Effectiveness of combined proton pump inhibitors and posaconazole prophylaxis against invasive fungal infections in patients with hematologic malignancies: A retrospective study

Effectiveness of combined proton pump inhibitors and posaconazole prophylaxis against invasive fungal infections in patients with hematologic malignancies: A retrospective study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effectiveness of combined proton pump inhibitors and posaconazole prophylaxis against invasive fungal infections in patients with hematologic malignancies: A retrospective study Ruochen Qu, Yan Liu, Yan Zhao, Ziyi Wang, Shizhao Yuan, Jing Yu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4326408/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Dec, 2024 Read the published version in International Journal of Clinical Pharmacy → Version 1 posted 6 You are reading this latest preprint version Abstract Background : Posaconazole (POS) is widely recommended for the prophylaxis and treatment of invasive fungal infections (IFIs) in immunocompromised patients, particularly those with prolonged neutropenia and a high risk of infection. The oral suspension form of POS, although commonly used, has its concentration influenced by various factors, impacting its effectiveness and safety. Aim : This retrospective study aimed to investigate the effects of PPIs on POS concentrations and C/D to explore their impact on prophylactic outcomes and examine other potential factors that influence POS concentration. Method : This retrospective study involved patients who received POS for IFI prophylaxis or treatment. The study specifically focused on the effects of PPIs on POS plasma trough concentrations (C min ) and concentration-to-dose (C/D) ratios. Results : The analysis included 283 POS trough concentrations from 86 patients. The incidence of probable and proven IFIs was 6.4% (5/78). The use of PPI reduced POS C min levels but did not significantly affect the effectiveness of prophylaxis. Esomeprazole and rabeprazole were found to lower POS C min . The occurrence of hepatotoxicity was associated with the co-administration of drugs known to cause liver damage, indicating that POS was not the sole factor in these cases. Conclusion : Co-administration of esomeprazole or rabeprazole with posaconazole reduces its plasma concentrations but does not compromise prophylactic effectiveness against invasive fungal infections. This observation underscores the critical importance of vigilant management and comprehensive follow-up to optimize therapeutic outcomes in this high-risk patient population. Figures Figure 1 Figure 2 Figure 3 Impact statements This study highlights the significant impact of proton pump inhibitors (PPIs) such as esomeprazole and rabeprazole on the plasma concentrations of posaconazole, a critical antifungal drug. The findings underscore the importance of careful drug management and follow-up in patients undergoing posaconazole treatment, especially those who also receive PPIs. The research provides evidence-based insights that can guide future prophylactic strategies in immunocompromised patients, highlighting the need for regular therapeutic drug monitoring to ensure optimal dosing and to avoid potential drug interactions that could compromise treatment effectiveness. Introduction Invasive fungal infections (IFIs) are infectious diseases in which fungi infiltrate the body, increasing in tissues, organs, or the bloodstream. They induce inflammation, causing tissue damage, and are associated with elevated rates of morbidity and mortality. Aspergillus spp . and Candida spp . are the main contributors to invasive infections, followed by Mucor spp . and Cryptococcus spp .[1, 2]. Immunocompromised individuals, especially those diagnosed with hematologic malignancies, are highly prone to IFIs [3, 4]. Fungal invasiveness poses a significant public health threat due to the difficulty of timely identification. Some fungal species have developed resistance to antifungals in recent years [5, 6], leading to increased healthcare costs. Antifungal prophylaxis reduces IFIs and hospital mortality in patients with acute leukemia undergoing induction chemotherapy [7]. Therefore, antifungal prophylaxis is imperative for the populations most vulnerable to IFIs, such as those with hematologic malignancies. Posaconazole, a triazole with broad-spectrum antifungal properties, acts as a non-competitive inhibitor of lanosterol 14-alpha-demethylase, a crucial enzyme in the fungal ergosterol biosynthesis pathway. Ergosterol is vital as the main sterol component of the fungal cell membrane. Ergosterol depletion disrupts cell membrane integrity, leading to leakage of cell contents, cell lysis, and ultimately cell death [8, 9]. Posaconazole oral suspension (POS), delayed-release tablet, and intravenous formulation have been available since 2006. POS is recommended for high-risk immunocompromised patients to prevent invasive Aspergillus and Candida infections [10-12]. However, POS absorption is inadequate, and its bioavailability is variable and unpredictable. Physiological factors such as diarrhea, mucositis, and the concurrent use of acid-lowering drugs can decrease blood concentrations after POS administration [13], making it challenging to achieve sufficient concentrations. Some patients with hematologic malignancies and who undergo chemotherapy frequently receive proton pump inhibitors (PPI) or histamine-2 antagonists (H2A) for stress ulcer prophylaxis. Research has suggested a correlation between low posaconazole concentrations and the occurrence of breakthrough invasive fungal infections (bIFI) [14]. Therefore, monitoring posaconazole concentrations is imperative. POS was prescribed 200 mg three times daily for prevention and 400 mg twice daily for treatment. The recommended concentrations are > 700 ng/mL for prophylaxis and > 1,000 ng/mL for treatment [15-17]. A meta-analysis suggested 500 ng/mL as an effective concentration for preventive use [18], with a toxicity limit for the trough set at 3,750 ng/mL. In a retrospective observational analysis of 81 patients, the use of lansoprazole or pantoprazole decreased the concentration-to-dose ratio (C/D) of POS, although the impact of clinical outcomes was not examined [19]. Another prospective study indicated that PPIs reduced posaconazole blood concentration but did not influence the IFI breakthrough point. However, no individual PPI analyses were conducted when POS was administered [20]. A recent meta-analysis found that PPIs caused a 48% reduction in POS bioavailability [21]. Aim This retrospective study aimed to investigate the effects of PPIs on POS concentrations and C/D to explore their impact on prophylactic outcomes and examine other potential factors that influence POS concentration. Ethics approval This retrospective study was approval by the Ethics Committee of the First Hospital of Hebei Medical University (approval number 20200638). Method Study design This retrospective observational study was conducted at the First Hospital of Hebei Medical University in Shijiazhuang, China, from September 2021 to September 2023. The inclusion criteria were: 1) individuals aged 13 years or older with hematologic malignancies who received POS for the prevention or treatment of IFIs for at least 7 days, and 2) those who had at least one steady-state POS concentration monitored by therapeutic drug monitoring (TDM) during the treatment period. Patients who refused to sign the informed consent form, or those with inaccurate or missing data on concentration or dosage, were excluded. An inaccurate POS concentration was defined as a measurement that was not taken after regular medication administration when a steady-state concentration was reached. Missing dose data refers to cases where the actual dose administered was not correctly recorded. The diagnosis of IFIs adhered to the criteria set by the European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSG). IFI was classified as proven or probable. Data collection Plasma POS trough levels (C min ) were routinely measured approximately one week after taking POS. C min was obtained 2 h before the scheduled dose. Demographic and clinical data were extracted from the hospital information system (HIS). The following data were extracted: age, sex, body mass index (BMI), POS concentrations and C/D, hematological diagnosis, drugs, adverse drug reactions (ADRs), and biochemical parameters [alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), γ-glutamyl transferase (γ-GT), total bilirubin (TBIL), albumin, C-reactive protein (CRP), procalcitonin (PCT), urea, serum creatinine (SrCr), creatine kinase, and serum potassium. Outcome evaluation The primary outcome was the impact of concurrently administered PPI on POS C/D and C min , the frequency distribution of effective POS concentrations (C min ≥ 500 ng/mL), and the effectiveness of the POS therapy. Secondary outcomes included factors that influence POS concentrations and the incidence of ADRs. Statistical analysis Categorical variables are presented as numbers and percentages. Continuous variables are expressed as means and standard deviations (SD) when they follow a normal distribution, and as medians with interquartile ranges (IQR) for non-normally distributed data. For comparing two groups with normally distributed data, the t-test was used, while the Mann-Whitney U-test or the Kruskal-Wallis test was applied to non-normally distributed data. Categorical data comparisons were conducted using the chi-square test, with adjustments made using the Bonferroni correction. The correlation between factors, excluding PPIs, and the C/D ratio was assessed using the Spearman rank correlation coefficient. p < 0.05 was considered statistically significant. All statistical analyses were performed with SPSS version 22, and graphical representations were created with GraphPad Prism version 9.0. Results Patient characteristics A total of 89 patients met the inclusion criteria, and 3 were excluded (the duration of POS therapy < 7 days). Among the 86 participants, 49 were women (57.0%). Esomeprazole, rabeprazole, omeprazole, pantoprazole, or ilaprazole was administered to 36 patients. A total of 283 POS plasma trough samples were collected, 2.5 levels per patient (IQR 1.00-4.25). Among the participants, 77 patients (89.5%) received POS for primary prophylaxis, 1 (1.3%) for secondary prophylaxis, and 8 (9.3%) for treatment. Details are shown in Table 1 . Table 1 Demographic and clinical characteristics of patients Characteristics Total (n = 86) Prophylaxis (n = 78) Treatment (n = 8) Age (years) 54.50 (40.00–68.00) 53.50 (40.00–68.00) 63.00 (36.26-65.00) Male 37 32 5 Female 49 46 3 BMI (kg/m 2 ) 23.67 (21.04–26.37) 23.70 (20.88–26.51) 23.44 (21.48–26.12) Numbers of measurements 283 259 24 Days of taking medicine 14.00 (8.00–21.00) 14.00 (8.75–21.50) 12.50 (7.00-19.75) POS concentration C min (ng/mL) 1160.12 (590.75–2000.00) 1210.00 (610.00-2070.00) 730.00 (357.50-1107.50) C/D (ng/mL/mg) 1.73 (0.88–3.20) 1.90 (0.94–3.31) 1.12 (0.57–1.61) Underlying conditions ALL 7 (8.14%) 6 (7.69%) 1 (12.50%) MDS 10 (11.63%) 9 (11.54%) 1 (12.50%) AML 48 (55.81%) 44 (56.41%) 4 (50.00%) Others 21 (24.42%) 19 (24.36%) 2 (25.00%) Chemotherapy 49 (56.98%) 46 (58.97%) 3 (37.50%) PPIs Esomeprazole 15 (17.44%) 12 (15.38%) 3 (37.50%) Rabeprazole 16 (18.60%) 15 (19.23%) 1 (12.50%) Omeprazole 9 (10.47%) 6 (7.69%) 0 Pantoprazole 6 (6.98%) 5 (6.41) 1 (12.50%) Ilaprazole 1 (1.16%) 1 (1.28%) 0 Other Combined Drugs Metoclopramide 14 (16.28%) 11 (14.10%) 3 (37.50%) Famotidine 5 (5.81%) 4 (5.13%) 0 Sodium bicarbonate 9 (10.47%) 8 (10.26%) 1 (12.50%) Corticosteroids 78 (90.70%) 70 (89.74%) 8 (100.00%) Lorazepam 2 (2.33%) 2 (2.56%) 0 POS: posaconazole oral suspension; C/D: concentration-to-dose ratio; ALL: Acute lymphoblastic leukemia; MDS: Myelodysplastic syndrome; AML: Acute myeloid leukaemia; Others: Multiple myeloma/T-cell lymphoma/Aplastic anemia/Diffuse large B-cell lymphoma; PPIs: Proton pump inhibitors. Patient characteristics with bIFIs Among the 78 patients who received POS for primary IFI prevention, 5 (6.4%) were diagnosed with proven or probable bIFIs, and 7 (9%) had possible IFIs. Two patients were diagnosed with proven Candida or Aspergillus infections. Patients with bIFIs received a median of 1.0 (IQR 1.0-1.5) TDM assessments and had been on POS for 10.0 days (IQR 3.5–15.5 days). The most recent C min before diagnosis was 1,150.0 ng/mL (IQR 515.8-1,465.0 ng/mL). Except for a patient with a POS level of 470 ng/mL before the bIFI diagnosis, all other patients had POS concentrations ranging from 561 to 1,600 ng/mL. Patients who received prophylactic POS had 259 concentrations measured: 81.1% of the concentrations exceeded 500 ng/mL, and 71.8% exceeded 700 ng/mL. Specifically, 82.1% and 92.3% of the patients had at least one concentration level > 700 ng/mL and 500 ng/mL. The initial TDM for these patients was 894.13 ng/mL (IQR 564.0–1,388.5 ng/mL): 21.8% had concentrations < 500 ng/mL, and 35.9% had concentrations < 700 ng/mL. Impact of PPI on plasma posaconazole trough concentrations PPI significantly reduced the median posaconazole C min from 1,380.00 (IQR 1,449.07) ng/mL to 950.00 (IQR 1,022.27) ng/mL ( p = 0.000) and C/D from 2.25 (IQR 2.41) to 1.53 (IQR 1.77) ( p = 0.001), as shown in Fig. 1 . However, as detailed in Table 2 , the impact of PPI on POS C min and C/D did not negatively impact the outcomes of POS prophylaxis ( p = 1.000). Table 2 The effect of PPI on POS prophylactic and treatment outcome Prophylaxis (n, %) Treatment (n, %) ALL (n, %) Success Failure Success Failure Success Failure With PPI 30 (38.46%) 2 (2.56%) 3 (37.50%) 1 (12.50%) 33 (38.37%) 3 (3.49%) Without PPI 43 (55.13%) 3 (3.85%) 4 (50.00%) 0 47 (54.65%) 3 (3.49%) Total 73 (93.59%) 5 (6.41%) 7 (87.50%) 1 (12.50%) 80 (93.02%) 6 (6.98%) X 2 0.000 1.000 0.000 p -value 1.000 0.500 1.000 When analyzing the effects of specific PPI on posaconazole concentrations, only esomeprazole and rabeprazole were found to reduce POS trough concentrations (C min ), with a similar trend observed in the C/D ratios (Fig. 2 ). However, this reduction did not adversely affect the outcomes of POS prophylaxis ( p = 0.886). Compared to patients who did not take PPI, those who received PPI had a higher proportion of posaconazole trough concentrations (C min ) below 500 ng/mL (25.7% vs. 14.8%, p < 0.001). This trend was also evident in patients who received esomeprazole (26.8% vs. 14.8%, p < 0.001) or rabeprazole (43.8% vs. 14.8%, p 500 ng/mL) between patients treated with omeprazole, pantoprazole, or ilaprazole compared to those without PPI treatment. The relative frequency distributions for these seven groups are shown in Fig. 3 . Further analysis of specific PPI formulations indicated that esomeprazole magnesium enteric-coated tablets, esomeprazole sodium for injection, and rabeprazole sodium for injection significantly reduced POS C min and C/D ratios. In contrast, while esomeprazole magnesium enteric-coated capsules and rabeprazole sodium enteric-coated tablets also decreased POS C min and C/D, these reductions were not statistically significant (Table 3 ). Table 3 Impact of PPI formulation on POS C/D and concentration Formulations C min Z p -value Esomeprazole Magnesium Enteric-coated Tablets 830.00 (460.00-1320.00) -3.609 0.000 Esomeprazole Magnesium Enteric-coated Capsules 1100.00 (815.00-1435.00) -1.743 0.081 Esomeprazole Sodium for Injection 287.8965 (85.051-845.00) -2.482 0.013 Rabeprazole Sodium Enteric-coated Tablets 710.00 (1137.42-1326.15) -0.913 0.361 Rabeprazole Sodium for Injection 710.00 (425.68-1062.82) -4.104 0.000 Without PPIs 1380.00 (760.93–2210.00) - C/D Z P -value Esomeprazole Magnesium Enteric-coated Tablets 1.14 (0.68–1.97) -3.352 0.001 Esomeprazole Magnesium Enteric-coated Capsules 1.69 (1.36–2.20) -1.647 0.100 Esomeprazole Sodium for Injection 0.45 (0.11–1.41) -2.419 0.016 Rabeprazole Sodium Enteric-coated Tablets 1.18 (1.90–2.21) -0.664 0.506 Rabeprazole Sodium for Injection 1.18 (0.71–1.67) -3.876 0.000 Without PPIs 2.25 (1.12–3.53) - Other factors influencing POS concentrations Significant differences in POS C min [561.54 ng/mL vs. 1,255.00 ng/mL, p = 0.001] and C/D [0.94 vs. 1.99, p = 0.001) were observed between patients undergoing prophylactic treatment who developed bIFIs and those who did not. Patients with bIFIs had a higher frequency distribution of POS concentrations below 500 ng/mL (42.86% vs. 14.98%, p = 0.001). Although PPI affected POS concentrations, it did not influence the outcome of prophylactic treatment. Therefore, we explored other potential factors that could decrease POS concentrations and impact the effectiveness of prophylactic therapies. A Spearman rank correlation coefficient analysis was conducted to assess factors that could influence POS C min and C/D ratios. As shown in Supplementary Table 1, a significant positive correlation was found between albumin levels and the C/D ratio ( rs = 0.32, p = 0.003). In contrast, age, diarrhea, concomitant medications (including metoclopramide and PPIs such as esomeprazole and rabeprazole), the duration of POS co-administration with PPIs, and levels of CRP, PCT, and urea showed negative associations with the C/D ratio. POS-related adverse drug reactions During POS administration, 38.4% (33/86) of the patients reported ADRs, including hepatotoxicity (16.3%), hypokalemia (24.4%), rash (2.3%), and renal impairment (2.3%). Six patients stopped POS due to liver damage, and one due to rash. Hepatotoxicity in affected patients usually manifested as elevated liver function tests, often returning to normal with symptomatic treatment involving hepatoprotective drugs such as isoglycyrrhizinate magnesium injection or bicyclol tablets. POS C min [988.53 (IQR 854.02) ng/mL vs . 1,213.41 (IQR 1,433.04) ng/mL, p = 0.036) and C/D [1.44 (IQR 1.31) vs . 1.97 (IQR 2.38), p = 0.010] were significantly lower in patients who developed hepatotoxicity than in those who did not. Patients with a history of liver disease were more likely to develop liver damage ( p = 0.030). In particular, 85.7% of patients experiencing hepatotoxicity received chemotherapeutic agents, antibiotics such as tigecycline and linezolid, venetoclax, or other drugs with the potential to induce liver injury. Among patients receiving prophylactic POS, there were no statistically significant differences in the incidence of ADRs between those who developed bIFIs and those who did not (60.0% vs . 35.6%, p = 0.540). Furthermore, except for a significant increase in TBIL and γ-GT levels, other biochemical indicators such as ALT, AST, ALP, and urea did not show significant changes before or after POS administration. Discussion The correlation between posaconazole concentrations and clinical response is well-established [ 14 , 18 , 19 ]. POS delayed-release tablets and injections have effectively addressed issues related to variability and inconsistent bioavailability [ 23 ]. However, POS remains an essential alternative for patients who cannot swallow. Several factors, including high-fat meals, gastric pH and motility, diarrhea, and mucositis, have been identified as influences on POS concentrations [ 13 ]. Unlike other azoles, posaconazole is predominantly metabolized by UDP-glucuronosyltransferase (UGT) 1A4 rather than phase 1 CYP450 enzymes, and acts as an inhibitor and substrate of the P-glycoprotein (P-gp) transporter. Inhibitors (such as cyclosporine and quinidine) or inducers (such as rifampicin and certain anticonvulsants) of these pathways can significantly alter posaconazole levels, affecting therapeutic efficacy. TDM is recommended to ensure posaconazole efficacy [ 17 ]. Our study found that while esomeprazole or rabeprazole significantly decreased POS C min and C/D ratios, there were no significant differences in the occurrence of bIFIs between the groups. However, these PPIs did reduce the frequency distribution of effective POS concentrations, resulting in more patients with plasma concentrations below 500 ng/mL. Research has demonstrated the impact of intragastric pH on posaconazole levels; for example, pantoprazole and lansoprazole significantly decrease plasma POS concentrations [ 19 ], and similar effects were observed with omeprazole and lansoprazole, which is consistent with our findings [ 20 ]. Further investigation of specific formulations revealed that esomeprazole tablets and injections, as well as rabeprazole injections, markedly reduced POS C min . Injectable forms, being faster-acting, may have a greater impact on C min compared to other formulations. Therefore, patients taking POS are advised to avoid injectable PPIs. Our findings also indicate that POS C min decreases with prolonged co-administration of POS and PPIs, suggesting that close monitoring of posaconazole concentrations by physicians and pharmacists is crucial during long-term use. The probable or proven IFI incidence was 6.4%, and these patients had a mean posaconazole concentration of 1,022 ng/mL before bIFIs. Only two patients had concentrations below 700 ng/mL, and one had a concentration below 500 ng/mL before diagnosis. There were no significant differences in the duration of prophylactic POS administration between patients who developed IFIs and those who did not (10 days vs . 