Posaconazole: a broad-spectrum triazole antifungal

Posaconazole: a broad-spectrum triazole antifungal

Review Posaconazole: a broad-spectrum triazole antifungal Harrys A Torres, Ray Y Hachem, Roy F Chemaly, Dimitrios P Kontoyiannis, Issam I Raad Posac...

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Review

Posaconazole: a broad-spectrum triazole antifungal Harrys A Torres, Ray Y Hachem, Roy F Chemaly, Dimitrios P Kontoyiannis, Issam I Raad

Posaconazale is a new triazole drug being investigated in phase III clinical trials for the treatment and prevention of invasive fungal infections. In-vitro and in-vivo studies showed that posaconazole has broad-spectrum activity against most Candida species, Cryptococcus neoformans, Aspergillus species, Fusarium species, zygomycetes, and endemic fungi. Posaconazole is given orally two to four times daily. This triazole is widely distributed in the body, metabolised mainly by the liver, and is well tolerated, even in long-term courses. Adverse events are generally mild and include headache and gastrointestinal complaints. Posaconazole has shown promising clinical efficacy against lifethreatening fungal infections that are often refractory to the currently available antifungal therapies—eg, invasive aspergillosis, fusariosis, and the emerging zygomycosis.

Introduction Invasive fungal infections have emerged as a leading cause of death in cancer patients, haemopoietic stem-cell transplant (HSCT) recipients, and other highly immunocompromised patients. The increased incidence of invasive fungal infections such as those caused by Candida species other than Candida albicans, moulds, and other emerging fungi in these patient populations is a particularly serious problem because some of these pathogens are often resistant to most of the antifungals currently available.1–8 To date, only four classes of antifungal drugs have been approved for treating invasive fungal infections: the polyenes (eg, amphotericin B), the azoles (eg, ketoconazole, itraconazole, fluconazole, and voriconazole), flucytosine, and the echinocandins (eg, caspofungin).9,10 Failure rates of these agents, including the recently introduced agents, such as voriconazole and caspofungin, are high—in the range of 60% to 70% in allogeneic HSCT recipients.2–4,6,9,11,12 In addition, increasing use of antifungal agents has led to the development of resistance to the currently available antifungals.13 The addition of posaconazole to the antifungal armamentarium is welcome because of the drug’s broad spectrum and potent activity against a number of common and rare but emerging fungal pathogens, especially those refractory to standard antifungal therapy.14–16 Posaconazole is currently being investigated in phase III clinical trials for the treatment and prevention of invasive fungal infections.14,15,17 Posaconazole is structurally similar to the old broadspectrum triazole itraconazole but with fluorine substituents in place of chlorine and a furan ring in place of the dioxolane ring (figure 1).18 Posaconazole inhibits fungi by blocking ergosterol synthesis through inhibition of the enzyme lanosterol 14-demethylase (CYP51). Ergosterol depletion coupled with the accumulation of methylated sterol precursors results in inhibition of fungal cell growth, fungal cell death, or both.

such as Candida species, Aspergillus species, nonAspergillus hyalohyphomycetes, phaeohyphomycetes, zygomycetes, and endemic fungi.5,19–23 Posaconazole cross-resistance with fluconazole, itraconazole, or both, has been shown in some candida isolates,21,22,24,25 and this resistance appears to be Candida species specific. For example, cross-resistance with posaconazole and either fluconazole or itraconazole has been observed for C albicans24 but not for Candida krusei isolates.22 A certain degree of cross-resistance between posaconazole and itraconazole has also been reported for Aspergillus fumigatus isolates.26 The clinical importance of these in-vitro cross-resistance data has yet to be determined. In fact, in a study of more than 18 000 strains of clinically important yeast and moulds obtained from over 200 centres worldwide over a period of 10 years, posaconazole retained activity against many candida and aspergillus isolates that exhibited resistance to voriconazole, fluconazole, and amphotericin B.23

Lancet Infect Dis 2005; 5: 775–85 HAT is a clinical fellow, DPK is associated professor, RFC and RYH are assistant professors, and IIR is professor of medicine and chairman of the Department of Infectious Diseases, Infection Control and Employee Health, University of Texas M D Anderson Cancer Center, Houston, Texas, USA. Correspondence to: Professor Issam I Raad, Department of Infectious Diseases, Infection Control and Employee Health, Unit 402, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA. Tel +1 713 792 7943; fax +1 713 792 8233; [email protected]

Activity against yeasts In vitro, posaconazole is very active against Candida species. The drug is more active than itraconazole and fluconazole against all Candida species and Cryptococcus neoformans.20–22,27 The in-vitro activities of posaconazole, voriconazole, and fluconazole against 3932 isolates of Candida species Itraconazole N N

Cl

N

CH2 O O

Cl CH2 O

O N

N

N

CH3 N CH CH2 CH3 N

Posaconazole F

O O

F

N

N

N

N

OH

N O N

In-vitro activity Posaconazole’s antifungal spectrum is broad and includes causative agents of invasive fungal infections http://infection.thelancet.com Vol 5 December 2005

N

N

Figure 1: A comparison of the structures of itraconazole and posaconazole

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obtained from over 100 medical centres worldwide during 2001 and 2002 were recently examined.22 Posaconazole and voriconazole were very active against Candida species (97–98% susceptible at a minimum inhibitory concentration [MIC] 1 g/mL). These two triazoles were relatively comparable in both spectrum and potency, and exhibited an improved spectrum of activity relative to fluconazole against all Candida species.22 Posaconazole exhibited fungistatic and fungicidal activity in vitro and in vivo for most Candida species isolates,27,28 and inhibited 97% of Candida species isolates at concentrations of 1 g/mL or below.21 MICs for C albicans range from 0·007 g/mL to over 8 g/mL.22,28 C albicans is the most susceptible species of candida (the MIC at which 90% [MIC90] of the isolates were inhibited was 0·03–0·06 g/mL),20 whereas Candida glabrata and Candida pelliculosa (both of which have MIC90 values of 2–4 g/mL) are the least susceptible.21,22,25,27,29 However, posaconazole inhibits 80% of C glabrata and 44% of C pelliculosa isolates at concentrations of 1 g/mL or under.22 In a study of 2000 bloodstream candida isolates, most isolates had low posaconazole MICs (0·03–0·13 g/mL), with higher MICs noted for C glabrata and C krusei.30 For Candida parapsilosis and C krusei, MICs are in the ranges 0·015–1 g/mL and 0·12–2 g/mL, respectively.22 Posaconazole is active against fluconazole-resistant Candida norvegensis, Candida guilliermondii, C krusei, Candida inconspicua, and most fluconazole-resistant C albicans isolates.27,29 Decreases in posaconazole susceptibility of clinical C albicans isolates has been associated with multiple mutations in ERG11, which encodes the CYP450 enzyme lanosterol 14-demethylase.31,32 However, mutations in ERG11 appears to affect either voriconazole or fluconazole more than posaconazole.33 Posaconazole showed potent in-vitro activity against a globally diverse collection of 1646 C neoformans isolates.34 Posaconazole has been reported to have fungistatic and fungicidal activity in vitro and in vivo against C neoformans.28,35 Potent in-vitro activity was demonstrated against C neoformans var gatti and C neoformans var neoformans.35 Posaconazole inhibited 100% of C neoformans isolates at concentrations of 1 g/mL or below,22 and also inhibited fluconazoleresistant C neoformans.35 Low MICs of posaconazole have been reported for Rhodotorula species isolates, including Rhodotorula rubra.20,36 In addition, posaconazole exhibited fungistatic activity in vitro against Trichosporon species.28,37

