High detection rate of azole-resistant Aspergillus fumigatus after treatment with azole antifungal drugs among patients with chronic pulmonary aspergillosis in a single hospital setting with low azole resistance

2020 ◽  
Author(s):  
Keita Takeda ◽  
Junko Suzuki ◽  
Akira Watanabe ◽  
Teppei Arai ◽  
Tomohiro Koiwa ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Antifungal Therapy ◽  
Detection Rate ◽  
Hospital Setting ◽  
Antifungal Drugs ◽  
High Rate ◽  
Therapy Failure ◽  
National Hospital ◽  
Pulmonary Aspergillosis ◽  
Chronic Pulmonary Aspergillosis

Abstract The prevalence of azole-resistant Aspergillus fumigatus (ARAF) among chronic pulmonary aspergillosis (CPA) patients treated with azoles in Japan is unknown. The aim of this study was to determine the detection rate of ARAF in isolates from CPA patients who were treated with azoles for varying durations. The potential mechanism of acquiring resistance was examined by sequencing cyp51A and hmg1, two genes associated with ARAF. A. fumigatus isolates (n = 120) were collected from CPA patients (n = 104) between February 2012 and February 2019, at National Hospital Organization Tokyo National Hospital. The isolates were tested for susceptibility to the azole drugs itraconazole (ITCZ) and voriconazole (VRCZ). The detection rate of ARAF among all isolates was 8.3% (n = 10). Of the 10 resistant isolates, eight were ITCZ-resistant and five were VRCZ-resistant. Among 47 isolates obtained from 36 CPA patients who were treated with ITCZ (for an average of 256 days) and/or VRCZ (for an average of 29 days), the resistance rates were 17.0% and 10.6%, respectively. In addition, 46.2% of 13 isolates obtained from CPA patients with ongoing azole treatment at the time of antifungal therapy failure were resistant to azoles. Among the 10 ARAF isolates, a point mutation was detected in cyp51A in seven isolates and in hmg1 in two isolates. ARAF was detected at a high rate in CPA patients, particularly in those with ongoing long-term azole treatment, at the time of azole antifungal therapy failure.

scholarly journals Clinical outcomes of patients with chronic pulmonary aspergillosis managed surgically

2020 ◽  
Vol 58 (5) ◽  
pp. 997-1003 ◽  
Author(s):  
Findra Setianingrum ◽  
Riina Rautemaa-Richardson ◽  
Rajesh Shah ◽  
David W Denning
Keyword(s):  
Antifungal Therapy ◽  
Wedge Resection ◽  
Symptom Control ◽  
Therapy Failure ◽  
Postoperative Monitoring ◽  
Pulmonary Aspergillosis ◽  
Before And After ◽  
Lung Malignancies ◽  
Chronic Pulmonary Aspergillosis

Abstract OBJECTIVES Surgical resection is one treatment modality for chronic pulmonary aspergillosis (CPA), and sometimes a preoperative presumption of lung cancer turns out to be CPA. We have audited our surgical experience with regard to risk factors for relapse, and the value of postoperative monitoring of Aspergillus-immunogolubulin G (IgG) titres. METHODS All patients with CPA surgically treated at National Aspergillosis Centre (NAC), Manchester, UK (2007–2018), were retrospectively evaluated. Surgical procedures, underlying disorders, Aspergillus-IgG titres (ImmunoCap) and antifungal therapy were evaluated for symptom control, operative complications, CPA relapse and mortality. RESULTS A total of 61 patients with CPA (28 males, 33 females) were operated on primarily for antifungal therapy failure (51%, n = 31) and presumed lung malignancies (38%, n = 23). Procedures included lobectomy (64%, n = 39), wedge resection (28%, n = 17), segmentectomy (n = 3), pneumonectomy (n = 3) and decortication (n = 2). Overall, 25 (41%) patients relapsed, 26 months (standard deviation: 24.8 months) after surgery. Antifungal therapy before surgery (P = 0.002) or both before and after surgery (P = 0.005) were protective for relapse. The relapse rate within 3 years after surgery (33%, n = 20) was higher than the 3–10 years after surgery (8%, n = 5). At the end of follow-up, the median Aspergillus-IgG titre was lower than at relapse in 12 patients (67 vs 126 mg/l) (P = 0.016). CONCLUSIONS Surgery in these selected patients with CPA resulted in favourable outcomes. Relapse is common after surgical treatment of CPA but can be minimized with antifungal therapy, emphasizing the importance of an accurate diagnosis prior to surgery.

scholarly journals Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management

2015 ◽  
Vol 47 (1) ◽  
pp. 45-68 ◽  
Author(s):  
David W. Denning ◽  
Jacques Cadranel ◽  
Catherine Beigelman-Aubry ◽  
Florence Ader ◽  
Arunaloke Chakrabarti ◽  
...  
Keyword(s):  
Antifungal Therapy ◽  
Clinical Guidelines ◽  
Bronchial Artery ◽  
Invasive Pulmonary Aspergillosis ◽  
Immunological Response ◽  
Surgical Excision ◽  
Immunocompromised Patients ◽  
Pulmonary Aspergillosis ◽  
Thoracic Imaging ◽  
Chronic Pulmonary Aspergillosis

