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
CH2 O O
Cl CH2 O
CH3 N CH CH2 CH3 N
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
Figure 1: A comparison of the structures of itraconazole and posaconazole
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
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
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
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
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
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
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
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
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.
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.
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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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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