Activity against moulds Posaconazole is the most active triazole against filamentous fungi, inhibiting 95% of isolates at concentrations of 1 g/mL or below; by comparison, ravuconazole inhibits 91% of isolates and voriconazole 776

inhibits 90%.37 Posaconazole is four to 16 times as active as amphotericin B against Aspergillus species,39 inhibiting growth at concentrations below 0·03 g/mL.24,28 However, different Aspergillus species differ in their susceptibility to posaconazole.28 Posaconazole has been shown to have better in-vitro activity than voriconazole or itraconazole against A fumigatus.40 Posaconazole also inhibits A fumigatus that is resistant to itraconazole, voriconazole, and amphotericin B.24,41 Point mutations in the CYP51A gene, specifically in codon 54, are associated with posaconazole resistance in A fumigatus. The CYP51A gene encodes the presumed target site for posaconazole, cytochrome P450 14-demethylase.42 Posaconazole is active in vitro against Aspergillus terreus,38,43 a species resistant to amphotericin B.44–46 However, Aspergillus niger seems to be less susceptible to posaconazole.28 The clinical implications of raised posaconazole MICs are unclear since it may be possible to achieve clinical serum posaconazole concentrations higher than these MICs.26 Posaconazole is active against Fusarium species,47 with variable and species-dependent fungistatic activity.28 Posaconazole is apparently more active against Fusarium oxysporum than Fusarium solani.24,28,48 However, mixed results have been reported regarding the in-vitro activity of this triazole against F solani isolates.5,24,47 Posaconazole has promising activity against the zygomycetes.19,38,39,49 A recent comparative study with voriconazole and itraconazole showed that posaconazole exhibited the lowest MICs against 86 zygomycetes isolates, with MICs of 128 g/mL, 32 g/mL, and 4 g/mL, respectively.23 However, different zygomycetes differ in their susceptibility to posaconazole—eg, MIC ranges are 0·25–8 g/mL for Rhizopus species, 0·125–8 g/mL for Mucor species, 0·03–0·25 g/mL for Absidia corymbifera, and 0·03–1 g/mL for Cunninghamella species.49 Posaconazole appears to be less active than amphotericin B, more active than voriconazole, and fluconazole, and comparable to, or slightly more active than, itraconazole against clinical agents of zygomycosis.49 In a recent report on the in-vitro activity of itraconazole, fluconazole, amphotericin B, and posaconazole against 30 clinical isolates of Pseudallescheria boydii (Scedosporium apiospermum), posaconazole was the most active agent.50 However, not all studies have shown in-vitro activity of posaconazole against S apiospermum.24,39,51 Likewise, studies of the invitro activity of posaconazole against Scedosporium prolificans have had mixed results.5,24 Posaconazole appears to be active against Acremonium species, Paecilomyces lilacinus, Geotrichum species, and Trichoderma species.39,52–54

Activity against endemic fungi Posaconazole is highly active in vitro against Histoplasma capsulatum, Blastomyces dermatitidis (for http://infection.thelancet.com Vol 5 December 2005

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both, MIC0·01–2 g/mL), and Coccidioides immitis (MIC 0·25–1 g/mL), with less activity against Sporothrix schenckii (MIC0·12–4 g/mL).24,28,54,55

Posaconazole is active in vivo in experimental models of invasive aspergillosis15,44,46,59,60 and disseminated fusariosis.61 Posaconazole is effective in vivo against some species of zygomycetes. Specifically, posaconazole showed no beneficial effects against Rhizopus oryzae infection but demonstrated partial activity against A corymbifera infection in non-immunocompromised mice.62 In addition, posaconazole prolonged survival and reduced tissue burden in an immunosuppressed mouse model of Mucor species infection.63 Some studies have shown in-vivo activity of posaconazole against S apiospermum infection,50,51 particularly when this triazole is used at high doses (25 mg/kg).50 Posaconazole was also active in a murine model of S prolificans infection.64

plus amphotericin B had efficacy equal to or greater than that of either component alone.57 Synergy without evidence of antagonism was observed in 12% of interactions between terbinafine and posaconazole against clinical isolates of C glabrata with decreased susceptibility to azoles.71 Likewise, combinations of caspofungin and posaconazole were evaluated against 119 C glabrata isolates. Synergy was seen in 18% of isolates including 4% of fluconazole-resistant isolates, without evidence of antagonism.72 The combination of posaconazole and flucytosine was significantly more active (p0·01) than either drug alone against C neoformans in vitro and in vivo.73 However, animal models of C neoformans infection suggest that the combination of posaconazole and amphotericin B is not superior to amphotericin B alone.58 Of interest, antagonism has been described in vitro and in vivo for triazole/polyene combinations against Aspergillus species.74,75 However, no posaconazole/ amphotericin B antagonism was identified in a study of mice with Aspergillus flavus infection.59 Synergistic interaction has been reported in vitro for posaconazole in combination with caspofungin against A fumigatus.76 Whether combinations of posaconazole with other drugs such as polyenes or echinocandins are superior to posaconazole monotherapy requires further research in standardised animal models and controlled clinical trials. The combination of posaconazole and granulocytemacrophage-colony stimulating factor does not substantially affect the efficacy of posaconazole in murine models of invasive aspergillosis77,78 and S prolificans infection.64

