 41:841-843. . This paper turther hIghlIghts the broad-spectrum antifungal potency of voriconazole. 29.
Jezequel SG, Clark M, Cole S, Evans KE. Wastall P: UK- 109,496, a novel, wide-SDectrum triazole derivative for the treatment of fungal infections: pre-clinical pharmacokinetics tabstraci F761. In Proceedings and Abstracts of the 35th intersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:126.
1z
30.
Hitchcock CA, Andrews FU, Lewis BGH, Troke PF: UK- 109,496, a novel, wide-spectrum triazole for the treatment of fungal infections: antifungal activity in experimental infections with Aspergillus [abstract F741. In Proceedings and Abstracts of the 35th Intersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:126.
16. ..
Takashima K, Oki T: Azole antifungal agents. Ewp Opin Ther Patents 1996, 6:645-654. i useful, concise review of current and emerging triazole derivatives. 18. .
Dickinson RP, Bell AS, Hitchcock CA, Narayanaswami S, Ray SJ, Richardson K, Troke PF: Novel antiungal 2-aryl-l(1H-l ,2,4-triazol-1 -yl)butan-l-01 derivatives with high activity against Aspergillus fumigatus. Bioorg Med Chem Leti 1996, 6:2031-2036. This paper describes the key structure-activity relationships of exploratory triazoles. leading to the discovery of voriconazole and its potent antifungal activity in vitro and in t&o. 19.
Hitchcock CA, Pye GW, Oliver GP, Troke PF: UK-109,496. a novel wide-spectrum triazole derivative for the treatment of fungal infections: antifungal activity and selectivity in vitro [abstract F721. In Proceedings and Abstracts of the 35th Intersciences Conference on Antimicrobial Agents and Chemotherapy. Washington DC: American Society for Microbiology: 1995:125.
31. ..
Martin MV, Yates J, Hitchcock CA: Comparison of voriconazole (UK-109,496) and itraconazole in prevention 8nd treatment of Aspergillus timigatus endocarditis in guinea pigs. Anrimicrob Agents Chemother 1997, 41 :13-l 6. . .. This paper IS a good lllustratlon ot how vonconazole’s fungicidal mechanism of action against Aspergillus in vitro translates to cures in a guinea pig model of Aspergillus endocarditis. 32.
Troke PF, Brammer KW, Hitchcock CA, Yonren S, Sarantis N: UK-1 09,496, a novel, wide-spectrum triazole derivative for the treatment of fungal infections: activity in systemic candidiasis models and early clinical efficacy in oropharyngeal
182
Next generation therapeutics
candidiasis [abstract F731. In Proceedings
and Abstracts of the 35th Mersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:125.
33.
Hitchcock CA, Andrews RJ, Lewis BGH, Troke PF: UK-109,496, a novel, wide-spectrum triazole derivative for the treatment of fungal infections: antifungal activity in experimental infections with Crv~tococcus [abstract F751. In Proceedinos and Abstracts -. of the 35th lnrersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 19%:126 .z
34. .
George D, Miniter P, Andriole VT: Efficacy of UK-109,496. a new azole antifungal agent in an experimental model of invasive aspergillosis. Antimicrob Agents Cbemotber 1996, 40:86-91. This paper shows that although vonconazole IS eftectlve against lnvaslve aspergillosis in rabbits, it is not as active as would be predicted from its potency in vitro. This reflects the rapid metabolism of voriconazole in this species, in contrast to guinea pigs and man. 35.
Patterson BE, Coates PE: UK-109,496, a novel, wide-spectrum triazole derivative for the treatment of fungal infections: pharmacokinetics in man [abstract F781. In Proceedings and Abstracts of the 35th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:126.
36.
Denning D, del Favero A, Gluckman E, Norfolk D, Ruhnke M, Yonren S, Troke PF, Sarantis N: UK-109.496, a novel, widespectrum triazole derivative for the treatment of fungal infections: clinical efficacy in acute invasive aspergillosis [abstract F901. In Proceedings and Abstracts of the 35th Intersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:126.
37.
DuPont 8, Denning D, Lode H, Yonren S, Troke PF, Sarantis N: UK-109,496, a novel, wide-spectrum triazole derivative for the treatment of fungal infections: clinical efficacy in chronic invasive aspergillosis [abstract Fall. In Proceedings and Abstracts of the 35th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:127.
36. Fromtling RA, Castaner J: SCH-56592. Drugs future 1996, . 21:160-166. A useful review of the pre-clinical profile of SCH 56592, drawing on data that have been published in abstracts or full papers during the past two years. 39.