14 days, p = 0.146). A study found that only one of the nine allogeneic hematopoietic cell transplant recipients taking posaconazole had a mean concentration of less than 700 ng/mL shortly before the diagnosis of breakthrough infection [ 24 ]. Similarly, among patients with acute myeloid leukemia/myelodysplastic syndrome receiving venetoclax and posaconazole, five of seven patients who acquired IFI within one cycle of venetoclax had reached steady-state therapeutic trough levels (700 ng/mL) [ 25 ]. Five patients in this study developed bIFIs due to causes other than POS concentration not reaching the recommended preventive level. Corticosteroids (dexamethasone and methylprednisolone) were administered to these patients simultaneously with POS. Furthermore, one patient had diabetes, and four underwent chemotherapy, circumstances that could have potentially contributed to infections in confirmed patients [ 3 ], although the concentrations were sufficient. It should be noted that the genotype could also contribute to infections after low POS concentrations. Unlike patients with wild-type UGT1A4, UGT1A4 *3 is associated with decreased POS absorption [ 26 ]. In this study, a patient in the terminal stages of myelodysplastic syndrome receiving POS and amphotericin B therapy succumbed to respiratory failure resulting from a mixed fungal and bacterial infection. A higher percentage of low concentrations occurred in POS treatment patients compared to prophylactic patients. This could be because these patients were more seriously ill. Most were taking immunosuppressive drugs such as steroids and experiencing hypoalbuminemia, which could lead to a decrease in POS concentrations [ 27 , 28 ]. Furthermore, in critically ill patients receiving an intravenous formulation of posaconazole, the therapeutic threshold (1,000 ng/mL) was only reached in 26% of all concentrations. Exposure to posaconazole in critically ill individuals also differs from that in non-critically ill hematological patients [ 29 ]. Hospitalized patients diagnosed with a fungal disease had a higher prevalence of TDM than those without [ 30 ]. Patients who undergo treatment may require more frequent TDM than those on prophylaxis, suggesting a possible need to increase the POS treatment dose. In our study, patients with hepatotoxicity had lower POS concentrations, and 85.7% were taking medications known to cause hepatotoxicity. Simultaneous use of drugs with known risks of liver damage was identified as a possible contributing factor to the development of hepatotoxicity in patients treated with posaconazole [ 31 ]. Patients treated with POS concentrations greater than 5,000 ng/mL experienced a higher frequency of hepatotoxicity and a high incidence of symptomatic ADRs [ 32 ]. However, concentrations greater than 5,000 ng/mL were observed in only one patient in our study, and this patient did not develop hepatotoxicity. A network meta-analysis found that, while posaconazole ranked the worst among interventions, there were no statistically significant differences in increased liver enzymes between any antifungal drug and placebo [ 33 ]. Elevated posaconazole trough concentrations in lung transplant recipients were not associated with altered liver function [ 34 ]. In allogeneic hematopoietic cell transplant recipients receiving posaconazole, a retrospective study found no statistically significant differences in liver function tests between the initial phase and the end of treatment [ 24 ]. These findings may suggest that posaconazole-induced hepatotoxicity is modest and reversible, but patients with higher concentrations still need careful follow-up. Recent research has also suggested an association between posaconazole and pseudohyperaldosteronism, which can manifest with proteinuria [ 35 – 38 ]. However, this association was not observed in our study. This study examined the effects of pantoprazole, ilaprazole, rabeprazole, omeprazole, and esomeprazole on POS blood concentrations and the distribution of effective concentrations. Subsequent analysis focused on PPI formulations (esomeprazole and rabeprazole) that significantly impacted POS concentrations. Esomeprazole magnesium enteric-coated tablets, esomeprazole sodium for injection, and rabeprazole sodium for injection was the only formulation that significantly reduced POS trough concentrations (C min ). This study has several limitations. First, its retrospective design is susceptible to confounders, which may affect the validity of the findings. The lack of specific data on lansoprazole use restricts our ability to assess its impact on posaconazole concentrations or prophylactic efficacy. Second, there was no follow-up with patients who received adjusted POS doses due to inadequate concentrations, limiting our understanding of the long-term effects of dose adjustments. These factors require caution when interpreting the results and underscore the need for methodological improvements in future research. Conclusion Esomeprazole or rabeprazole reduces posaconazole concentrations in patients with hematologic malignancies without affecting prophylactic effectiveness Physicians and pharmacists should take into account factors such as age, prolonged PPI co-administration, diarrhea, and concurrent metoclopramide use. Continuous monitoring of posaconazole concentrations is recommended for effective fungal infection treatment. Vigilant management and monitoring are essential to optimize therapeutic outcomes. Declarations Acknowledgements We thank all our colleagues and patients, clinical pharmacists, and physicians for taking care of the patients with hematologic malignancies in the Hematology Department and for providing us with information on patient admissions. Funding This study was funded through the Medical Science Research Project of the Health Commission of Hebei Province (No. 20210368), the Department of Finance of Hebei, and the Health Commission of Hebei Province Funding for Outstanding Talent Cultivation Program in Clinical Medicine (No. ZF2024130). Conflicts of interests The authors confirm that the funding had no influence on the study results. There are no conflicts of interest associated with this publication. References Von Lilienfeld-Toal M, Wagener J, Einsele H, et al. Invasive Fungal Infection. Dtsch Arztebl Int. 2019;116(16):271-278. Lass-Flörl C, Steixner S. The changing epidemiology of fungal infections. Mol Aspects Med. 2023, 94: 101215. DOI:10.1016/j.mam.2023.101215. Fang W, Wu J, Cheng M, et al. Diagnosis of invasive fungal infections: challenges and recent developments. J Biomed Sci. 2023;30(1):42. Sprute R, Nacov JA, Neofytos D, et al. Antifungal prophylaxis and pre-emptive therapy: When and how?. 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Donnelly JP, Chen SC, Kauffman CA, et al. Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis. 2020;71(6):1367-1376. Chen L, Krekels EHJ, Heijnen AR, et al. An Integrated Population Pharmacokinetic Analysis for Posaconazole Oral Suspension, Delayed-Release Tablet, and Intravenous Infusion in Healthy Volunteers. Drugs. 2023;83(1):75-86. Kraljevic M, Khanna N, Medinger M, et al. Clinical considerations on posaconazole administration and therapeutic drug monitoring in allogeneic hematopoietic cell transplant recipients. Med Mycol. 2021;59(7):701-711. Reynolds G, Urbancic KF, Fong CY, et al. Invasive fungal infection following venetoclax and posaconazole co-administration. Br J Haematol. 2023;203(4):593-598. Suh HJ, Yoon SH, Yu KS, et al. The Genetic Polymorphism UGT1A4*3 Is Associated with Low Posaconazole Plasma Concentrations in Hematological Malignancy Patients Receiving the Oral Suspension. Antimicrob Agents Chemother. 2018;62(7):e02230-17. Cojutti PG, Candoni A, Lazzarotto D, et al. Co-administration of proton pump inhibitors and/or of steroids may be a risk factor for low trough concentrations of posaconazole delayed-released tablets in adult patients with haematological malignancies. Br J Clin Pharmacol. 2018;84(11):2544-2550. Oh J, Kang CI, Kim SH, et al. Antifungal prophylaxis with posaconazole tablet and oral suspension in patients with haematologic malignancy: Therapeutic drug monitoring, efficacy and risk factors for the suboptimal level. Mycoses. 2020;63(1):89-94. König C, Göpfert M, Kluge S, et al. Posaconazole exposure in critically ill ICU patients: a need for action. Infection. 2023;51(6):1767-1772. Benedict K, Gold JAW, Toda M, et al. Low Rates of Antifungal Therapeutic Drug Monitoring Among Inpatients Who Received Itraconazole, Posaconazole, or Voriconazole, United States, 2019-2021. Open Forum Infect Dis. 2023;10(8):ofad389. O'Flynn R, Zhou YP, Waskin H, et al. Hepatic safety of the antifungal triazole agent posaconazole: characterization of adverse event reports in a manufacturer's safety database. Expert Opin Drug Saf. 2022;21(8):1113-1120. Jensen K, Saleh OA, Chesdachai S, et al. Association of adverse effects with high serum posaconazole concentrations. Med Mycol. 2023;61(8):myad079. Yang YL, Xiang ZJ, Yang JH, et al. Adverse Effects Associated With Currently Commonly Used Antifungal Agents: A Network Meta-Analysis and Systematic Review. Front Pharmacol. 2021;12:697330. Sabatino DC, Lange NW, Salerno DM, et al. Elevated posaconazole trough concentrations are not associated with increased risk for posaconazole toxicity in lung transplant recipients. Clin Transplant. 2023;37(1):e14826. Parker RW, Ferré EMN, Myint-Hpu K, et al. Posaconazole-induced Pseudohyperaldosteronism Manifesting with Nephrotic-range Proteinuria. Clin Infect Dis. 2020;71(10):2768-2770. Tantiprawan J, Sunthornyothin S, Boonchaya-Anant P, et al. Posaconazole-induced Pseudohyperaldosteronism. Kaohsiung J Med Sci. 2021;37(3):253-254. Nguyen MH, Davis MR, Wittenberg R, et al. Posaconazole Serum Drug Levels Associated With Pseudohyperaldosteronism. Clin Infect Dis. 2020;70(12):2593-2598. Parker RW, Ferré EMN, Myint-Hpu K, et al. Posaconazole-induced Pseudohyperaldosteronism Manifesting with Nephrotic-range Proteinuria. Clin Infect Dis. 2020;71(10):2768-2770. DOI:10.1093/cid/ciaa119. Supplementary Files supplementarymaterial.docx Cite Share Download PDF Status: Published Journal Publication published 07 Dec, 2024 Read the published version in International Journal of Clinical Pharmacy → Version 1 posted Editorial decision: Major revisions 01 Jun, 2024 Reviewers agreed at journal 05 May, 2024 Reviewers invited by journal 04 May, 2024 Editor invited by journal 29 Apr, 2024 Editor assigned by journal 29 Apr, 2024 First submitted to journal 27 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4326408","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":298742471,"identity":"73b37210-7bee-4379-8735-4845669fa9fc","order_by":0,"name":"Ruochen Qu","email":"","orcid":"","institution":"The First Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ruochen","middleName":"","lastName":"Qu","suffix":""},{"id":298742472,"identity":"ecc95967-5ef2-436b-bd97-657e86fa8868","order_by":1,"name":"Yan Liu","email":"","orcid":"","institution":"The First Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Liu","suffix":""},{"id":298742473,"identity":"05537d95-7e77-484d-ba9f-09cab9f4b7b5","order_by":2,"name":"Yan Zhao","email":"","orcid":"","institution":"The First Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Zhao","suffix":""},{"id":298742474,"identity":"29435129-aa2f-4aa0-b35a-7e2e941d79fe","order_by":3,"name":"Ziyi Wang","email":"","orcid":"","institution":"The First Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ziyi","middleName":"","lastName":"Wang","suffix":""},{"id":298742475,"identity":"a0f765be-5885-44be-980c-73218a3d3d31","order_by":4,"name":"Shizhao Yuan","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shizhao","middleName":"","lastName":"Yuan","suffix":""},{"id":298742476,"identity":"1298beea-c5fb-4954-873c-4110de6965f4","order_by":5,"name":"Jing Yu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzklEQVRIiWNgGAWjYHCChAMMDDYJDBJgDjPRWtJI0wICh0nQYnAj4eHhgl/n8/ilu9MkGCqsExvYzx4gpCXh8My+28WSc85uk2A4k57YwJOXQFgLb8/txA03crdJMLYdTmyQ4DEgRsu5xP1gLf+I1cLz40DiBgmQlgYitEieeQC0pSE5ccads5stEo6lG7fx5ODXwnc8J/kzzx+7xP7ZvRtvfKixlu1nP4Nfi8IBngQGxjYoLwGI2fCqBwL5BvYDDAx/CCkbBaNgFIyCEQ0AvFdQD3CsZgAAAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0008-7692-9816","institution":"The First Hospital of Hebei Medical University","correspondingAuthor":true,"prefix":"","firstName":"Jing","middleName":"","lastName":"Yu","suffix":""}],"badges":[],"createdAt":"2024-04-26 00:25:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4326408/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4326408/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11096-024-01841-8","type":"published","date":"2024-12-07T15:57:24+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":56397798,"identity":"4fe38270-ac3d-4f3b-8214-e3033a21b1ea","added_by":"auto","created_at":"2024-05-13 15:51:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":66768,"visible":true,"origin":"","legend":"\u003cp\u003eThe distribution of posaconazole trough level C\u003csub\u003emin\u003c/sub\u003e\u003c/p\u003e\n\u003cp\u003eThe medians and quartiles are represented by horizontal red lines.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4326408/v1/aa24c17b1576337ec5f623a7.png"},{"id":56398926,"identity":"94db1d6d-5c7f-4718-839c-6ea96503f9ca","added_by":"auto","created_at":"2024-05-13 15:59:14","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":70821,"visible":true,"origin":"","legend":"\u003cp\u003eThe distribution of posaconazole trough (C\u003csub\u003emin\u003c/sub\u003e) by proton pump inhibitors\u003c/p\u003e\n\u003cp\u003eHorizontal red lines represent the medians and quartiles. *** indicates a statistically significant difference in C\u003csub\u003emin\u003c/sub\u003e and C/D in the combined esomeprazole and rabeprazole group over those without a PPI.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eESO:\u003c/strong\u003e\u0026nbsp;Esomeprazole; RAB: Rabeprazole; OME: Omeprazole; PAN: Pantoprazole; ILA: Ilaprazole; PPI: Proton pump inhibitor\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4326408/v1/e8ce72855e8076463de6c3a9.png"},{"id":56397800,"identity":"7265efd9-ce34-4bc3-8ff4-0722548b2c17","added_by":"auto","created_at":"2024-05-13 15:51:14","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":79826,"visible":true,"origin":"","legend":"\u003cp\u003eThe frequency distribution of effective concentration for each group\u003c/p\u003e\n\u003cp\u003e*** indicates statistically significant differences in effective concentration frequency distribution between the combined PPI group, the esomeprazole group, and the rabeprazole group compared to the group without a combined PPI.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4326408/v1/a0721b235c1f83b8321ed392.png"},{"id":70964704,"identity":"fa215510-e95c-47dd-a71e-351540516974","added_by":"auto","created_at":"2024-12-09 16:14:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":819603,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4326408/v1/d2229248-a163-4ff1-914f-959862b90550.pdf"},{"id":56397801,"identity":"7bf6c1c1-2784-46aa-b646-fdc052727774","added_by":"auto","created_at":"2024-05-13 15:51:15","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":17604,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-4326408/v1/e9bd3ef636fb1e4af7d707a9.docx"}],"financialInterests":"","formattedTitle":"Effectiveness of combined proton pump inhibitors and posaconazole prophylaxis against invasive fungal infections in patients with hematologic malignancies: A retrospective study","fulltext":[{"header":"Impact statements","content":"\u003cul\u003e\n \u003cli\u003eThis study highlights the significant impact of proton pump inhibitors (PPIs) such as esomeprazole and rabeprazole on the plasma concentrations of posaconazole, a critical antifungal drug.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe findings underscore the importance of careful drug management and follow-up in patients undergoing posaconazole treatment, especially those who also receive PPIs.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe research provides evidence-based insights that can guide future prophylactic strategies in immunocompromised patients, highlighting the need for regular therapeutic drug monitoring to ensure optimal dosing and to avoid potential drug interactions that could compromise treatment effectiveness.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eInvasive fungal infections (IFIs) are infectious diseases in which fungi infiltrate the body, increasing in tissues, organs, or the bloodstream. They induce inflammation, causing tissue damage, and are associated with elevated rates of morbidity and mortality. \u003cem\u003eAspergillus spp\u003c/em\u003e. and \u003cem\u003eCandida spp\u003c/em\u003e. are the main contributors to invasive infections, followed by \u003cem\u003eMucor spp\u003c/em\u003e. and \u003cem\u003eCryptococcus spp\u003c/em\u003e.[1, 2]. Immunocompromised individuals, especially those diagnosed with hematologic malignancies, are highly prone to IFIs [3, 4]. Fungal invasiveness poses a significant public health threat due to the difficulty of timely identification. Some fungal species have developed resistance to antifungals in recent years [5, 6], leading to increased healthcare costs. Antifungal prophylaxis reduces IFIs and hospital mortality in patients with acute leukemia undergoing induction chemotherapy [7]. Therefore, antifungal prophylaxis is imperative for the populations most vulnerable to IFIs, such as those with hematologic malignancies.\u003c/p\u003e\n\u003cp\u003ePosaconazole, a triazole with broad-spectrum antifungal properties, acts as a non-competitive inhibitor of lanosterol 14-alpha-demethylase, a crucial enzyme in the fungal ergosterol biosynthesis pathway. Ergosterol is vital as the main sterol component of the fungal cell membrane. Ergosterol depletion disrupts cell membrane integrity, leading to leakage of cell contents, cell lysis, and ultimately cell death [8, 9]. Posaconazole oral suspension (POS), delayed-release tablet, and intravenous formulation have been available since 2006. POS is recommended for high-risk immunocompromised patients to prevent invasive \u003cem\u003eAspergillus\u003c/em\u003e and \u003cem\u003eCandida\u003c/em\u003e infections [10-12].\u003c/p\u003e\n\u003cp\u003eHowever, POS absorption is inadequate, and its bioavailability is variable and unpredictable. Physiological factors such as diarrhea, mucositis, and the concurrent use of acid-lowering drugs can decrease blood concentrations after POS administration [13], making it challenging to achieve sufficient concentrations. Some patients with hematologic malignancies and who undergo chemotherapy frequently receive proton pump inhibitors (PPI) or histamine-2 antagonists (H2A) for stress ulcer prophylaxis. Research has suggested a correlation between low posaconazole concentrations and the occurrence of breakthrough invasive fungal infections (bIFI) [14]. Therefore, monitoring posaconazole concentrations is imperative. POS was prescribed 200 mg three times daily for prevention and 400 mg twice daily for treatment. The recommended concentrations are \u0026gt; 700 ng/mL for prophylaxis and \u0026gt; 1,000 ng/mL for treatment [15-17]. A meta-analysis suggested 500 ng/mL as an effective concentration for preventive use [18], with a toxicity limit for the trough set at 3,750 ng/mL.\u003c/p\u003e\n\u003cp\u003eIn a retrospective observational analysis of 81 patients, the use of lansoprazole or pantoprazole decreased the concentration-to-dose ratio (C/D) of POS, although the impact of clinical outcomes was not examined [19]. Another prospective study indicated that PPIs reduced posaconazole blood concentration but did not influence the IFI breakthrough point. However, no individual PPI analyses were conducted when POS was administered [20]. A recent meta-analysis found that PPIs caused a 48% reduction in POS bioavailability [21].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAim\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study aimed to investigate the effects of PPIs on POS concentrations and C/D to explore their impact on prophylactic outcomes and examine other potential factors that influence POS concentration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study was approval by the Ethics Committee of the First Hospital of Hebei Medical University (approval number 20200638).\u0026nbsp;\u003c/p\u003e"},{"header":"Method","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis retrospective observational study was conducted at the First Hospital of Hebei Medical University in Shijiazhuang, China, from September 2021 to September 2023. The inclusion criteria were: 1) individuals aged 13 years or older with hematologic malignancies who received POS for the prevention or treatment of IFIs for at least 7 days, and 2) those who had at least one steady-state POS concentration monitored by therapeutic drug monitoring (TDM) during the treatment period. Patients who refused to sign the informed consent form, or those with inaccurate or missing data on concentration or dosage, were excluded. An inaccurate POS concentration was defined as a measurement that was not taken after regular medication administration when a steady-state concentration was reached. Missing dose data refers to cases where the actual dose administered was not correctly recorded. The diagnosis of IFIs adhered to the criteria set by the European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSG). IFI was classified as proven or probable.