Activity against endemic fungi

Pharmacology

Posaconazole reduced organ infection burdens in experimental models of infection with H capsulatum, B dermatitidis, or C immitis.55,65,66

Posaconazole is available for oral use in clinical trials; exposure is greater when it is administered as an oral suspension than when it is administered as a tablet.79,80 No intravenous formulation of posaconazole has yet been used in clinical trials; this might be a disadvantage when compared with other broad-spectrum antifungal agents with intravenous formulations (eg, voriconazole). Posaconazole is generally given at a dosage of 200 mg orally four times daily for about 7 days (loading dose) and then 400 mg twice daily (maintenance therapy). In healthy individuals, divided daily dose administration (every 12 or 6 hours) substantially increases posaconazole exposure.81 A daily dose of 800 mg given as 400 mg twice daily provided the greatest posaconazole exposure in severely ill patients,82 especially among patients who are able to eat. Doses ranging from 800 mg/day to 1600 mg/day are well tolerated.82 However, absorption of posaconazole is not increased at doses above 800 mg/day in healthy volunteers or severely ill patients.81,82 Posaconazole absorption is enhanced (2·6-fold to fourfold) by co-administration

Activity against other fungi Posaconazole has in-vitro activity against several phaeohyphomycetes, including Exophiala jeanselmei and Rhinocladiella species.56

In-vivo activity Activity against yeasts The in-vivo data regarding posaconazole’s activity against yeasts broadly accord with in-vitro data. For example, posaconazole has been used successfully against C albicans infection57 and C neoformans infection58 in animal models.

Activity against moulds

Activity against other fungi Posaconazole reduces the fungal burdens in tissues, leading to prolonged survival in mouse models of phaeohyphomycosis caused by Wangiella dermatitidis, Cladophialophora bantiana, or Ramichloridium obovoideum.67–69

In-vitro and in-vivo combination studies Currently, antifungal combination therapy is a proposed strategy against invasive fungal infections in highly immunocompromised patients, especially against invasive fungal infections produced by resistant moulds.4,12,45 Many investigators have studied combinations of antifungal drugs in the laboratory and in animal models.70 In mice infected with C albicans, survival curves showed that the combination of posaconazole http://infection.thelancet.com Vol 5 December 2005

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Characteristic

Posaconazole

Voriconazole

Current status Derivative Formulation Pharmacokinetics and tissue distribution Metabolism

Phase III trials Itraconazole Oral Bioavailability increases with food or nutritional supplements Hepatic. Inhibits hepatic CYP3A4 but no other isoenzymes

Pharmacokinetics Steady-state concentrations Median terminal elimination half-life Dose adjustment

Linear 7–10 days 15–35 hours Neither renal nor hepatic impairment have substantial influence on single-dose pharmacokinetics

Approved Fluconazole Oral and intravenous Bioavailability decreases to about 80% with fatty meals Hepatic, primarily via N-oxidation. Metabolised via several hepatic CYP isoenzymes, including CYP2C19, CYP2C9, and CYP3A4 Non-linear in adults; linear in children 5–6 days* 6–12 hours Necessary for patients with liver dysfunction

*Plasma concentrations close to steady-state are achieved within 1 day when a loading-dose regimen of 6 mg/kg intravenously or 400 mg orally every 12 hours for two doses is given.

Table 1: Comparison of several pharmacokinetic characteristics of posaconazole and voriconazole

with food or nutritional supplements.14,80 In healthy volunteers, posaconazole absorption, unlike itraconazole absorption,83 is not influenced by changes in gastric pH.14 Additional studies are needed to address posaconazole absorption among patients receiving antiulcer agents—eg, sucralfate. Key pharmacokinetic properties of posaconazole and of voriconazole, the first of the newer broad-spectrum triazoles approved in the USA and the EU for treatment of invasive fungal infections, are compared in table 1.10,11,14,16,79,84–86 After oral administration, posaconazole has a long terminal elimination half-life, which is dose dependent.14,79,87,88 Plasma concentrations appear to be similar in paediatric and adult patients with invasive fungal infections.89 However, experience with this triazole in children of different ages is limited to compassionate data and dosing continues to be experimental.90,91 Posaconazole pharmacokinetic

parameters need to be evaluated in critically ill patients with gastrointestinal tract dysfunction, such as those with ileus or graft-versus-host disease, as well as among haematology patients with severe mucositis or those who had a known malabsorption state. Posaconazole is widely distributed into the tissues, with a volume of distribution of 343–1341 L.14,79 Plasma concentrations of posaconazole (at doses 6 mg/kg per day) exceed 1 g/mL for the entire dosing interval.15 In a neutropenic rabbit model of invasive aspergillosis, the concentration of posaconazole in lung tissue exceeded 2 g/g at a dose of 6 mg/kg.60 Posaconazole is degraded mainly in the liver where it undergoes glucuronidation, and its metabolites are inactive. These degradation products are mainly excreted as parent compound in the faeces (70·6–77% of the radiolabelled administered dose) and to a lesser extent in the urine; renal excretion is a minor elimination pathway.79,84 Since posaconazole is metabolised by the liver, it might be an appropriate alternative to amphotericin B for patients with impaired renal function.92 Posaconazole is not removed by haemodialysis.92 Posaconazole is selective for fungal CYP450 enzyme systems and active against many of the CYP51A1 mutants.79 Posaconazole is highly protein bound.88 Although its penetration into cerebrospinal fluid is poor,35 case reports and case series suggest that posaconazole is active against central nervous system infections.68,93,94

Drug interactions The drug interactions of posaconazole and voriconazole are compared in table 2. Since posaconazole is a substrate for the CYP450 enzymes, interactions are expected with drugs that are metabolised via CYP3A4 (table 2).10,11,16,33,43,60,84,93,95–112 Posaconazole may have a similar drug interaction profile as itraconazole, and a

Characteristic

Posaconazole

Voriconazole

Potential or documented drug interactions

Posaconazole may have a similar drug interaction profile as itraconazole Thus far, interactions have been described with tacrolimus, ciclosporin, glipizide, zidovudine, lamivudine, ritonavir, and indinavir Contraindicated with cimetidine, rifabutin, and phenytoin

