Posaconazole Prophylaxis in Experimental Azole-Resistant Invasive Pulmonary Aspergillosis

Seyedmousavi, Seyedmojtaba; Mouton, Johan W.; Melchers, Willem J. G.; Verweij, Paul E.

doi:10.1128/aac.03850-14

Cited by 23 publications

(21 citation statements)

References 55 publications

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“…The data also confirm our previous findings in experimental murine models of IA, in which equal levels of exposure-response relationships were required for treating neutropenic and nonneutropenic mice with azole antifungals (46)(47)(48). Of note, this effect might be related to the fungicidal or fungistatic mode of action of the antifungals studied (49).…”

Section: Figsupporting

confidence: 88%

“…In the neutropenic groups, mice were rendered immunosuppressed by injection of 150 mg of cyclophosphamide/kg of body weight intraperitoneally on days Ϫ4 and Ϫ1 and day ϩ4. For steroid immunosuppression, cortisone acetate (100 mg/kg/day) was administered subcutaneously 3 days before and 5 days after infection as described previously (46,53).…”

Section: Fungal Strains the Following Two Clinical A Fumigatus Isolmentioning

confidence: 99%

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In Vivo Efficacy of Liposomal Amphotericin B against Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates in Two Different Immunosuppression Models of Invasive Aspergillosis

Seyedmousavi

Mouton

Melchers

et al. 2017

Antimicrob Agents Chemother

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Using an immunocompetent murine model of invasive aspergillosis (IA), we previously reported that the efficacy of liposomal amphotericin B (L-AmB) (Ambisome) is not hampered by the presence of azole resistance mutations in Aspergillus fumigatus (S. Seyedmousavi, W. J. G. Melchers, J. W. Mouton, and P. E. Verweij, Antimicrob Agents Chemother 57:1866 -1871, 2013, https://doi.org/10.1128/AAC.02226 -12). We here investigated the role of immune suppression, i.e., neutropenia and steroid treatment, in L-AmB efficacy in mice infected with wild-type (WT) A. fumigatus and with azole-resistant A. fumigatus harboring a TR 34 /L98H mutation in the cyp-51A gene. Survival of treated animals at day 14 in both immunosuppressed models was significantly better than that of nontreated controls. A dose-response relationship was observed that was independent of the azole-resistant mechanism and the immunosuppression method used. In the neutropenic model, 100% survival was reached at an L-AmB dose of 16 mg/kg of body weight for the WT strain and the TR 34 /L98H isolate. In the steroid-treated group, 90.9% survival and 100% survival were achieved for the WT isolate and the TR 34 /L98H isolate with an L-AmB dose of 16 mg/kg, respectively. The 50% effective dose (ED 50 ) was 1.40 mg/kg (95% confidence interval [CI], 0.66 to 3.00 mg/kg) for the WT isolate and 1.92 mg/kg (95% CI, 0.60 to 6.17 mg/kg) for the TR 34 /L98H isolate in the neutropenic model and was 2.40 mg/kg (95% CI, 1.93 to 2.97 mg/kg) for the WT isolate and 2.56 mg/kg (95% CI, 1.43 to 4.56 mg/kg) for the TR 34 /L98H isolate in the steroid-treated group. Overall, there were no significant differences between the two different immunosuppressed conditions in the efficacy of L-AmB against the wild-type and azole-resistant isolates (P Ͼ 0.9). However, the required L-AmB exposure was significantly higher than that seen in the immunocompetent model.

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Section: Figsupporting

confidence: 88%

Section: Fungal Strains the Following Two Clinical A Fumigatus Isolmentioning

confidence: 99%

In Vivo Efficacy of Liposomal Amphotericin B against Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates in Two Different Immunosuppression Models of Invasive Aspergillosis

Seyedmousavi

Mouton

Melchers

et al. 2017

Antimicrob Agents Chemother

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“…On day 0, mice were infected with the A. fumigatus isolate through instillation of conidial suspension in the nares. The infection model was confirmed by 0% survival in survival experiments with untreated control animals (n ϭ 44 mice) (10,11). Blood and bronchoalveolar lavage (BAL) samples were drawn at 8 predefined time points postinfection (0, 0.5, 1, 2, 4, 8, 12, and 24 h, 3 mice per each time point), as described previously (12).…”

mentioning

confidence: 93%

“…Urea in BAL aspirate and plasma was measured utilizing a modified enzymatic assay (QuantiChrom urea assay kit, DIUR-500; BioAssay Systems) (14, 15). The concentration of posaconazole in ELF was then determined by using the ratio of urea concentration in BAL fluid to that in plasma as described previously (10,11,(14)(15)(16)(17)(18)(19): drug concentration ELF ϭ drug concentration BAL ϫ urea plasma /urea BAL .…”

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Intrapulmonary Posaconazole Penetration at the Infection Site in an Immunosuppressed Murine Model of Invasive Pulmonary Aspergillosis Receiving Oral Prophylactic Regimens

