Comparing posaconazole and itraconazole for antifungal prophylaxis in critically ill lung transplant recipients: Efficacy and plasma concentrations

Posaconazole and itraconazole are commonly used for systemic antifungal prophylaxis after lung transplantation. The aim of this study on critically ill lung transplant recipients was to assess the rate of adequate plasma concentrations and the frequency of fungal‐induced transitions from antifungal prophylaxis to therapy after the administration of either posaconazole or itraconazole for systemic prophylaxis.


| INTRODUC TI ON
Fungal infections remain a challenge in immunocompromised patients, such as lung transplant recipients. Approximately 8%-19% of the lung transplant recipients develop a fungal infection, and the mortality rate is up to 60%. [1][2][3][4] Lung transplant recipients receive immunosuppressants to reduce the risk of an allograft rejection. However, immunosuppression increases the risk of a fungal infection, with Aspergillus spp. and Candida spp. being the most frequently observed pathogens. 1 Consequently, lung transplant recipients need an effective antifungal prophylaxis. The Infectious Diseases Society of America recommended the use of triazoles or inhalative amphotericin B as prophylaxis for 3 to 4 months after lung transplantation. 5  recipients. 6 The antifungal activity of posaconazole and itraconazole includes yeasts (eg, Candida spp.) and Aspergillus spp. 1 Critically ill patients are, in general, due to pharmacokinetic alterations (eg, an increased volume of distribution), at risk of suboptimal drug exposure with standard dosing. 7 Previous studies showed indeed a high variability and subtherapeutic concentrations of itraconazole and posaconazole in this population. 8,9 In addition, there have been several drug-drug interactions reported in previous studies for azoles. For example, proton pump inhibitors (PPI), metoclopramide, and rifampicin lower drug concentrations, whereas macrolide antibiotics, amiodaron, ciprofloxacin, and some antiviral drugs raise the azole plasma concentration. 3,10,11 However, critically ill lung transplant recipients depend on an effective prophylaxis, as they have a high risk to develop a fungal infection, because the allograft is exposed to the environment and high steroid doses are administered; catheters further increase the risk of a fungal infection. 1,12,13 As a result, therapeutic drug monitoring (TDM) is recommended for both drugs. 8,[14][15][16] The British Society of Mycology recommended a target concentration in steady state of ≥500 µg/L for itraconazole and ≥700 µg/L for posaconazole as prophylaxis. Lower azole plasma levels were associated with a higher mortality. 2,15,17 In our intensive care unit (ICU) at the LMU hospital in Munich, either itraconazole or posaconazole is administered at the discretion of the responsible physician as antifungal prophylaxis in the postoperative period of lung transplant recipients. TDM is regularly performed.
Previous studies investigated antifungal prophylaxis mainly in patients with hematologic malignancies, neutropenic patients, or non-critically ill lung transplant recipients in general wards. 2,3,[18][19][20] This retrospective study in critically ill lung transplant patients aimed to compare the rate of adequate plasma concentrations after posaconazole or itraconazole administration as systemic prophylaxis in critically ill lung transplant recipients and the frequency of fungalinduced transitions from prophylaxis to targeted therapy (FITPTs).

| Laboratory measurements and data collection
All clinical-chemical parameters were extracted from electronic patient records. The azole plasma concentrations were measured with an isotope-dilution liquid chromatography tandem mass spectrometry method using a commercially available IVD kit (Chromsystems, Gräfelfing, Germany). All measured values of antimycotic plasma concentrations, corresponding doses, and additional laboratory measurements including albumin, aspartate-aminotransferase, alanine-aminotransferase, bilirubin, creatinine, the glomerular filtration rate (GFR) calculated according to the Chronic Kidney Disease Epidemiology Collaboration, C-reactive protein (CRP), and Interleukin 6 (IL-6) were collected. 21 The Simplified Acute Physiology Score II was assessed at the first day of the azole use. 22

| Fungal-induced transition from prophylaxis to therapy
Positive fungal cultures (Candida spp. or Aspergillus spp.) or

