When Primary Antifungal Therapy Fails

Nucci, Márcio; Perfect, John R.

doi:10.1086/587101

Cited by 83 publications

(63 citation statements)

References 78 publications

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“…Nevertheless, failure of antifungal therapy and relapse remain a substantial issue. When they occur, the clinician is usually tempted to attribute therapeutic failure to specific drug resistance, as observed in the scenario of invasive mycoses (317). However, acquired or natural resistance of melanized fungi to triazoles is uncommon.…”

Section: Criteria Of Curementioning

confidence: 99%

Chromoblastomycosis

et al. 2017

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SUMMARY Chromoblastomycosis (CBM), also known as chromomycosis, is one of the most prevalent implantation fungal infections, being the most common of the gamut of mycoses caused by melanized or brown-pigmented fungi. CBM is mainly a tropical or subtropical disease that may affect individuals with certain risk factors around the world. The following characteristics are associated with this disease: (i) traumatic inoculation by implantation from an environmental source, leading to an initial cutaneous lesion at the inoculation site; (ii) chronic and progressive cutaneous and subcutaneous tissular involvement associated with fibrotic and granulomatous reactions associated with microabscesses and often with tissue proliferation; (iii) a nonprotective T helper type 2 (Th2) immune response with ineffective humoral involvement; and (iv) the presence of muriform (sclerotic) cells embedded in the affected tissue. CBM lesions are clinically polymorphic and are commonly misdiagnosed as various other infectious and noninfectious diseases. In its more severe clinical forms, CBM may cause an incapacity for labor due to fibrotic sequelae and also due to a series of clinical complications, and if not recognized at an early stage, this disease can be refractory to antifungal therapy.

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Section: Criteria Of Curementioning

confidence: 99%

Chromoblastomycosis

et al. 2017

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“…The clinical signs and symptoms of an invasive fungal infection (IFI) can be absent until the infection is at an advanced stage due to the reduction or absence of a systemic inflammatory response in patients with profound neutropenia or receiving steroids (40,41). Therefore, it is generally believed that in addition to antifungal therapy, control of underlying medical or immunosuppressive conditions is mandatory for successful management of patient with IFIs (32,42).…”

Section: Figmentioning

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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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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“…Failure to respond to antifungal therapy is not uncommon in patients with A-Leuk 112 and is related to persistent profound myelosuppression, immunosuppression, or both. Measures to enhance immunity in "Other measures to prevent IFDs" can be considered.…”

Section: How Do We Manage Refractory Ifds?mentioning

confidence: 99%

How we treat invasive fungal diseases in patients with acute leukemia: the importance of an individualized approach

Nucci

Anaissie

2014

Blood

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Invasive fungal diseases (IFDs) represent an important cause of treatment failure in adults with acute leukemia. Because of leukemia’s heterogeneity, the risk for IFDs is highly variable. We therefore apply a risk-adapted antifungal strategy with strong emphasis on pretreatment and day-15 posttreatment to allow earlier and more individualized interventions. We determine pretreatment risks for IFDs based on 4 factors: (1) host fitness for standard therapy (ie, fit, unfit, or frail); (2) leukemia resistance (high vs low probability of achieving complete remission [CR]); (3) anticipated treatment-related toxicity such as neutropenia, mucositis, and steroid-induced immunosuppression; and (4) patient exposure to opportunistic fungi. Accordingly, we stratify patients as high, intermediate, or low risk for IFDs and apply risk-adapted antifungal strategies, including primary or secondary prophylaxis and diagnostic-based preemptive or empiric therapy. Prevention of IFDs also relies on optimizing organ function, decreasing exposure to opportunistic fungi, and improving net state of immunosuppression with use of better-tolerated and investigational agents for unfit patients and those with adverse leukemia biology. Novel targeted and safe therapies that can achieve higher rates of sustained CR among patients with adverse genetics offer the best promise for reducing the burden of IFDs in these patients.

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When Primary Antifungal Therapy Fails

Cited by 83 publications

References 78 publications

Chromoblastomycosis

Chromoblastomycosis

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

How we treat invasive fungal diseases in patients with acute leukemia: the importance of an individualized approach

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