Interactions described with ciclosporin, tacrolimus, prednisolone, benzodiazepines, zolpidem, buspirone, protease inhibitors (other than indinavir), sulfonylurea, omeprazole, warfarin, calcium channel blockers, busulfan, and phenytoin. Contraindicated with HMG-CoA reductase inhibitors, carbamazepine, long-acting barbiturates, pimozide, efavirenz, astemizole, cisapride, ergot alkaloids, vinca-alkaloids, quinidine, sirolimus, terfenadine, astemizole, bepridil, sertindole, dofetilide, and halofantrine, rifampicin, and rifabutin

Probable* Yes* Yes* Yes* Yes* Probable* Probable* Mostly gastrointestinal complaints and headaches. No visual disturbances or rash. See Table 4 for more details

To be determined† Yes Yes Yes No To be determined† To be determined† Visual adverse events (ie, transient altered perception of light, photopsia, chromatopsia, or photophobia) (25–45%), liver function test abnormalities (10–20%), hallucinations or confusion (10%), and skin reactions (10%). Serious adverse effects requiring the discontinuation (2–13%)

Used for treatment of cryptococcal meningitis aspergillosis fusariosis scedosporiosis zygomycosis histoplasmosis coccidioidomycosis Common side-effects

*Based on clinical trials of posaconazole as salvage therapy. †Not recommended by some investigators11 HMG-CoA=3-hydroxy-3-methylglutaryl co-enzyme A

Table 2: Comparison of drug interactions, clinical uses, and adverse effects of posaconazole and voriconazole

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less wide interaction profile compared with voriconazole.33 The clearance of posaconazole increased twofold in the presence of rifabutin (an inducer of CYP3A4). Therefore, co-administration of these two drugs is not recommended.109 Likewise, concomitant use of posaconazole with phenytoin or cimetidine should be avoided because these drugs decrease posaconazole concentrations by approximately 50% and 40%, respectively.108,110 The dose of ritonavir and indinavir may need to be lowered when administered with posaconazole.33 Either a dose reduction or monitoring of ciclosporin and tacrolimus is also recommended.33 No dose adjustments are needed when posaconazole is coadministered with drugs such as glipizide, zidovudine, or lamivudine.33 Although no data with posaconazole are available, the known interaction between other CYP3A4 inhibitors and sirolimus is also a concern. Furthermore, several agents known to undergo metabolism via cytochrome P450 enzymes need to be evaluated.113

Clinical uses In the clinical setting, posaconazole has been used mainly as salvage therapy against a wide variety of refractory invasive fungal infections, including oropharyngeal and oesophageal candidiasis, invasive candidiasis, invasive aspergillosis, fusariosis, zygomycosis, pseudallescheriasis, endemic mycoses, mycetoma, and chromoblastomycosis (table 2, figure 2). No controlled clinical trials have been reported on the use of posaconazole for prophylaxis of invasive fungal infections. There are thus far a limited number of studies published in full evaluating the role of posaconazole in patients with invasive fungal infections. Preliminary data on efficacy studies have been presented only on abstract forms in international meetings, with considerable lack of information on concomitant use of other treatment modalities such as surgery, reduction or recovery in immunosuppression, and use of adjuvant therapies, such as intravenous immunoglobulin or colony stimulating growth factors. In a double-blinded, multicentre clinical trial for prophylaxis of invasive fungal infections, posaconazole was compared with fluconazole in patients who had undergone HSCT with graft-versus-host disease. 600 patients were enrolled, 301 received posaconazole (200 mg every 8 hours), and 299 received fluconazole (400 mg once a day) for up to 16 weeks. Posaconazole was significantly superior (p0·01) to fluconazole in preventing aspergillosis and comparable to fluconazole in preventing other breakthrough invasive fungal infections.17 Despite the cross-resistance between posaconazole and the older generation of azoles,13,25 some studies suggested that infections caused by fungi resistant to the old azoles can be successfully treated with posaconazole. These studies include reports of posaconazole therapy for oropharyngeal and oesophageal candidiasis http://infection.thelancet.com Vol 5 December 2005

Figure 2: Proven invasive pulmonary aspergillosis due to A fumigatus in a 51-year-old man with metastatic renal cell carcinoma who underwent HSCT Chest radiograph shows a cavitary lesion and small pneumothorax in the lower lobe of the right lung. This infection was refactory to antifungal combination therapy (liposomal amphotericin B plus caspofungin and itraconazole) and partial resection of the right lower lobe (A). Posaconazole monotherapy for 9 months resulted in a successful outcome with chest radiograph showing no significant infiltrate (B).

refractory to fluconazole or itraconazole,105 fluconazoleresistant intra-abdominal candida infection,114 itraconazole-resistant disseminated invasive aspergillosis,115 and azole-resistant disseminated zygomycosis.116 In a small series of patients with chronic granulomatous disease and invasive fungal infections, posaconazole as salvage therapy led to a complete response in most patients (seven of eight patients, 88%), including those with breakthrough infections during itraconazole prophylaxis.117 In a case series of patients treated with posaconazole as salvage therapy for invasive fungal infections unresponsive to voriconazole— including invasive aspergillosis, invasive candidiasis, and histoplasmosis—posaconazole was effective in four 779

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Fungal infection

Number of Predominant underlying condition Response patients treated (proportion of patients affected) rate (%)

Oropharyngeal and oesophageal candidiasis105 Central nervous system infections93 Cryptococcal meningitis93 Invasive aspergillosis104 Invasive aspergillosis due to Aspergillus fumigatus43 Invasive aspergillosis due to Aspergillus terreus43 Fusariosis103 Zygomycosis98 Histoplasmosis100 Coccidioidomycosis101 Pseudallescheriasis106

199 10* 29 107 8 9 20 23 7 15 7

HIV/AIDS (100%) Haematological malignancy (40%) HIV/AIDS (97%) Haematological malignancy (74%) Haematological malignancy (100%) Haematological malignancy (100%) Haematological malignancy (75%) Haematological malignancy (61%) HIV/AIDS (43%) Not reported Haematological malignancy (43%)

75 50 48 42 50 44 45 70 83 73 43

*Aspergillus fumigatus (three patients), Pseudallescheria boydii (two patients); Aspergillus spp, Coccidioides immitis, Histoplasma capsulatum, Ramichloridium mackenziei, and Apophysomyces elegans plus a Basidiomycetes species (in one patient each).