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003ePlasma POS trough levels (C\u003csub\u003emin\u003c/sub\u003e) were routinely measured approximately one week after taking POS. C\u003csub\u003emin\u003c/sub\u003e was obtained 2 h before the scheduled dose. Demographic and clinical data were extracted from the hospital information system (HIS). The following data were extracted: age, sex, body mass index (BMI), POS concentrations and C/D, hematological diagnosis, drugs, adverse drug reactions (ADRs), and biochemical parameters [alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), γ-glutamyl transferase (γ-GT), total bilirubin (TBIL), albumin, C-reactive protein (CRP), procalcitonin (PCT), urea, serum creatinine (SrCr), creatine kinase, and serum potassium.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eOutcome evaluation\u003c/h2\u003e \u003cp\u003eThe primary outcome was the impact of concurrently administered PPI on POS C/D and C\u003csub\u003emin\u003c/sub\u003e, the frequency distribution of effective POS concentrations (C\u003csub\u003emin\u003c/sub\u003e \u0026ge; 500 ng/mL), and the effectiveness of the POS therapy. Secondary outcomes included factors that influence POS concentrations and the incidence of ADRs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCategorical variables are presented as numbers and percentages. Continuous variables are expressed as means and standard deviations (SD) when they follow a normal distribution, and as medians with interquartile ranges (IQR) for non-normally distributed data. For comparing two groups with normally distributed data, the t-test was used, while the Mann-Whitney U-test or the Kruskal-Wallis test was applied to non-normally distributed data. Categorical data comparisons were conducted using the chi-square test, with adjustments made using the Bonferroni correction. The correlation between factors, excluding PPIs, and the C/D ratio was assessed using the Spearman rank correlation coefficient. \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. All statistical analyses were performed with SPSS version 22, and graphical representations were created with GraphPad Prism version 9.0.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003ePatient characteristics\u003c/h2\u003e\n \u003cp\u003eA total of 89 patients met the inclusion criteria, and 3 were excluded (the duration of POS therapy\u0026thinsp;\u0026lt;\u0026thinsp;7 days). Among the 86 participants, 49 were women (57.0%). Esomeprazole, rabeprazole, omeprazole, pantoprazole, or ilaprazole was administered to 36 patients. A total of 283 POS plasma trough samples were collected, 2.5 levels per patient (IQR 1.00-4.25). Among the participants, 77 patients (89.5%) received POS for primary prophylaxis, 1 (1.3%) for secondary prophylaxis, and 8 (9.3%) for treatment. Details are shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDemographic and clinical characteristics of patients\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;86)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eProphylaxis (n\u0026thinsp;=\u0026thinsp;78)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTreatment (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54.50 (40.00\u0026ndash;68.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53.50 (40.00\u0026ndash;68.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63.00 (36.26-65.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.67 (21.04\u0026ndash;26.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.70 (20.88\u0026ndash;26.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.44 (21.48\u0026ndash;26.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumbers of measurements\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e283\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e259\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDays of taking medicine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.00 (8.00\u0026ndash;21.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.00 (8.75\u0026ndash;21.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.50 (7.00-19.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePOS concentration\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eC\u003csub\u003emin\u003c/sub\u003e (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1160.12 (590.75\u0026ndash;2000.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1210.00 (610.00-2070.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e730.00 (357.50-1107.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eC/D (ng/mL/mg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.73 (0.88\u0026ndash;3.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.90 (0.94\u0026ndash;3.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.12 (0.57\u0026ndash;1.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnderlying conditions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eALL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (8.14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (7.69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (12.50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (11.63%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (11.54%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (12.50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAML\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48 (55.81%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44 (56.41%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (50.00%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (24.42%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (24.36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (25.00%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49 (56.98%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46 (58.97%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (37.50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePPIs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEsomeprazole\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (17.44%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (15.38%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (37.50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRabeprazole\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (18.60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (19.23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (12.50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOmeprazole\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (10.47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (7.69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePantoprazole\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (6.98%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (6.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (12.50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIlaprazole\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eOther Combined Drugs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMetoclopramide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (16.28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (14.10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (37.50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFamotidine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (5.81%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (5.13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSodium bicarbonate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (10.47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (10.26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (12.50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCorticosteroids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78 (90.70%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70 (89.74%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (100.00%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLorazepam\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003ePOS: posaconazole oral suspension; C/D: concentration-to-dose ratio; ALL: Acute lymphoblastic leukemia; MDS: Myelodysplastic syndrome; AML: Acute myeloid leukaemia; Others: Multiple myeloma/T-cell lymphoma/Aplastic anemia/Diffuse large B-cell lymphoma; PPIs: Proton pump inhibitors.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003ePatient characteristics with bIFIs\u003c/h2\u003e\n \u003cp\u003eAmong the 78 patients who received POS for primary IFI prevention, 5 (6.4%) were diagnosed with proven or probable bIFIs, and 7 (9%) had possible IFIs. Two patients were diagnosed with proven \u003cem\u003eCandida\u003c/em\u003e or \u003cem\u003eAspergillus\u003c/em\u003e infections. Patients with bIFIs received a median of 1.0 (IQR 1.0-1.5) TDM assessments and had been on POS for 10.0 days (IQR 3.5\u0026ndash;15.5 days). The most recent C\u003csub\u003emin\u003c/sub\u003e before diagnosis was 1,150.0 ng/mL (IQR 515.8-1,465.0 ng/mL). Except for a patient with a POS level of 470 ng/mL before the bIFI diagnosis, all other patients had POS concentrations ranging from 561 to 1,600 ng/mL.\u003c/p\u003e\n \u003cp\u003ePatients who received prophylactic POS had 259 concentrations measured: 81.1% of the concentrations exceeded 500 ng/mL, and 71.8% exceeded 700 ng/mL. Specifically, 82.1% and 92.3% of the patients had at least one concentration level\u0026thinsp;\u0026gt;\u0026thinsp;700 ng/mL and 500 ng/mL. The initial TDM for these patients was 894.13 ng/mL (IQR 564.0\u0026ndash;1,388.5 ng/mL): 21.8% had concentrations\u0026thinsp;\u0026lt;\u0026thinsp;500 ng/mL, and 35.9% had concentrations\u0026thinsp;\u0026lt;\u0026thinsp;700 ng/mL.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eImpact of PPI on plasma posaconazole trough concentrations\u003c/h2\u003e\n \u003cp\u003ePPI significantly reduced the median posaconazole C\u003csub\u003emin\u003c/sub\u003e from 1,380.00 (IQR 1,449.07) ng/mL to 950.00 (IQR 1,022.27) ng/mL (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000) and C/D from 2.25 (IQR 2.41) to 1.53 (IQR 1.77) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), as shown in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. However, as detailed in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, the impact of PPI on POS C\u003csub\u003emin\u003c/sub\u003e and C/D did not negatively impact the outcomes of POS prophylaxis (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.000).