Seyedmousavi

Brüggemann

Melchers

et al. 2014

Antimicrob Agents Chemother

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c Adequate penetration to the infection/colonization site is crucial to attain optimal efficacy of posaconazole against Aspergillus fumigatus diseases. We evaluated posaconazole exposure in pulmonary epithelial lining fluid (ELF) in a murine model of invasive pulmonary aspergillosis. The posaconazole exposure (area under the plasma concentration-time curve from time zero to 24 h postinfusion [AUC 0 -24 ]) in ELF was 20% to 31% of that in plasma for total drug after the third dose, and the relationship between plasma and ELF exposure was linear (r 2 ‫؍‬ 0.97, P ‫؍‬ 0.016). Inhalation of Aspergillus fumigatus conidia is the most common route of infection in invasive aspergillosis (IA), with the lung being the primary site of infection. Adequate drug penetration to the infection site is therefore crucial for optimal efficacy. Posaconazole is the recommended drug for prophylaxis of Aspergillus diseases in neutropenic patients and stem cell transplantation (SCT) recipients (1-3). Notably, despite relatively low levels of free (unbound) posaconazole exposure in plasma (4-6), there appears to be an adequate protection (adequate prophylaxis) against infection due to Aspergillus fumigatus with an MIC higher than susceptible breakpoints to posaconazole. This is somewhat surprising, compared to some other triazole antifungals in similar animal models and clinical trials of invasive candidiasis (7). This phenomenon could possibly be related to a higher-than-predicted posaconazole penetration at the infection/colonization site, particularly in case of lung infection. Therefore, we set out to explore the posaconazole concentrations and corresponding exposure in pulmonary epithelial lining fluid (ELF) compared to those in blood levels.A clinical A. fumigatus isolate (posaconazole MIC of 0.5 mg/ liter) obtained from a patient with proven IA was used in the experiments. Strain identification was confirmed by sequencebased analysis, as described previously (8). The isolate had been stored in 10% glycerol broth at Ϫ80°C. Before performing the experiment, the isolate was cultured once on Sabouraud dextrose agar (SDA) for 5 to 7 days at 35 to 37°C and subcultured twice on 15-cm Takashio slants for 5 to 7 days at 35 to 37°C. The conidia were harvested in 20 ml of sterile phosphate-buffered saline (PBS) and 0.1% Tween 80 (Boom B.V. Meppel, the Netherlands). The conidial suspension was filtered through sterile gauze folded four times to remove any hyphae, and the number of conidia was counted in a hemocytometer. After the inoculum was adjusted to the required concentration, the conidial suspension was stored overnight at 4°C. The in vitro antifungal susceptibility test was performed based on the EUCAST guidelines, using a broth microdilution format (9).A total of 96 outbred CD-1 (Charles River, the Netherlands) female mice, 4 to 5 weeks old, weighing 20 to 22 g, were used. To render the mice neutropenic, cyclophosphamide (150 mg/kg of body weight on day Ϫ4 and 100 mg/kg on day Ϫ1) was administered. Animals received 4, 8, 16, or 32 mg/k...

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Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial

et al. 2021

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Purpose Influenza-associated pulmonary aspergillosis (IAPA) is a frequent complication in critically ill influenza patients, associated with significant mortality. We investigated whether antifungal prophylaxis reduces the incidence of IAPA. Methods We compared 7 days of intravenous posaconazole (POS) prophylaxis with no prophylaxis (standard-of-care only, SOC) in a randomised, open-label, proof-of-concept trial in patients admitted to an intensive care unit (ICU) with respiratory failure due to influenza (ClinicalTrials.gov, NCT03378479). Adult patients with PCR-confirmed influenza were block randomised (1:1) within 10 days of symptoms onset and 48 h of ICU admission. The primary endpoint was the incidence of IAPA during ICU stay in patients who did not have IAPA within 48 h of ICU admission (modified intention-to-treat (MITT) population). Results Eighty-eight critically ill influenza patients were randomly allocated to POS or SOC. IAPA occurred in 21 cases (24%), the majority of which (71%, 15/21) were diagnosed within 48 h of ICU admission, excluding them from the MITT population. The incidence of IAPA was not significantly reduced in the POS arm (5.4%, 2/37) compared with SOC (11.1%, 4/36; between-group difference 5.7%; 95% CI − 10.8 to 21.7; p = 0.32). ICU mortality of early IAPA was high (53%), despite rapid antifungal treatment. Conclusion The higher than expected incidence of early IAPA precludes any definite conclusion on POS prophylaxis. High mortality of early IAPA, despite timely antifungal therapy, indicates that alternative management strategies are required. After 48 h, still 11% of patients developed IAPA. As these could benefit from prophylaxis, differentiated strategies are likely needed to manage IAPA in the ICU. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06431-0.

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Posaconazole Prophylaxis in Experimental Azole-Resistant Invasive Pulmonary Aspergillosis

Cited by 23 publications

References 55 publications

In Vivo Efficacy of Liposomal Amphotericin B against Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates in Two Different Immunosuppression Models of Invasive Aspergillosis

In Vivo Efficacy of Liposomal Amphotericin B against Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates in Two Different Immunosuppression Models of Invasive Aspergillosis

Intrapulmonary Posaconazole Penetration at the Infection Site in an Immunosuppressed Murine Model of Invasive Pulmonary Aspergillosis Receiving Oral Prophylactic Regimens

Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial

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