| Covariates
The existing literature was screened for potential influencing comedications. We identified PPI, immunosuppressants (tacrolimus and ciclosporin), cytochrome P450 inhibitors (ciprofloxacin, isoniazid, clarithromycin, and erythromycin), cytochrome P450 inductors (glucocorticoids, rifampicin, carbamazepine, and barbiturate), norepinephrine, and amiodaron as potential influencing co-medication for itraconazole. For posaconazole, we included PPI, norepinephrine, H2 antagonists (ranitidine and cimetidine), and phase-2 enzyme inhibitors and inductors including ciclosporin, erythromycin, carbamazepine, phenytoin, and rifampicin. All co-medications that might influence the antimycotic plasma concentrations were collected from our hospital's electronic patient records. The norepinephrine dose was evaluated at each timepoint when the patients received the azole. 3,11,20,26,27 The type of food intake was divided in four categories: no food (1), tube feeding (2), normal food (3), and tube feeding + normal food (4). Protein drinks were included in the tube feeding group.

| Definition of target attainment
Target attainment was defined as recommended by the British
Seven patients received itraconazole and posaconazole one after the other during the observed period and were therefore included twice in the analysis. Table 1 shows the patient characteristics. The most frequent underlying disease leading to lung transplantation was pulmonary fibrosis (45%), followed by COPD (22%) and cystic fibrosis (18%). Patients received PPIs 90% of the days observed and predominantly received tube feeding (42% of days observed), followed by normal food intake (20%) or normal food intake supported by tube feeding (27%). The median daily dose was 800, 300, and 350 mg for posaconazole suspensions, posaconazole tablets, and itraconazole, respectively. Dose adjustments were made by the responsible physician in 0, 11, and 5 patients in the posaconazole tablet group, the posaconazole suspension group, and the itraconazole group, respectively.

| Plasma concentrations of posaconazole and itraconazole
Overall, 60% of the measured posaconazole plasma concentrations were subtherapeutic, and the median concentration was 496 µg/L.   showed at least one sample below the target attainment. There was no significant correlation between the administered median daily amount of the azole and the plasma concentration (itraconazole P-value: .26; posaconazole P-value: .62). In Figures 1 and 2, the measured plasma concentrations are displayed related to the median daily dose.

| Covariates
All patients were immunosuppressed with a calcineurin-inhibitor

| Fungal-induced transition from prophylaxis to therapy
In total, 19 patients (26%) showed an FITPT in our study with a me-

| D ISCUSS I ON
To the best of our knowledge, this is the first study investigating The initiation of an antifungal therapy in the itraconazole group seemed to be independent of the achieved plasma concentrations.
Even attaining the target concentrations (>500 ng/L) provided by the British Society of Mycology did not appear to be protective against an FITPT. 15 It has been previously reported that the defined target might be too low. 15 The number of FITPTs in our population (26%) appears to be high but has been similarly described in previous studies. 13  recipients, the observed ratio seems to be high. 33 Our findings could be related to the early observation period of the study (patients were excluded from the study when transferred to a general ward).
Infections by Candida spp. regularly occur within the first month after transplantation, whereas infections by Aspergillus spp. tend to occur after 3-12 months. 34 Therefore, the extent to which itraconazole and posaconazole protect against infections by Aspergillus spp.
can only be interpreted to a limited extent. However, posaconazole seems to be more effective in prophylaxis against Candida spp. infections, which usually dominate in the postoperative period. Seven FITPTs occurred before the steady state was reached in the itraconazole group. Therefore, it can be concluded that especially in the first period of prophylaxis, administration of itraconazole tablets does not provide adequate protection against fungal detection.
Other routes of administration (inhalative, IV) may offer advantages by reaching adequate exposure more quickly. could lead to a higher rate of target attainment and a higher efficacy in prophylaxis using itraconazole.
Our study has several limitations. It cannot be assumed that all However, although the same definition was applied to patients receiving itraconazole and posaconazole, a bias (ie, clinicians were less "comfortable" when cultures were positive in patients they knew were on itraconazole) cannot be completely excluded because of the retrospective, unblinded study design.
The structured evaluation of radiologic, bronchoscopic, and histologic results would have been desirable for our study.
Unfortunately, no uniform diagnostics were carried out for patients with positive microbiological results making a meaningful evaluation not feasible in this study.
Finally, due to the retrospective study design, a bias due to unobserved confounders cannot be excluded. Therefore, future prospective studies are needed to confirm our results.

E TH I C S A PPROVA L A N D CO N S E NT TO PA RTI CI PATE
The local institutional review board approved the study (registration number 20-168).

CO N FLI C T O F I NTE R E S T
All authors declare that they have no competing interests.