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eThe effect of PPI on POS prophylactic and treatment outcome\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"7\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eProphylaxis (n, %)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eTreatment (n, %)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eALL (n, %)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSuccess\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFailure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSuccess\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFailure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSuccess\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFailure\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWith PPI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (38.46%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (37.50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (12.50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33 (38.37%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (3.49%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWithout PPI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43 (55.13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (3.85%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (50.00%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47 (54.65%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (3.49%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73 (93.59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (6.41%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (87.50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (12.50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e80 (93.02%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (6.98%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eX\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eWhen analyzing the effects of specific PPI on posaconazole concentrations, only esomeprazole and rabeprazole were found to reduce POS trough concentrations (C\u003csub\u003emin\u003c/sub\u003e), with a similar trend observed in the C/D ratios (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). However, this reduction did not adversely affect the outcomes of POS prophylaxis (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.886).\u003c/p\u003e\n \u003cp\u003eCompared to patients who did not take PPI, those who received PPI had a higher proportion of posaconazole trough concentrations (C\u003csub\u003emin\u003c/sub\u003e) below 500 ng/mL (25.7% vs. 14.8%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). This trend was also evident in patients who received esomeprazole (26.8% vs. 14.8%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) or rabeprazole (43.8% vs. 14.8%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), relative to those who did not take any PPIs. In contrast, there were no significant differences in the distribution of effective POS concentrations (C\u003csub\u003emin\u003c/sub\u003e \u0026gt; 500 ng/mL) between patients treated with omeprazole, pantoprazole, or ilaprazole compared to those without PPI treatment. The relative frequency distributions for these seven groups are shown in Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\n \u003cp\u003eFurther analysis of specific PPI formulations indicated that esomeprazole magnesium enteric-coated tablets, esomeprazole sodium for injection, and rabeprazole sodium for injection significantly reduced POS C\u003csub\u003emin\u003c/sub\u003e and C/D ratios. In contrast, while esomeprazole magnesium enteric-coated capsules and rabeprazole sodium enteric-coated tablets also decreased POS C\u003csub\u003emin\u003c/sub\u003e and C/D, these reductions were not statistically significant (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eImpact of PPI formulation on POS C/D and concentration\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFormulations\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eC\u003csub\u003emin\u003c/sub\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eZ\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEsomeprazole Magnesium Enteric-coated Tablets\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e830.00 (460.00-1320.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-3.609\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEsomeprazole Magnesium Enteric-coated Capsules\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1100.00 (815.00-1435.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.743\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.081\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEsomeprazole Sodium for Injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e287.8965 (85.051-845.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.482\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRabeprazole Sodium Enteric-coated Tablets\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e710.00 (1137.42-1326.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.913\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.361\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRabeprazole Sodium for Injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e710.00 (425.68-1062.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-4.104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWithout PPIs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1380.00 (760.93\u0026ndash;2210.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eC/D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eZ\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEsomeprazole Magnesium Enteric-coated Tablets\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.14 (0.68\u0026ndash;1.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-3.352\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEsomeprazole Magnesium Enteric-coated Capsules\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.69 (1.36\u0026ndash;2.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.647\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEsomeprazole Sodium for Injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.45 (0.11\u0026ndash;1.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.419\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.016\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRabeprazole Sodium Enteric-coated Tablets\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.18 (1.90\u0026ndash;2.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.664\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.506\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRabeprazole Sodium for Injection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.18 (0.71\u0026ndash;1.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-3.876\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWithout PPIs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.25 (1.12\u0026ndash;3.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eOther factors influencing POS concentrations\u003c/h2\u003e\n \u003cp\u003eSignificant differences in POS C\u003csub\u003emin\u003c/sub\u003e [561.54 ng/mL vs. 1,255.00 ng/mL, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001] and C/D [0.94 vs. 1.99, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) were observed between patients undergoing prophylactic treatment who developed bIFIs and those who did not. Patients with bIFIs had a higher frequency distribution of POS concentrations below 500 ng/mL (42.86% vs. 14.98%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). Although PPI affected POS concentrations, it did not influence the outcome of prophylactic treatment. Therefore, we explored other potential factors that could decrease POS concentrations and impact the effectiveness of prophylactic therapies.\u003c/p\u003e\n \u003cp\u003eA Spearman rank correlation coefficient analysis was conducted to assess factors that could influence POS C\u003csub\u003emin\u003c/sub\u003e and C/D ratios. As shown in \u003cstrong\u003eSupplementary Table\u0026nbsp;1, a\u003c/strong\u003e significant positive correlation was found between albumin levels and the C/D ratio (\u003cem\u003ers\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.32, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). In contrast, age, diarrhea, concomitant medications (including metoclopramide and PPIs such as esomeprazole and rabeprazole), the duration of POS co-administration with PPIs, and levels of CRP, PCT, and urea showed negative associations with the C/D ratio.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003ePOS-related adverse drug reactions\u003c/h2\u003e\n \u003cp\u003eDuring POS administration, 38.4% (33/86) of the patients reported ADRs, including hepatotoxicity (16.3%), hypokalemia (24.4%), rash (2.3%), and renal impairment (2.3%). Six patients stopped POS due to liver damage, and one due to rash. Hepatotoxicity in affected patients usually manifested as elevated liver function tests, often returning to normal with symptomatic treatment involving hepatoprotective drugs such as isoglycyrrhizinate magnesium injection or bicyclol tablets.\u003c/p\u003e\n \u003cp\u003ePOS C\u003csub\u003emin\u003c/sub\u003e [988.53 (IQR 854.02) ng/mL \u003cem\u003evs\u003c/em\u003e. 1,213.41 (IQR 1,433.04) ng/mL, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036) and C/D [1.44 (IQR 1.31) \u003cem\u003evs\u003c/em\u003e. 1.97 (IQR 2.38), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010] were significantly lower in patients who developed hepatotoxicity than in those who did not. Patients with a history of liver disease were more likely to develop liver damage (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030). In particular, 85.7% of patients experiencing hepatotoxicity received chemotherapeutic agents, antibiotics such as tigecycline and linezolid, venetoclax, or other drugs with the potential to induce liver injury.\u003c/p\u003e\n \u003cp\u003eAmong patients receiving prophylactic POS, there were no statistically significant differences in the incidence of ADRs between those who developed bIFIs and those who did not (60.0% \u003cem\u003evs\u003c/em\u003e. 35.6%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.540). Furthermore, except for a significant increase in TBIL and \u0026gamma;-GT levels, other biochemical indicators such as ALT, AST, ALP, and urea did not show significant changes before or after POS administration.