Chronic pulmonary aspergillosis (CPA) is an uncommon and problematic pulmonary disease, complicating many other respiratory disorders, thought to affect ∼240 000 people in Europe. The most common form of CPA is chronic cavitary pulmonary aspergillosis (CCPA), which untreated may progress to chronic fibrosing pulmonary aspergillosis. Less common manifestations include:Aspergillusnodule and single aspergilloma. All these entities are found in non-immunocompromised patients with prior or current lung disease. Subacute invasive pulmonary aspergillosis (formerly called chronic necrotising pulmonary aspergillosis) is a more rapidly progressive infection (<3 months) usually found in moderately immunocompromised patients, which should be managed as invasive aspergillosis. Few clinical guidelines have been previously proposed for either diagnosis or management of CPA. A group of experts convened to develop clinical, radiological and microbiological guidelines. The diagnosis of CPA requires a combination of characteristics: one or more cavities with or without a fungal ball present or nodules on thoracic imaging, direct evidence ofAspergillusinfection (microscopy or culture from biopsy) or an immunological response toAspergillusspp. and exclusion of alternative diagnoses, all present for at least 3 months.Aspergillusantibody (precipitins) is elevated in over 90% of patients. Surgical excision of simple aspergilloma is recommended, if technically possible, and preferablyviavideo-assisted thoracic surgery technique. Long-term oral antifungal therapy is recommended for CCPA to improve overall health status and respiratory symptoms, arrest haemoptysis and prevent progression. Careful monitoring of azole serum concentrations, drug interactions and possible toxicities is recommended. Haemoptysis may be controlled with tranexamic acid and bronchial artery embolisation, rarely surgical resection, and may be a sign of therapeutic failure and/or antifungal resistance. Patients with singleAspergillusnodules only need antifungal therapy if not fully resected, but if multiple they may benefit from antifungal treatment, and require careful follow-up.

scholarly journals Antifungal effect of all-trans retinoic acid against Aspergillus fumigatus in vitro and in a pulmonary aspergillosis in vivo model

2020 ◽  
Author(s):  
Elena Campione ◽  
Roberta Gaziano ◽  
Elena Doldo ◽  
Daniele Marino ◽  
Mattia Falconi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Aspergillus Fumigatus ◽  
Rat Model ◽  
Fungal Infections ◽  
Invasive Pulmonary Aspergillosis ◽  
Antifungal Drugs ◽  
Pulmonary Aspergillosis ◽  
Fungistatic Activity

AIM: Aspergillus fumigatus is the most common opportunistic fungal pathogen and causes invasive pulmonary aspergillosis (IPA), with high mortality among immunosuppressed patients. Fungistatic activity of all-trans retinoic acid (ATRA) has been recently described in vitro. We evaluated the efficacy of ATRA in vivo and its potential synergistic interaction with other antifungal drugs. MATERIALS AND METHODS: A rat model of IPA and in vitro experiments were performed to assess the efficacy of ATRA against Aspergillus in association with classical antifungal drugs and in silico studies used to clarify its mechanism of action. RESULTS: ATRA (0.5 and 1 mM) displayed a strong fungistatic activity in Aspergillus cultures, while at lower concentrations, synergistically potentiated fungistatic efficacy of sub-inhibitory concentration of Amphotericin B (AmB) and Posaconazole (POS). ATRA also enhanced macrophagic phagocytosis of conidia. In a rat model of IPA, ATRA reduced mortality similarly to Posaconazole. CONCLUSION: Fungistatic efficacy of ATRA alone and synergistically with other antifungal drugs was documented in vitro, likely by inhibiting fungal Hsp90 expression and Hsp90-related genes. ATRA reduced mortality in a model of IPA in vivo. Those findings suggest ATRA as suitable fungistatic agent, also to reduce dosage and adverse reaction of classical antifungal drugs, and new therapeutic strategies against IPA and systemic fungal infections.

scholarly journals Aspergillus fumigatus and Aspergillus flavus-Specific IgG Cut-Offs for the Diagnosis of Chronic Pulmonary Aspergillosis in Pakistan

2020 ◽  
Vol 6 (4) ◽  
pp. 249
Author(s):  
Kauser Jabeen ◽  
Joveria Farooqi ◽  
Nousheen Iqbal ◽  
Khalid Wahab ◽  
Muhammad Irfan
Keyword(s):  
Aspergillus Fumigatus ◽  
Sensitivity And Specificity ◽  
Aspergillus Flavus ◽  
Diagnostic Algorithm ◽  
Pulmonary Aspergillosis ◽  
Significant Difference ◽  
Ethical Approval ◽  
Chronic Pulmonary Aspergillosis ◽  
Specific Igg ◽  
First Time

