Although posaconazole is similar to voriconazole in its activity against
Aspergillus species, use of posaconazole is preserved for salvage therapy in patients who are refractory or intolerant to voriconazole [
36,
44,
45]. In case of voriconazole treatment failure, a switch of antifungal drug class is generally recommended [
44]. Nevertheless, compared with amphotericin B, itraconazole, voriconazole, or echinocandins, posaconazole is associated with higher response rates [
46]. The efficacy and safety of the posaconazole oral suspension, which was the only available formulation at that moment, as monotherapy was investigated in patients with IA who were refractory or intolerant to conventional antifungal therapy and was found both save and effective (40–70 % of patients) as salvage treatment for patients which had previously been treated with another triazole [
44,
46]. Given these results and its spectrum of activity, posaconazole may be an effective primary agent for the treatment of IA as well [
45]. However, the place of posaconazole as first-line treatment should be tested in a randomized, controlled trial comparing the intravenous and tablet formulations against the current standard therapy (voriconazole with TDM), before recommendation as initial therapy [
45,
46]. This study is currently ongoing [
47].
Azole resistance is an emerging problem for
Aspergillus species [
3•,
4]. The majority of reports concern
Aspergillus fumigatus, although azole resistance has been reported sporadically in other species as well [
3•]. Azole-resistant
A. fumigatus isolates have been reported in several countries around the world, and clinical failures have been attributed to microbiological resistance [
4]. A wide range of mutations in
A. fumigatus have been described conferring azole resistance commonly involving modifications in the CYP51 gene [
3•,
4,
48], the target of antifungal azoles. Acquired resistance may be developed in patients with chronic cavitating aspergillosis treated after long-term azole exposure, when a susceptible isolate obtains the ability to resist the activity of the antifungal agent [
3•,
36,
49]. In addition, increasing agricultural use of azole compounds over many years is held responsible for the environmental contamination (acquired resistance), leading to primary resistant isolates in azole-naive patients [
3•,
36]. As long-term therapy of aspergillosis is required in most individuals, and the azoles are the only clinically available agents that can be administered orally, the development of azole resistance in
A. fumigatus is worrisome [
4]. If a role for the azoles remains in the management of azole-resistant aspergillosis, optimizing drug exposure is critical to increase the probability of treatment success [
3•]. In this context, measuring MIC values to the azole compounds is crucial to increase the clinical response [
3•]. Seyedmousavi et al. proposed break points of 0.25 to 0.5 mg/l for posaconazole, which are higher than the EUCAST break points for
Aspergillus spp. [
3•,
31,
50]. Reduced susceptibility to azoles has significant impact on the ability to achieve the pharmacodynamic target, and sometimes, targets can only be achieved at the cost of increased toxicity. Posaconazole exposure (estimated by the AUC) correlates linearly with the dose; thus, a higher dose of the azole is required to achieve similar efficacy when azole-resistant strains are present (Table
2) [
3•]. With the conventional suspension and dosing of 200 mg four times a day, sufficient exposures may be difficult to attain. However, such levels may be obtained with the new posaconazole delayed-release tablets (Table
2). A case report of a patient with a cerebral IA which was successfully treated with the tablet formulation has been recently published [
51]. The patient has been treated for a brain abscess with voriconazole for 1 year, but MRI imaging showed a new frontal epidural fluid collection. It was assumed that susceptibility to voriconazole was reduced, and therefore, the patient was switched to posaconazole tablets, 300 mg twice daily. The trough level after 2 weeks of treatment was 5.3 mg/l. The dose was reduced to 300 mg once daily, leading to a trough level of 2.0 mg/l [
51]. As cultures were negative, they were unable to determine MICs. The patient responded well to the posaconazole, and a repeated MRI of the brain 4 months after posaconazole initiation showed a significant improvement consistent with the resolving infection [
51].
Clinical effectiveness of posaconazole salvage treatment has been shown to be dependent on posaconazole plasma levels in an externally controlled study [
13]. Higher plasma concentrations of posaconazole were associated with greater response rates. For patients with average plasma concentrations of >1.25 mg/l, clinical effectiveness was increased to 75 % compared to 24–53 % for patients with lower plasma levels [
13]. Importantly, these levels were only reached in 24 % of the patients in this study with the oral suspension [
13]. Moreover, based on the AUC/MIC targets indicated in Table
2, target trough levels of 1.8 mg/l are suggested, which can be reached with the new formulations in most but not all patients, and therefore, TDM is warranted to assure efficacy (Fig.
1) [
30 •]. Unlike the prophylaxis setting [
52], no early target (48 h) levels are currently available to assure adequate exposure early in treatment.