Table 3: Recent clinical trials of posaconazole as salvage therapy against difficult-to-treat fungal infections

of the eight patients treated.118 Therefore, posaconazole might be a therapeutic option for invasive fungal infections refractory to other triazoles, including voriconazole.117,118 The empiric use of posaconazole among voriconazole-pretreated patients with suspected invasive fungal infections needs to be studied. A multicentre, randomised, open-label, parallel-group study evaluating the efficacy of posaconazole in patients with refractory invasive fungal infections or febrile neutropenia that required empiric antifungal therapy showed complete or partial clinical responses in nine (43%) of 21 patients with invasive fungal infections and 45 (63%) of 71 patients with febrile neutropenia.82

Yeast infections Posaconazole (50–400 mg orally) was as effective as fluconazole (100 mg orally) in two randomised Adverse effect Gastrointestinal effects Nausea Vomiting Abdominal pain Diarrhoea Constipation, anorexia Flatulence Headache Fever Dry mouth Asthenia Dizziness, confusion Musculo-skeletal pain Hypotension Menstrual disorder Raised liver function tests Neutropenia Eye pain Rash Less common: asthenia,* fatigue, weight loss, somnolence, meningitis,* and peripheral neuropathy*

Patients affected (%) 18 5–11 4–9 5–9 4–12 5–7 4–6 5–17 12 9 4 6 7 6 6 1–5 7 4 3 1

*Observed after 6 months of therapy

Table 4: Adverse effects associated with posaconazole therapy

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Reference(s) 16,33,82,87,88 103,105,107, 119,137,138

33,82,87,103,104, 106,136,137 107 87,138 16,107,137* 87,107,138 107 107 33 33,103,105,137,138 103,105,137,138 107 93 33,87,137

comparative studies in HIV-infected patients with oropharyngeal candidiasis.97,119 In an open-label trial of posaconazole for oropharyngeal and oesophageal candidiasis refactory to fluconazole or itraconazole in 199 HIV-infected patients, posaconazole was effective in 75% of the patients.105 No studies, however, have specifically evaluated the role of posaconazole in patients with candidaemia. Posaconazole therapy was successful in 15 (48%) of the 31 patients with cryptococcosis who were intolerant of, or had infection refractory to, standard antifungal therapy; most of these patients (94%) had cryptococcal meningitis.93,102 A recent report described a patient with chronic granulomatous disease and Trichosporon inkin pulmonary infection that did not resolve with posaconazole therapy.120

Mould infections In a retrospective study, posaconazole monotherapy was compared with amphotericin B lipid formulations alone or in combination with itraconazole as salvage therapy for invasive aspergillosis in patients with haematological malignancies. Patients receiving posaconazole required less mechanical ventilation, and the efficacy of posaconazole was similar to that of combinations of amphotericin B lipid formulations and itraconazole, and superior to that of amphotericin B lipid formulation alone.95 In another retrospective study, we compared posaconazole monotherapy with our previous experience of patients with haematological malignancies treated with amphotericin B lipid formulation in combination with caspofungin as salvage therapy for invasive aspergillosis. The efficacy of posaconazole was equivalent to that of the combination of amphotericin B and caspofungin.121 Hachem and colleagues43 showed that posaconazole as salvage therapy against invasive aspergillosis refractory to amphotericin B was successful in nine (53%) of 17 patients, and response rates were similar in patients infected with A fumigatus or A terreus (table 3). The study showed that posaconazole would be an appropriate alternative for treating infection with A terreus, a pathogen resistant to the standard therapy with amphotericin B and against which there are very few additional therapeutic options.45 In an open-label, externally controlled multicentre study evaluating the efficacy and safety of posaconazole for the treatment of invasive aspergillosis in patients who were intolerant of, or had infections refractory to conventional antifungal therapy, the overall success rate was 42% in the 107 patients treated with posaconazole, compared with 26% in the 86 patients in the control group (p0·01).104 Posaconazole appears to be an appropriate therapeutic option in patients with fusariosis who are either intolerant of, or have infection refractory to standard antifungal therapy.107,122,123 Of 26 patients with fusariosis treated with posaconazole—as salvage http://infection.thelancet.com Vol 5 December 2005

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therapy in 20 patients and as non-salvage therapy in six patients—13 (50%) had a complete or partial response; the response rate was 45% (9/20) in the salvage therapy group and 66% (4/6) in the non-salvage therapy group.103 In general, most failures occurred in patients who had undergone HSCT, had disseminated fusariosis, or had persistent neutropenia.103 Of note, responses were seen in patients infected with F solani and in those infected with non-solani Fusarium species such as F proliferatum. Posaconazole also appears to be effective in the treatment of zygomycosis, an emerging, rapidly progressive, lethal infection.124–128 The mortality rate associated with zygomycosis may be as high as 100% in non-treated patients.126,129,130 The currently available azoles (itraconazole, fluconazole, and voriconazole) are not effective against zygomycetes; only amphotericin B has shown efficacy against zygomycosis.126,129,130 Several case reports showed that posaconazole is potentially useful in the treatment of patients with zygomycosis,116 including patients with zygomycosis occurring as a breakthrough infection during voriconazole therapy.127,131 In an openlabel, multicentre study that evaluated the clinical responses to posaconazole in patients with zygomycosis intolerant of, or with disease refractory to standard therapies, the response rate was 70% (16 of 23 patients).98 In this study, more than 90% of patients received previous antifungal treatment with amphotericin B alone or in combination with other antifungals, and approximately two-thirds of the patients underwent surgical interventions in addition to posaconazole therapy. In an international multicentre, open-label study evaluating the efficacy of posaconazole as salvage therapy for patients with S apiospermum infection who were intolerant of, or had infection refractory to other antifungal therapies, posaconazole produced successful outcomes in three (43%) of the seven patients.106 In addition, posaconazole monotherapy was effective in a patient with acute leukaemia and multiple S apiospermum brain abscesses who had experienced progressive infection despite neurosurgical drainage and treatment with itraconazole, amphotericin B, and ketoconazole.132 A successful outcome was also observed in a leukaemic patient with Acremonium strictum pulmonary infection treated with posaconazole after failure of amphotericin B.133 Salvage treatment with posaconazole was ineffective in one patient with chronic granulomatous disease and hyalohyphomycoses caused by Paecilomyces variotti.117