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe correlation between posaconazole concentrations and clinical response is well-established [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. POS delayed-release tablets and injections have effectively addressed issues related to variability and inconsistent bioavailability [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. However, POS remains an essential alternative for patients who cannot swallow. Several factors, including high-fat meals, gastric pH and motility, diarrhea, and mucositis, have been identified as influences on POS concentrations [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Unlike other azoles, posaconazole is predominantly metabolized by UDP-glucuronosyltransferase (UGT) 1A4 rather than phase 1 CYP450 enzymes, and acts as an inhibitor and substrate of the P-glycoprotein (P-gp) transporter. Inhibitors (such as cyclosporine and quinidine) or inducers (such as rifampicin and certain anticonvulsants) of these pathways can significantly alter posaconazole levels, affecting therapeutic efficacy. TDM is recommended to ensure posaconazole efficacy [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur study found that while esomeprazole or rabeprazole significantly decreased POS C\u003csub\u003emin\u003c/sub\u003e and C/D ratios, there were no significant differences in the occurrence of bIFIs between the groups. However, these PPIs did reduce the frequency distribution of effective POS concentrations, resulting in more patients with plasma concentrations below 500 ng/mL. Research has demonstrated the impact of intragastric pH on posaconazole levels; for example, pantoprazole and lansoprazole significantly decrease plasma POS concentrations [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], and similar effects were observed with omeprazole and lansoprazole, which is consistent with our findings [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Further investigation of specific formulations revealed that esomeprazole tablets and injections, as well as rabeprazole injections, markedly reduced POS C\u003csub\u003emin\u003c/sub\u003e. Injectable forms, being faster-acting, may have a greater impact on C\u003csub\u003emin\u003c/sub\u003e compared to other formulations. Therefore, patients taking POS are advised to avoid injectable PPIs. Our findings also indicate that POS C\u003csub\u003emin\u003c/sub\u003e decreases with prolonged co-administration of POS and PPIs, suggesting that close monitoring of posaconazole concentrations by physicians and pharmacists is crucial during long-term use.\u003c/p\u003e \u003cp\u003eThe probable or proven IFI incidence was 6.4%, and these patients had a mean posaconazole concentration of 1,022 ng/mL before bIFIs. Only two patients had concentrations below 700 ng/mL, and one had a concentration below 500 ng/mL before diagnosis. There were no significant differences in the duration of prophylactic POS administration between patients who developed IFIs and those who did not (10 days \u003cem\u003evs\u003c/em\u003e. 14 days, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.146). A study found that only one of the nine allogeneic hematopoietic cell transplant recipients taking posaconazole had a mean concentration of less than 700 ng/mL shortly before the diagnosis of breakthrough infection [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Similarly, among patients with acute myeloid leukemia/myelodysplastic syndrome receiving venetoclax and posaconazole, five of seven patients who acquired IFI within one cycle of venetoclax had reached steady-state therapeutic trough levels (700 ng/mL) [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFive patients in this study developed bIFIs due to causes other than POS concentration not reaching the recommended preventive level. Corticosteroids (dexamethasone and methylprednisolone) were administered to these patients simultaneously with POS. Furthermore, one patient had diabetes, and four underwent chemotherapy, circumstances that could have potentially contributed to infections in confirmed patients [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], although the concentrations were sufficient. It should be noted that the genotype could also contribute to infections after low POS concentrations. Unlike patients with wild-type UGT1A4, UGT1A4 *3 is associated with decreased POS absorption [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, a patient in the terminal stages of myelodysplastic syndrome receiving POS and amphotericin B therapy succumbed to respiratory failure resulting from a mixed fungal and bacterial infection. A higher percentage of low concentrations occurred in POS treatment patients compared to prophylactic patients. This could be because these patients were more seriously ill. Most were taking immunosuppressive drugs such as steroids and experiencing hypoalbuminemia, which could lead to a decrease in POS concentrations [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Furthermore, in critically ill patients receiving an intravenous formulation of posaconazole, the therapeutic threshold (1,000 ng/mL) was only reached in 26% of all concentrations. Exposure to posaconazole in critically ill individuals also differs from that in non-critically ill hematological patients [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Hospitalized patients diagnosed with a fungal disease had a higher prevalence of TDM than those without [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Patients who undergo treatment may require more frequent TDM than those on prophylaxis, suggesting a possible need to increase the POS treatment dose.\u003c/p\u003e \u003cp\u003eIn our study, patients with hepatotoxicity had lower POS concentrations, and 85.7% were taking medications known to cause hepatotoxicity. Simultaneous use of drugs with known risks of liver damage was identified as a possible contributing factor to the development of hepatotoxicity in patients treated with posaconazole [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Patients treated with POS concentrations greater than 5,000 ng/mL experienced a higher frequency of hepatotoxicity and a high incidence of symptomatic ADRs [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. However, concentrations greater than 5,000 ng/mL were observed in only one patient in our study, and this patient did not develop hepatotoxicity. A network meta-analysis found that, while posaconazole ranked the worst among interventions, there were no statistically significant differences in increased liver enzymes between any antifungal drug and placebo [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eElevated posaconazole trough concentrations in lung transplant recipients were not associated with altered liver function [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. In allogeneic hematopoietic cell transplant recipients receiving posaconazole, a retrospective study found no statistically significant differences in liver function tests between the initial phase and the end of treatment [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. These findings may suggest that posaconazole-induced hepatotoxicity is modest and reversible, but patients with higher concentrations still need careful follow-up. Recent research has also suggested an association between posaconazole and pseudohyperaldosteronism, which can manifest with proteinuria [\u003cspan additionalcitationids=\"CR36 CR37\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. However, this association was not observed in our study.\u003c/p\u003e \u003cp\u003eThis study examined the effects of pantoprazole, ilaprazole, rabeprazole, omeprazole, and esomeprazole on POS blood concentrations and the distribution of effective concentrations. Subsequent analysis focused on PPI formulations (esomeprazole and rabeprazole) that significantly impacted POS concentrations. Esomeprazole magnesium enteric-coated tablets, esomeprazole sodium for injection, and rabeprazole sodium for injection was the only formulation that significantly reduced POS trough concentrations (C\u003csub\u003emin\u003c/sub\u003e).\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, its retrospective design is susceptible to confounders, which may affect the validity of the findings. The lack of specific data on lansoprazole use restricts our ability to assess its impact on posaconazole concentrations or prophylactic efficacy. Second, there was no follow-up with patients who received adjusted POS doses due to inadequate concentrations, limiting our understanding of the long-term effects of dose adjustments. These factors require caution when interpreting the results and underscore the need for methodological improvements in future research.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eEsomeprazole or rabeprazole reduces posaconazole concentrations in patients with hematologic malignancies without affecting prophylactic effectiveness Physicians and pharmacists should take into account factors such as age, prolonged PPI co-administration, diarrhea, and concurrent metoclopramide use. Continuous monitoring of posaconazole concentrations is recommended for effective fungal infection treatment. Vigilant management and monitoring are essential to optimize therapeutic outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all our colleagues and patients, clinical pharmacists, and physicians for taking care of the patients with hematologic malignancies in the Hematology Department and for providing us with information on patient admissions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded through the Medical Science Research Project of the Health Commission of Hebei Province (No. 20210368), the Department of Finance of Hebei, and the Health Commission of Hebei Province Funding for Outstanding Talent Cultivation Program in Clinical Medicine (No. ZF2024130).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors confirm that the funding had no influence on the study results. There are no conflicts of interest associated with this publication.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eVon Lilienfeld-Toal M, Wagener J, Einsele H, et al. Invasive Fungal Infection. Dtsch Arztebl Int. 2019;116(16):271-278.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eLass-Fl\u0026ouml;rl C, Steixner S. The changing epidemiology of fungal infections. Mol Aspects Med. 2023, 94: 101215. DOI:10.1016/j.mam.2023.101215.\u003c/li\u003e\n \u003cli\u003eFang W, Wu J, Cheng M, et al.\u0026nbsp;Diagnosis of invasive fungal infections: challenges and recent developments. J Biomed Sci. 2023;30(1):42.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSprute R, Nacov JA, Neofytos D, et al. Antifungal prophylaxis and pre-emptive therapy: When and how?. Mol Aspects Med. 2023;92:101190.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eVitiello A, Ferrara F, Boccellino M, et al.\u0026nbsp;Antifungal Drug Resistance: An Emergent Health Threat. 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Posaconazole in prophylaxis and treatment of invasive fungal infections: a pharmacokinetic, pharmacodynamic and clinical evaluation. Expert Opin Drug Metab Toxicol. 2020;16(7):539-550.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDolton MJ, Ray JE, Chen SC, et al. Multicenter study of posaconazole therapeutic drug monitoring: exposure-response relationship and factors affecting concentration. Antimicrob Agents Chemother. 2012;56(11):5503-5510.