Despite a high burden of chronic pulmonary aspergillosis (CPA) in Pakistan, Aspergillus-specific IgG testing is currently not available. Establishing cut-offs for Aspergillus-specific IgG for CPA diagnosis is crucial due to geographical variation. In settings such as Pakistan, where non-Aspergillus fumigatus (mainly A. flavus) Aspergillus species account for the majority of CPA cases, there is a need to explore additional benefit of Aspergillus flavus-specific IgG detection along with A. fumigatus-specific IgG detection. This study was conducted at the Aga Khan University, Karachi, Pakistan after ethical approval. Serum for IgG detection were collected after informed consent from healthy controls (n = 21), diseased controls (patients with lung diseases, n = 18), and CPA patients (n = 21). A. fumigatus and A. flavus IgG were detected using Siemens immulite assay. The sensitivity and specificity of A. fumigatus-specific IgG were 80.95% and 82.05%, respectively at a cut-off of 20 mg/L. The sensitivity and specificity of A. flavus-specific IgG were 80.95% and 79.49% at a cut-off of 30 mg/L. We report, for the first time, performance of A. flavus-specific IgG for CPA diagnosis. Although there was no statistically significant difference between the performance of both antigens, it seems contextually relevant to include A. flavus IgG in the CPA diagnostic algorithm in regions with higher non-A. fumigatus CPA infections.

scholarly journals Emergence of Echinocandin Resistance Due to a Point Mutation in the fks1 Gene of Aspergillus fumigatus in a Patient with Chronic Pulmonary Aspergillosis

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Cristina Jiménez-Ortigosa ◽  
Caroline Moore ◽  
David W. Denning ◽  
David S. Perlin
Keyword(s):  
Aspergillus Fumigatus ◽  
Point Mutation ◽  
Hot Spot ◽  
Pulmonary Aspergillosis ◽  
Content Type ◽  
First Case ◽  
Chronic Pulmonary Aspergillosis ◽  
Echinocandin Resistance

ABSTRACT We have identified the first case of an fks1 hot spot 1 point mutation causing echinocandin resistance in a clinical Aspergillus fumigatus isolate recovered from a chronic pulmonary aspergillosis patient with an aspergilloma who first failed azole and polyene therapy and subsequently failed micafungin treatment.

scholarly journals Case Report: Chronic Pulmonary Aspergillosis—An Unusual Long-Term Complication of Lung Cancer Treatment

2022 ◽  
Vol 8 ◽  
Author(s):  
Katarzyna Guziejko ◽  
Katarzyna Klukowska ◽  
Urszula Budzińska ◽  
Robert Marek Mróz
Keyword(s):  
Lung Cancer ◽  
Fungal Infection ◽  
Antifungal Therapy ◽  
Rare Complication ◽  
Locally Advanced ◽  
Delayed Diagnosis ◽  
Pulmonary Aspergillosis ◽  
Radical Treatment ◽  
Significant Clinical Improvement ◽  
Chronic Pulmonary Aspergillosis

Background: Chronic pulmonary aspergillosis (CPA) is a rare complication of radiochemotherapy for lung cancer. It may develop months or years after radical treatment. The diagnosis of CPA is challenging and complex. Not only fungal infection but also cancer relapse always have to be taken under consideration. Antifungal therapy is the base treatment, especially in the case when a surgical procedure is not possible. Standard treatment for at least 6 months is recommended but the optimal duration of the antifungal therapy is unknown. We present the clinical case of CPA, in which we had to perform multidirectional diagnostic tests to confirm the diagnosis and modified treatment due to the recurrence of the disease.Case Presentation: We report a patient who developed CPA three and a half years after concurrent radiochemotherapy for locally advanced non-small-cell lung cancer. Non-specific symptoms were the cause of delayed diagnosis of fungal infection. Samples collected during bronchoscopy allowed to exclude the recurrence of lung cancer and establish the diagnosis of CPA. The patient was treated with itraconazole for 6 months. A few months later, controlled chest CT scans revealed the progression of CPA. Initially, retreatment with itraconazole was implemented. Due to the progression of fungal infection, voriconazole was used in the second line of treatment. Unfortunately, this therapy was complicated by the side effects and deterioration of the patient's condition. The reintroduction of itraconazole resulted in clinical and radiological improvement. Treatment is scheduled for at least 12 months.Conclusion: Chronic pulmonary aspergillosis (CPA) was the cause of clinical deterioration and radiological progression in a patient after the radical treatment of lung cancer. In the described case, the diagnosis of CPA was delayed because of the suspicion of the recurrence of lung cancer. As the surgery was not possible, antifungal therapy with itraconazole was implemented and the proper dosage and duration led to significant clinical improvement.

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