Endemic mycoses Endemic mycoses remain an important cause of morbidity and mortality in immunocompromised patients.134,135 In an international multicentre, open-label trial of posaconazole in seven patients with histoplasmosis who were intolerant of, or had infection refractory to amphotericin B, fluconazole, itraconazole, or voriconazole, successful outcomes were observed in http://infection.thelancet.com Vol 5 December 2005

six cases (83%). This result highlights the potential role of posaconazole for salvage treatment of histoplasmosis.100 In a prospective, multicentre, open-label study, 11 (69%) of 16 patients with coccidioidomycosis who were intolerant of, or had infection refractory to standard antifungal therapy had a successful outcome with posaconazole, suggesting that posaconazole may also have an important therapeutic role in the treatment of this endemic mycosis.101,102 Six patients of this open-label study with disseminated coccidioidomycosis caused by Coccidioides posadasii were further analysed. Three patients were immunocompromised. Five of the six patients had received previous antifungal treatment with azoles (fluconazole, itraconazole, or both), and/or amphotericin B without clinical response. Overall, successful outcomes at the end of posaconazole salvage therapy were observed in five of the six patients.136

Other fungal infections In a multinational study from South America, posaconazole treatment was successful in 11 (73%) of 15 patients with chronic, difficult-to-treat fungal infections—eg, mycetoma (caused by either Madurella species or Scedosporium species) and chromoblastomycosis (caused by Fonsecaea pedrosoi).99 Salvage treatment with posaconazole was safe and effective in treating two patients with chronic granulomatous disease and phaeohyphomycosis caused by Phaeoacremonium parasiticum refractory to amphotericin B lipid complex, liposomal amphotericin B, caspofungin, and voriconazole.117 Posaconazole therapy resulted in a successful outcome of a renal transplant recipient with cerebral phaeohyphomycosis caused by Ramichloridium mackenziei refractory to liposomal amphotericin B, itraconazole, and flucytosine.94 Posaconazole was also efficacious as salvage therapy in a patient with a 9-year history of cutaneous phaeohyphomycosis caused by Exophiala spinifera refractory to itraconazole, flucytosine, amphotericin B, and terbinafine.107

Adverse events and toxic effects Adverse events are reported in up to 43% of patients treated with posaconazole and are most common during the first 6 months of therapy.136 The most common adverse events seem to be gastrointestinal complaints and headaches (table 4). In recent series of patients with invasive fungal infections, posaconazole therapy was well tolerated and not associated with substantial adverse events in treatment courses lasting up to 1 year.98,106 Drug safety and tolerability were comparable for both posaconazole or fluconazole in a doubleblinded, multicentre clinical trial on the use of these antifungals for prevention of invasive fungal infections.17 Potential interaction could occur with concomitant use of posaconazole and cisapride, astemizole, terfenadine, quinidine, pimozide, bepridil, sertindole, dofetilide, and 781

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Search strategy and selection criteria Information for this review was identified by searches of Medline and of the extensive files of the authors. Search terms used included “posaconazole” and the drug’s original code number, “SCH 56592”. We reviewed all articles and conference abstracts published in 2000 or later.

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halofantrine based on QT interval prolongation with torsade de pointe reported for other azoles.112 However, based on recent data, posaconazole seems to have no effect on the QTc interval or cause negative cardiac inotropic effects in healthy volunteers or ill patients.93,139 Posaconazole therapy is also safe and well tolerated in paediatric and elderly patients.89,96,117 Treatment-related discontinuations are uncommon.82,117,137 Thus, posaconazole is less toxic than amphotericin B, which is still the standard therapy against many invasive fungal infections. To date, no idiosyncratic toxic effects have been described for posaconazole.

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Posaconazole is a promising broad-spectrum triazole effective in vitro and in vivo against several fungi that are highly resistant to standard antifungals. Mounting evidence highlights the role of posaconazole as salvage therapy against difficult-to-treat fungal infections such as invasive aspergillosis, fusariosis, and zygomycosis. The use of posaconazole as a prophylactic agent in patients at high risk for developing invasive fungal infections and as primary therapy for these infections needs to be explored in comparative trials to better define the role of this new triazole. Finally, posaconazole appears to be safe and well tolerated, even when it is given in long-term courses. Conflicts of interest HAT has no conflicts of interest to declare. RYH receives grant support from Schering-Plough. RFC received grant support from Valiant Pharmaceuticals and is a member of the Speakers’ Bureau for Wyeth Pharmaceuticals, Elan, and Cubist. DPK received grant support and honoraria from Pfizer, Merck, Fujisawa Healthcare, and Enzon and honoraria from Schering-Plough. IIR receives grant support from, and is a member of the Speakers’ Bureau for Merck, Pfizer, and Fujisawa Healthcare, and has received grant support from Schering-Plough, Pharmacia, Cook, Aventis, and Vicuron. His is a co-inventor of medical device technologies licensed to Cook through The University of Texas M D Anderson Cancer Center. DPK and RYH have attended an advisory board meeting on posaconazole in 2005 and received a one-time honorarium. Acknowledgments We thank Stephanie Deming for editorial assistance. No funding sources were involved in the writing of this review or decision to submit for publication. References 1 Marr KA, Patterson T, Denning D. Aspergillosis. Pathogenesis, clinical manifestations, and therapy. Infect Dis Clin North Am 2002; 16: 875–94. 2 Patterson TF, Kirkpatrick WR, White M, et al. Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. Medicine (Baltimore) 2000; 79: 250–60.