Parmegiani R, Cacciapuoti A, Loebenberg D, Antonacci B, Norris C, Yarosh-Tomaine T, Michalski M, Hare RS, Miller GH: fn vitro activity of sch 56592. an orally active broad-spectrum antifungal agent [abstract F621. In Proceedings and Abstracts of the 35th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:123.
40.
Law D, Denning DW: In vitro activity of Schering 56592 compared with fluconazole and itraconazole against Candida spp. [abstract F881. In Proceedings and Abstracts of the 36th Intersciences Conference on Anrimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:l 15.
41.
DuPont 8, lmprovisi L, Dromer F: In vitro and in vivo activity of a new antifunoal aaent SCH 58592 [abstract F931. In Proceedings andlbst&ts of the 36th ~lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1996:116.
43. .
Galgiani JN, Lewis ML: In vitro studies of activities of the antifungal triazoles SCH56592 and itraconazole against Candid8 albicans, Cryptococcos neoformans, and other pathogenic yeasts. Antimicrob Agents Cbemotber 1997, 41 :180-l 63. This paper shows that SCH-56592 has potent, itraconazole-like activity against a wide range of yeasts. It also highlights that the results of susceptibility tests in standard media may be influenced by the method used to solubilise SCH-56592 and itraconazole. 44. .
Pfaller MA, Messer S, Jones RN: Activity of a new triazole, Sch 56592, compared with those of four other antifungal agents tested against clinical isolates of Candida spp.8nd Saccharomyces cerevisiae. Anfimicrob Agents Cbemotber 1997, 411233-235. This paper demonstrates that SCH.56592 is at least equivalent to itraconazole and significantly more potent than fluconazole against a wide range of clinically important yeasts. 45.
Fothergill AW, Sutton DA, Rinaldi MG: An in vitro headto-head comparison of Schering 56592, amphotericin B, fluconazole and itraconazole against a spectrum of filamentous fungi [abstract F891. In Proceedings and Abskacfs of the 36th Mersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1996:115.
46.
Oakley KL, Morrissey G, Denning DW: Efficacy of SCH56592 in 2 immunocompromised murine models of invasive aspergillosis [abstract F971. In Proceedings and Abstracts of the 36th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1996:116.
47.
Patterson TF, Kirkpatrick WR, Mcattee RK, Loebenberg D: Efficacy of SCH 56592 in a rabbit model of invasive asoeraillosis [abstract F981. In froceedinos and Abstracts . of the 36th lntersciences Conference on Akimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1996:l 16.
48.
Graybill J, Najvar L, Bocanegra R, Fothergill A, Luther M: Treatment of murine pulmonary aspergillosis with SCH 56592 [abstract F991. In Proceedings and Abstracts of the 36th lntersciences Conference on Antimicrobial Aaents and Chemotherapy. Washington, DC: American Society for Microbiology; 1996:l 1 7.
49.
Cacciapuoti A, Parmegiani A, Loebenberg D, Antonacci B, Moss EL, Menzel F, Norris C, Hare RS, Miller GH: Efficacy of SCH 56592 in pulmonary aspergillosis and candidiaiis in mice [abstract F671. In Proceedings and Absrracts of the 35th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:123.
50.
Cacciapuoti A, Loebenberg D, Frank D, Moss EL, Menzel F, Michalski M, Norris C. Yaremko B, Hare RS, Miller GH: Effect of delayed or extended treatment with SCH 56592 or concomitant treatment with amphotericin B in murine models of pulmonary aspergillosis and systemic candidiasis [abstract F961. In Proceedings and Abstracts of the 36th lntersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1996:116.
51.
Nomeir A, Kumari P, Hilberi MJ, Loebenberg D, Cacciapuoti A, Menzel I. Moss E. Hare R. Miller GH. Caven N. Lin CC: Comparative pharmacokinetics of a new triazole antifungal agent Sch 56592 in mice, rats, rabbits, dogs and cynomolgus monkeys [abstract F681. In Proceedings and Abstracts of the 35th Intersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1995:124.
52.
De Wit S, DuPont B, Cartledge JD, Hawkins DA, Gezzard BG, Clumeck N, Denning DW: A dose-comparison study of a new triazole antifungal (D0870) in HIV-positive patients with oral candidiasis. ADS 1997, 11:759-763
42. .
Perfect JR. Cox GM. Dodae RK. Schell WA: In vitro and in vivb efficacies of ihe a;ole SCH-56592 against Cryptococcus neoformans. Antimicrob Agents Cbemotber 1996, 40:1910-1913 This paper shows that the potent activity of SCH.56592 against Crypfococcus in vitro translates to good efficacy in a rabbit model of cryptococcal meningitis.