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eKably B, Launay M, Derobertmasure A, et al. Antifungal Drugs TDM: Trends and Update. Ther Drug Monit. 2022;44(1):166-197.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eMcCreary EK, Davis MR, Narayanan N, et al. Utility of triazole antifungal therapeutic drug monitoring: Insights from the Society of Infectious Diseases Pharmacists: Endorsed by the Mycoses Study Group Education and Research Consortium. Pharmacotherapy. 2023;43(10):1043-1050.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eG\u0026oacute;mez-L\u0026oacute;pez A. Antifungal therapeutic drug monitoring: focus on drugs without a clear recommendation. Clin Microbiol Infect. 2020;26(11):1481-1487.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eChen L, Wang Y, Zhang T, et al.\u0026nbsp;Utility of posaconazole therapeutic drug monitoring and assessment of plasma concentration threshold for effective prophylaxis of invasive fungal infections: a meta-analysis with trial sequential analysis. BMC Infect Dis. 2018;18(1):155.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eJia MM, Zhang QW, Qin ZF, et al.\u0026nbsp;Deciphering the Relationship Between the Trough Concentration of Posaconazole and Its Efficacy and Safety in Chinese Patients With Hematological Disorders. Front Pharmacol. 2020;11:575463.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eLi W, Xia F, Zhou H, et al.\u0026nbsp;Efficacy of Posaconazole Prophylaxis for Fungal Disease in Hematology Patients Treated With Chemotherapy and Transplantation: An Open-Label, Prospective, Observational Study. Front Microbiol. 2020;11:349.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eChen L, Krekels EHJ, Dong Y, et al.\u0026nbsp;Meta-pharmacokinetic analysis of posaconazole following dosing of oral suspension, delayed-release tablet, and intravenous infusion in patients vs. healthy volunteers: Impact of clinical characteristics and race. Int J Antimicrob Agents. 2023;62(6):106995.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDonnelly JP, Chen SC, Kauffman CA, et al.\u0026nbsp;Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis. 2020;71(6):1367-1376.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eChen L, Krekels EHJ, Heijnen AR, et al. An Integrated Population Pharmacokinetic Analysis for Posaconazole Oral Suspension, Delayed-Release Tablet, and Intravenous Infusion in Healthy Volunteers. Drugs. 2023;83(1):75-86.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eKraljevic M, Khanna N, Medinger M, et al. Clinical considerations on posaconazole administration and therapeutic drug monitoring in allogeneic hematopoietic cell transplant recipients. Med Mycol. 2021;59(7):701-711.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eReynolds G, Urbancic KF, Fong CY, et al. Invasive fungal infection following venetoclax and posaconazole co-administration. Br J Haematol. 2023;203(4):593-598.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSuh HJ, Yoon SH, Yu KS, et al. The Genetic Polymorphism UGT1A4*3 Is Associated with Low Posaconazole Plasma Concentrations in Hematological Malignancy Patients Receiving the Oral Suspension. Antimicrob Agents Chemother. 2018;62(7):e02230-17.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eCojutti PG, Candoni A, Lazzarotto D, et al. Co-administration of proton pump inhibitors and/or of steroids may be a risk factor for low trough concentrations of posaconazole delayed-released tablets in adult patients with haematological malignancies. Br J Clin Pharmacol. 2018;84(11):2544-2550.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eOh J, Kang CI, Kim SH, et al.\u0026nbsp;Antifungal prophylaxis with posaconazole tablet and oral suspension in patients with haematologic malignancy: Therapeutic drug monitoring, efficacy and risk factors for the suboptimal level. Mycoses. 2020;63(1):89-94.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eK\u0026ouml;nig C, G\u0026ouml;pfert M, Kluge S, et al. Posaconazole exposure in critically ill ICU patients: a need for action. Infection. 2023;51(6):1767-1772.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eBenedict K, Gold JAW, Toda M, et al. Low Rates of Antifungal Therapeutic Drug Monitoring Among Inpatients Who Received Itraconazole, Posaconazole, or Voriconazole, United States, 2019-2021. Open Forum Infect Dis. 2023;10(8):ofad389.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eO\u0026apos;Flynn R, Zhou YP, Waskin H, et al. Hepatic safety of the antifungal triazole agent posaconazole: characterization of adverse event reports in a manufacturer\u0026apos;s safety database. Expert Opin Drug Saf. 2022;21(8):1113-1120.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eJensen K, Saleh OA, Chesdachai S, et al. Association of adverse effects with high serum posaconazole concentrations. Med Mycol. 2023;61(8):myad079.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eYang YL, Xiang ZJ, Yang JH, et al. Adverse Effects Associated With Currently Commonly Used Antifungal Agents: A Network Meta-Analysis and Systematic Review. Front Pharmacol. 2021;12:697330.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSabatino DC, Lange NW, Salerno DM, et al. Elevated posaconazole trough concentrations are not associated with increased risk for posaconazole toxicity in lung transplant recipients. Clin Transplant. 2023;37(1):e14826.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eParker RW, Ferr\u0026eacute; EMN, Myint-Hpu K, et al. Posaconazole-induced Pseudohyperaldosteronism Manifesting with Nephrotic-range Proteinuria. Clin Infect Dis. 2020;71(10):2768-2770.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTantiprawan J, Sunthornyothin S, Boonchaya-Anant P, et al. Posaconazole-induced Pseudohyperaldosteronism. Kaohsiung J Med Sci. 2021;37(3):253-254.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNguyen MH, Davis MR, Wittenberg R, et al. Posaconazole Serum Drug Levels Associated With Pseudohyperaldosteronism. Clin Infect Dis. 2020;70(12):2593-2598.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eParker RW, Ferr\u0026eacute; EMN, Myint-Hpu K, et al. Posaconazole-induced Pseudohyperaldosteronism Manifesting with Nephrotic-range Proteinuria. Clin Infect Dis. 2020;71(10):2768-2770. DOI:10.1093/cid/ciaa119.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-pharmacy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijcp","sideBox":"Learn more about [International Journal of Clinical Pharmacy](https://www.springer.com/journal/11096)","snPcode":"11096","submissionUrl":"https://submission.nature.com/new-submission/11096/3","title":"International Journal of Clinical Pharmacy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4326408/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4326408/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Posaconazole (POS) is widely recommended for the prophylaxis and treatment of invasive fungal infections (IFIs) in immunocompromised patients, particularly those with prolonged neutropenia and a high risk of infection. The oral suspension form of POS, although commonly used, has its concentration influenced by various factors, impacting its effectiveness and safety.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAim\u003c/strong\u003e: This retrospective study aimed to investigate the effects of PPIs on POS concentrations and C/D to explore their impact on prophylactic outcomes and examine other potential factors that influence POS concentration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod\u003c/strong\u003e: This retrospective study involved patients who received POS for IFI prophylaxis or treatment. The study specifically focused on the effects of PPIs on POS plasma trough concentrations (C\u003csub\u003emin\u003c/sub\u003e) and concentration-to-dose (C/D) ratios.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: The analysis included 283 POS trough concentrations from 86 patients. The incidence of probable and proven IFIs was 6.4% (5/78). The use of PPI reduced POS C\u003csub\u003emin\u003c/sub\u003e levels but did not significantly affect the effectiveness of prophylaxis. Esomeprazole and rabeprazole were found to lower POS C\u003csub\u003emin\u003c/sub\u003e. The occurrence of hepatotoxicity was associated with the co-administration of drugs known to cause liver damage, indicating that POS was not the sole factor in these cases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Co-administration of esomeprazole or rabeprazole with posaconazole reduces its plasma concentrations but does not compromise prophylactic effectiveness against invasive fungal infections. This observation underscores the critical importance of vigilant management and comprehensive follow-up to optimize therapeutic outcomes in this high-risk patient population.\u003c/p\u003e","manuscriptTitle":"Effectiveness of combined proton pump inhibitors and posaconazole prophylaxis against invasive fungal infections in patients with hematologic malignancies: A retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-13 15:51:09","doi":"10.21203/rs.3.rs-4326408/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2024-06-01T16:36:03+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-05-06T01:45:15+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-04T18:20:08+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"International Journal of Clinical Pharmacy","date":"2024-04-29T10:03:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-29T04:57:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Pharmacy","date":"2024-04-27T08:29:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-pharmacy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijcp","sideBox":"Learn more about [International Journal of Clinical Pharmacy](https://www.springer.com/journal/11096)","snPcode":"11096","submissionUrl":"https://submission.nature.com/new-submission/11096/3","title":"International Journal of Clinical Pharmacy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"141e4650-f790-4778-814d-1fdd842706e3","owner":[],"postedDate":"May 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-09T16:01:28+00:00","versionOfRecord":{"articleIdentity":"rs-4326408","link":"https://doi.org/10.1007/s11096-024-01841-8","journal":{"identity":"international-journal-of-clinical-pharmacy","isVorOnly":false,"title":"International Journal of Clinical Pharmacy"},"publishedOn":"2024-12-07 15:57:24","publishedOnDateReadable":"December 7th, 2024"},"versionCreatedAt":"2024-05-13 15:51:09","video":"","vorDoi":"10.1007/s11096-024-01841-8","vorDoiUrl":"https://doi.org/10.1007/s11096-024-01841-8","workflowStages":[]},"version":"v1","identity":"rs-4326408","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4326408","identity":"rs-4326408","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}