Pharmacodynamics and Dose-Response Relationships of Liposomal Amphotericin B against Different Azole-Resistant Aspergillus fumigatus Isolates in a Murine Model of Disseminated Aspergillosis

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

doi:10.1128/aac.02226-12

Cited by 39 publications

(28 citation statements)

References 49 publications

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“…Voriconazole is recommended for IPA due to A. fumigatus if the isolate is voriconazole-susceptible (susceptible if MIC ≤1 mg/L) whilst in the case of resistance (MIC >2 mg/L) LAmB therapy is preferred. Where the voriconazole MIC equals 2 mg/L (intermediate) the response to voriconazole monotherapy is unknown [58]. A growing problem in IPA treatment is the intrinsic resistance to polyenes and azoles or the acquired resistance to azoles during azole therapy mainly in patients with chronic pulmonary aspergillosis (CPA) [59].…”

Section: Invasive Aspergillosismentioning

confidence: 99%

Intensive care medicine research agenda on invasive fungal infection in critically ill patients

et al. 2017

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Purpose:To describe concisely the current standards of care, major recent advances, common beliefs that have been contradicted by recent trials, areas of uncertainty, and clinical studies that need to be performed over the next decade and their expected outcomes with regard to Candida and Aspergillus infections in non-neutropenic patients in the ICU setting. Methods:A systematic review of the medical literature taking account of national and international guidelines and expert opinion. Results:Severe invasive fungal infections (IFIs) are becoming increasingly frequent in critically ill patients. Approximately 80% of IFIs are due to Candida spp. and 0.3-19% to Aspergillus spp. Recent observations emphasize the necessity of building a worldwide sentinel network to monitor the emergence of new fungal species and changes in susceptibility. Robust data on the attributable mortality are essential for the design of clinical studies with mortality endpoints. Although early antifungal therapy for Candida has been recommended in patients with risk factors, sepsis of unknown cause, and positive Candida serum biomarkers [β-1 → 3-d-glucan (BDG) and Candida albicans germ tube antibody (CAGTA)], its usefulness and influence on outcome need to be confirmed. Future studies may specifically address the optimal diagnostic and therapeutic strategies for patients with abdominal candidiasis. Better knowledge of the pharmacokinetics of antifungal molecules and tissue penetration is a key issue for intensivists. Regarding invasive aspergillosis, further investigation is needed to determine its incidence in the ICU, its relationship with influenza outbreaks, the clinical impact of rapid diagnosis, and the significance of combination treatment. Conclusions:Fundamental questions regarding IFI have to be addressed over the next decade. The clinical studies described in this research agenda should provide a template and set priorities for the clinical investigations that need to be performed.

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Section: Invasive Aspergillosismentioning

confidence: 99%

Intensive care medicine research agenda on invasive fungal infection in critically ill patients

et al. 2017

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“…We have previously shown that liposomal amphotericin B (L-AmB) (Ambisome) is effective against azole-resistant IA using a nonneutropenic murine model of disseminated infection (31). A dose-response relationship was observed that was independent of the presence of an azole resistance mechanism.…”

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confidence: 95%

“…We previously investigated the efficacy of L-AmB monotherapy in an immunocompetent murine model of IA. In that study, the ED 50 values were 0.29 mg/kg (95% CI, 0.05 to 1.65 mg/kg) for the WT isolate and 0.59 mg/kg (95% CI, 0.02 to 14.80 mg/kg) for the TR 34 /L98H isolate (31). There were also no significant differences in L-AmB efficacy against the WT and azole-resistant isolates in immunocompetent mice (P value ϭ 0.83).…”

Section: Figmentioning

confidence: 99%

“…Surveillance studies indicate that azole resistance is increasing in Europe, the Middle East, Asia, Africa, and Australia and, most recently, in North and South America as well (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Azole-resistant IA has been shown to be associated with a very high mortality rate; therefore, alternative treatment regimens need to be investigated to improve the outcome of patients (18,31,32).…”

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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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“…The activity of amphotericin B and the echinocandins in vitro remained unaffected. Liposomal amphotericin B has shown good efficacy in a nonneutropenic murine model of acute azoleresistant invasive aspergillosis (14).…”

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High-Level Pan-Azole-Resistant Aspergillosis

et al. 2015

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High-level pan-azole-resistant Aspergillus fumigatus was recovered from four patients with chronic lung disease. In one patient, the development of progressive resistance followed long-term azole therapy and switching between antifungal azoles. The highlevel pan-azole-resistant phenotypes were not associated with a specific cyp51A gene mutation. New strategies that avoid the development of progressive azole resistance are needed.A zole resistance in Aspergillus fumigatus is an emerging problem which is associated with treatment failure in patients with aspergillus diseases (1). Resistance is commonly due to mutations in the cyp51A gene (1) that typically lead to high-level resistance (MIC, Ն8 mg/liter) against one azole and low-level resistance (MICs close to the resistance breakpoint) against others (2, 3).We identified four A. fumigatus isolates with MIC of Ն8 mg/ liter for all mold-active azoles, measured using EUCAST methodology (4). We labeled this unique phenotype high-level pan-azole resistance. We analyzed the cyp51A gene sequence of the isolates, using previously published algorithms (5), and retrieved clinical data for these four patients (Table 1).The first patient was a 22-year-old male with cystic fibrosis. After being diagnosed with allergic bronchopulmonary aspergillosis (ABPA), he commenced itraconazole and steroid maintenance therapy. Fungal sputum cultures after 8 months of itraconazole therapy revealed an A. fumigatus isolate with the high-level pan-azole-resistant phenotype. The patient continued itraconazole maintenance therapy, and the high-level pan-azole-resistant isolate was not recovered from repeat cultures.The second patient was a 71-year-old male with a medical history of asthma, bronchiectasis, and intermittent culture positivity with itraconazole-and voriconazole-susceptible A. fumigatus. The patient did not meet diagnostic criteria for ABPA and was never treated with azoles. The high-level pan-azole-resistant A. fumigatus isolate was isolated once from a sputum sample; follow-up sputum cultures yielded azole-susceptible A. fumigatus.The third patient was a 47-year-old female with severe pulmonary sarcoidosis, complicated by a pneumothorax with subsequent pleural empyema. From this empyema, an azole-susceptible A. fumigatus isolate was cultured (itraconazole and voriconazole MICs, 0.5 mg/ liter; posaconazole MIC, 0.063 mg/liter). Treatment with itraconazole was started, later changed to voriconazole, and ultimately changed to posaconazole as a chronic suppressive therapy. After 18 months of azole therapy, the patient's disease progressed, and a sputum sample was ordered for fungal culture. This sample grew the high-level pan-azole-resistant isolate and induced a switch to liposomal amphotericin B therapy. Despite treatment, the patient's condition deteriorated, and she died of respiratory failure.The fourth patient was a 39-year-old male diagnosed with chronic granulomatous disease and ABPA. The patient had been treated for multiple episodes of invasive pulmonary aspergillosis, and...

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Pharmacodynamics and Dose-Response Relationships of Liposomal Amphotericin B against Different Azole-Resistant Aspergillus fumigatus Isolates in a Murine Model of Disseminated Aspergillosis

Cited by 39 publications

References 49 publications

Intensive care medicine research agenda on invasive fungal infection in critically ill patients

Intensive care medicine research agenda on invasive fungal infection in critically ill patients

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

High-Level Pan-Azole-Resistant Aspergillosis

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