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Graybill JR, Hernandez S, Bocanegra R, Najvar LK. Antifungal therapy of murine Aspergillus terreus infection. Antimicrob Agents Chemother 2004; 48: 3715–19. Steinbach WJ, Benjamin DK Jr, Kontoyiannis DP, et al. Infections due to Aspergillus terreus: a multicenter retrospective analysis of 83 cases. Clin Infect Dis 2004; 39: 192–98. Walsh TJ, Petraitis V, Petraitiene R, et al. Experimental pulmonary aspergillosis due to Aspergillus terreus: pathogenesis and treatment of an emerging fungal pathogen resistant to amphotericin B. J Infect Dis 2003; 188: 305–19. Paphitou NI, Ostrosky-Zeichner L, Paetznick VL, Rodriguez JR, Chen E, Rex JH. In vitro activities of investigational triazoles against Fusarium species: effects of inoculum size and incubation time on broth microdilution susceptibility test results. Antimicrob Agents Chemother 2002; 46: 3298–300. Torres HA, Raad II, Kontoyiannis DP. Infections caused by Fusarium species. J Chemother 2003; 15 (suppl 2): 28–35. Sun QN, Fothergill AW, McCarthy DI, Rinaldi MG, Graybill JR. In vitro activities of posaconazole, itraconazole, voriconazole, amphotericin B, and fluconazole against 37 clinical isolates of zygomycetes. Antimicrob Agents Chemother 2002; 46: 1581–82. Gonzalez G, Tijerina R, Najvar L, et al. Therapeutic efficacy of posaconazole in a murine Pseudallescheria boydii infection. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; Chicago, IL, USA; Dec 6–9, 2001. Gonzalez GM, Tijerina R, Najvar LK, et al. Activity of posaconazole against Pseudallescheria boydii: in vitro and in vivo assays. Antimicrob Agents Chemother 2003; 47: 1436–38. Safdar A. Progressive cutaneous hyalohyphomycosis due to Paecilomyces lilacinus: rapid response to treatment with caspofungin and itraconazole. Clin Infect Dis 2002; 34: 1415–17. Pfaller MA, Messer SA, Hollis RJ, Jones RN. Antifungal activities of posaconazole, ravuconazole, and voriconazole compared to those of itraconazole and amphotericin B against 239 clinical isolates of Aspergillus spp. and other filamentous fungi: report from SENTRY Antimicrobial Surveillance Program, 2000. Antimicrob Agents Chemother 2002; 46: 1032–37. Gonzalez GM, Fothergill AW, Sutton DA, Rinaldi MG, Loebenberg D. In vitro activities of new and established triazoles against opportunistic filamentous and dimorphic fungi. Med Mycol 2005; 43: 281–84. Gonzalez GM, Tijerina R, Najvar LK, et al. In vitro and in vivo activities of posaconazole against Coccidioides immitis. Antimicrob Agents Chemother 2002; 46: 1352–56. Nucci M, Akiti T, Barreiros G, et al. Nosocomial fungemia due to Exophiala jeanselmei var. jeanselmei and a Rhinocladiella species: newly described causes of bloodstream infection. J Clin Microbiol 2001; 39: 514–18. Cacciapuoti A, Gurnani M, Halpern J, Norris C, Patel R, Loebenberg D. Interaction between posaconazole and amphotericin B in concomitant treatment against Candida albicans in vivo. Antimicrob Agents Chemother 2005; 49: 638–42. Barchiesi F, Spreghini E, Schimizzi AM, et al. Posaconazole and amphotericin B combination therapy against Cryptococcus neoformans infection. Antimicrob Agents Chemother 2004; 48: 3312–16. Najvar LK, Cacciapuoti A, Hernandez S, et al. Activity of posaconazole combined with amphotericin B against Aspergillus flavus infection in mice: comparative studies in two laboratories. Antimicrob Agents Chemother 2004; 48: 758–64. Groll AH, Mickiene D, Petraitiene R, et al. Pharmacokinetics and pharmacodynamics of posaconazole (SCH 56592) in a neutropenic animal model of invasive pulmonary aspergillosis. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; Toronto, Canada; Sept 7–12, 2000. Lozano-Chiu M, Arikan S, Paetznick VL, Anaissie EJ, Loebenberg D, Rex JH. Treatment of murine fusariosis with SCH 56592. Antimicrob Agents Chemother 1999; 43: 589–91. Dannaoui E, Meis JF, Loebenberg D, Verweij PE. Activity of posaconazole in treatment of experimental disseminated zygomycosis. Antimicrob Agents Chemother 2003; 47: 3647–50. Sun QN, Najvar LK, Bocanegra R, Loebenberg D, Graybill JR. In vivo activity of posaconazole against Mucor spp. in an immunosuppressed-mouse model. Antimicrob Agents Chemother 2002; 46: 2310–12.

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Simitsopoulou M, Gil-Lamaignere C, Avramidis N, et al. Antifungal activities of posaconazole and granulocyte-macrophage colony-stimulating factor ex vivo and in mice with disseminated infection due to Scedosporium prolificans. Antimicrob Agents Chemother 2004; 48: 3801–05. Connolly P, Wheat LJ, Schnizlein-Bick C, et al. Comparison of a new triazole, posaconazole, with itraconazole and amphotericin B for treatment of histoplasmosis following pulmonary challenge in immunocompromised mice. Antimicrob Agents Chemother 2000; 44: 2604–08. Sugar AM, Liu XP. In vitro and in vivo activities of SCH 56592 against Blastomyces dermatitidis. Antimicrob Agents Chemother 1996; 40: 1314–16. Graybill JR, Najvar LK, Johnson E, Bocanegra R, Loebenberg D. Posaconazole therapy of disseminated phaeohyphomycosis in a murine model. Antimicrob Agents Chemother 2004; 48: 2288–91. Al-Abdely HM, Najvar L, Bocanegra R, et al. SCH 56592, amphotericin B, or itraconazole therapy of experimental murine cerebral phaeohyphomycosis due to Ramichloridium obovoideum (“Ramichloridium mackenziei”). Antimicrob Agents Chemother 2000; 44: 1159–62. Al-Abdely HM, Najvar LK, Bocanegra R, Graybill JR. Antifungal therapy of experimental cerebral phaeohyphomycosis due to Cladophialophora bantiana. Antimicrob Agents Chemother 2005; 49: 1701–07. Kontoyiannis DP, Lewis RE. Toward more effective antifungal therapy: the prospects of combination therapy. Br J Haematol 2004; 126: 165–75. Perea S, Gonzalez G, Fothergill AW, Sutton DA, Rinaldi MG. In vitro activities of terbinafine in combination with fluconazole, itraconazole, voriconazole, and posaconazole against clinical isolates of Candida glabrata with decreased susceptibility to azoles. J Clin Microbiol 2002; 40: 1831–33. Oliveira ER, Fothergill AW, Kirkpatrick WR, Coco BJ, Patterson TF, Redding SW. In vitro interaction of posaconazole and caspofungin against clinical isolates of Candida glabrata. Antimicrob Agents Chemother 2005; 49: 3544–45. Barchiesi F, Schimizzi AM, Najvar LK, et al. Interactions of posaconazole and flucytosine against Cryptococcus neoformans. Antimicrob Agents Chemother 2001; 45: 1355–59. Kontoyiannis DP, Lewis RE, Sagar N, May G, Prince RA, Rolston KV. Itraconazole-amphotericin B antagonism in Aspergillus fumigatus: an E-test-based strategy. Antimicrob Agents Chemother 2000; 44: 2915–18. Lewis RE, Prince RA, Chi J, Kontoyiannis DP. Itraconazole preexposure attenuates the efficacy of subsequent amphotericin B therapy in a murine model of acute invasive pulmonary aspergillosis. Antimicrob Agents Chemother 2002; 46: 3208–14. Manavathu EK, Alangaden GJ, Chandrasekar PH. Differential activity of triazoles in two-drug combinations with the echinocandin caspofungin against Aspergillus fumigatus. J Antimicrob Chemother 2003; 51: 1423–25. Patera AC, Menzel F, Jackson C, et al. Effect of granulocyte colonystimulating factor combination therapy on efficacy of posaconazole (SCH56592) in an inhalation model of murine pulmonary aspergillosis. Antimicrob Agents Chemother 2004; 48: 3154–58. Graybill JR, Bocanegra R, Najvar LK, Loebenberg D, Luther MF. Granulocyte colony-stimulating factor and azole antifungal therapy in murine aspergillosis: role of immune suppression. Antimicrob Agents Chemother 1998; 42: 2467–73. Herbrecht R. Posaconazole: a potent, extended-spectrum triazole anti-fungal for the treatment of serious fungal infections. Int J Clin Pract 2004; 58: 612–24. Courtney R, Wexler D, Radwanski E, Lim J, Laughlin M. Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults. Br J Clin Pharmacol 2004; 57: 218–22. Ezzet F, Wexler D, Courtney R, Krishna G, Lim J, Laughlin M. Oral bioavailability of posaconazole in fasted healthy subjects: comparison between three regimens and basis for clinical dosage recommendations. Clin Pharmacokinet 2005; 44: 211–20. Ullmann AJ, Cornely OA, Burchardt A, et al. Safety and efficacy of posaconazole in a pharmacokinetic study in patients with febrile neutropenia or refractory invasive fungal infections. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; Chicago, IL, USA; Sept 14–17, 2003.

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Lim SG, Sawyerr AM, Hudson M, Sercombe J, Pounder RE. Short report: the absorption of fluconazole and itraconazole under conditions of low intragastric acidity. Aliment Pharmacol Ther 1993; 7: 317–21. 84 Krieter P, Flannery B, Musick T, Gohdes M, Martinho M, Courtney R. Disposition of posaconazole following single-dose oral administration in healthy subjects. Antimicrob Agents Chemother 2004; 48: 3543–51. 85 Groll AH, Gea-Banacloche JC, Glasmacher A, Just-Nuebling G, Maschmeyer G, Walsh TJ. Clinical pharmacology of antifungal compounds. Infect Dis Clin North Am 2003; 17: 159–91. 86 Courtney RD, Laughlin M, Gontz H, et al. Single-dose pharmacokinetics of posaconazole in subjects with various degrees of chronic liver disease. AAPS PharmSci 2000; 2: A1852. 87 Courtney R, Pai S, Laughlin M, Lim J, Batra V. Pharmacokinetics, safety, and tolerability of oral posaconazole administered in single and multiple doses in healthy adults. Antimicrob Agents Chemother 2003; 47: 2788–95. 88 Stevens DA. New azoles. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; Toronto, Canada; Sept 7–12, 2000. 89 Krishna G, Wexler D, Courtney R, et al. Posaconazole plasma concentrations in pediatric patients with invasive fungal infections. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; Washington, DC, USA; Oct 30–Nov 2, 2004. 90 Zaoutis TE, Benjamin DK, Steinbach WJ. Antifungal treatment in pediatric patients. Drug Resist Updat 2005; 8: 235–45. 91 Antachopoulos C, Walsh TJ. New agents for invasive mycoses in children. Curr Opin Pediatr 2005; 17: 78–87. 92 Courtney R, Sansone A, Smith W, et al. Posaconazole pharmacokinetics, safety, and tolerability in subjects with varying degrees of chronic renal disease. J Clin Pharmacol 2005; 45: 185–92. 93 Pitisuttithum P, Negroni R, Graybill J, et al. Activity of posaconazole in the treatment of central nervous system fungal infections. J Antimicrob Chemother. 2005; 56: 745–55. 94 Al-Abdely HM, Alkhunaizi AM, Al-Tawfiq JA, Hassounah M, Rinaldi MG, Sutton DA. Successful therapy of cerebral phaeohyphomycosis due to Ramichloridium mackenziei with the new triazole posaconazole. Med Mycol 2005; 43: 91–95. 95 Raad II, Boktour MR, Hanna HA, Kontoyiannis DP, Hachem RY. Posaconazole compared to amphotericin B lipid formulations alone or in combination with itraconazole as salvage therapy for invasive aspergillosis in patients with hematologic malignancy. 42nd Meeting of the Infectious Diseases Society of America; Boston, MA, USA; Sept 30–Oct 3, 2004. 96 Perfect JR, Graham DR, Corcoran G, Pedicone L, Raad II. Posaconazole safety and efficacy in elderly patients with invasive fungal infections. 42nd Meeting of the Infectious Diseases Society of America; Boston, MA, USA; Sept 30–Oct 3, 2004. 97 Nieto L, Northland R, Pittisuttithum P, et al. Posaconazole equivalent to fluconazole in the treatment of oropharyngeal candidiasis. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; Toronto, Canada; Sept 7–12, 2000. 98 Greenberg RN, Anstead G, Herbrecht R, et al. Posaconazole experience in the treatment of zygomycosis. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; Chicago, IL, USA; Sept 14–17, 2003. 99 Negroni R, Tobon A, Bustamante A, Yasuda MAS, Hare R, Patino H. Posaconazole treatment of mycetoma and chromoblastomycosis. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; Chicago, IL, USA; Sept 14–17, 2003. 100 Restrepo A, Clark B, Graham D, et al. Treatment of histoplasmosis with posaconazole. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; Chicago, IL, USA; Sept 14–17, 2003. 101 Stevens DA, Rendon A, Gaona V, et al. Posaconazole therapy for chronic refractory coccidioidomycosis. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; Washington DC, USA; Oct 30–Nov 2, 2004. 102 Raad I, Chapman S, Bradsher R, et al. Posaconazole salvage therapy for invasive fungal infections. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; Washington, DC, USA; Oct 30–Nov 2, 2004.

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