Abstract
The diagnosis and treatment of mucormycosis are challenging. The incidence of the disease seems to be increasing. Hematological malignancies are the most common underlying disease in ...countries with high income and uncontrolled diabetes in developing countries. Clinical approach to diagnosis lacks sensitivity and specificity. Radiologically, multiple (≥10) nodules and pleural effusion are reportedly associated with pulmonary mucormycosis. Another finding on computerized tomography (CT) scan, which seems to indicate the presence of mucormycosis, is the reverse halo sign. Microscopy (direct and on histopathology) and culture are the cornerstones of diagnosis. Molecular assays can be used either for detection or identification of mucormycetes, and they can be recommended as valuable add-on tools that complement conventional diagnostic procedures. Successful management of mucormycosis is based on a multimodal approach, including reversal or discontinuation of underlying predisposing factors, early administration of active antifungal agents at optimal doses, complete removal of all infected tissues, and use of various adjunctive therapies. Our armamentarium of antifungals is slightly enriched by the addition of two newer azoles (posaconazole and isavuconazole) to liposomal amphotericin B, which remains the drug of choice for the initial antifungal treatment, according to the recently published guidelines by ECIL-6, as well as those published by ECMM/ESCMID. Despite the efforts for better understanding of the pathogenesis, early diagnosis and aggressive treatment of mucormycosis, the mortality rate of the disease remains high.
To investigate azole resistance in clinical Aspergillus isolates, we conducted prospective multicenter international surveillance. A total of 3,788 Aspergillus isolates were screened in 22 centers ...from 19 countries. Azole-resistant A. fumigatus was more frequently found (3.2% prevalence) than previously acknowledged, causing resistant invasive and noninvasive aspergillosis and severely compromising clinical use of azoles.
Zygomycosis is an important emerging fungal infection, associated with high morbidity and mortality. The Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) ...prospectively collected cases of proven and probable zygomycosis in 13 European countries occurring between 2005 and 2007. Cases were recorded by a standardized case report form, entered into an electronic database and analysed descriptively and by logistic regression analysis. During the study period, 230 cases fulfilled pre-set criteria for eligibility. The median age of the patients was 50 years (range, 1 month to 87 years); 60% were men. Underlying conditions included haematological malignancies (44%), trauma (15%), haematopoietic stem cell transplantation (9%) and diabetes mellitus (9%). The most common manifestations of zygomycosis were pulmonary (30%), rhinocerebral (27%), soft tissue (26%) and disseminated disease (15%). Diagnosis was made by both histology and culture in 108 cases (44%). Among 172 cases with cultures, Rhizopus spp. (34%), Mucor spp. (19%) and Lichtheimia (formerly Absidia) spp. (19%) were most commonly identified. Thirty-nine per cent of patients received amphotericin B formulations, 7% posaconazole and 21% received both agents; 15% of patients received no antifungal therapy. Total mortality in the entire cohort was 47%. On multivariate analysis, factors associated with survival were trauma as an underlying condition (p 0.019), treatment with amphotericin B (p 0.006) and surgery (p <0.001); factors associated with death were higher age (p 0.005) and the administration of caspofungin prior to diagnosis (p 0.011). In conclusion, zygomycosis remains a highly lethal disease. Administration of amphotericin B and surgery, where feasible, significantly improve survival.
Fluconazole in vitro susceptibility test results determined by the CLSI M44-A disk diffusion method for 11,240 isolates of noncandidal yeasts were collected from 134 study sites in 40 countries from ...June 1997 through December 2007. Data were collected for 8,717 yeast isolates tested with voriconazole from 2001 through 2007. A total of 22 different species/organism groups were isolated, of which Cryptococcus neoformans was the most common (31.2% of all isolates). Overall, Cryptococcus (32.9%), Saccharomyces (11.7%), Trichosporon (10.6%), and Rhodotorula (4.1%) were the most commonly identified genera. The overall percentages of isolates in each category (susceptible, susceptible dose dependent, and resistant) were 78.0%, 9.5%, and 12.5% and 92.7%, 2.3%, and 5.0% for fluconazole and voriconazole, respectively. Less than 30% of fluconazole-resistant isolates of Cryptococcus spp., Cryptococcus albidus, Cryptococcus laurentii, Trichosporon beigelii/Trichosporon cutaneum, Rhodotorula spp., Rhodotorula rubra/Rhodotorula mucilaginosa, and Rhodotorula glutinis remained susceptible to voriconazole. Emerging resistance to fluconazole was documented among isolates of C. neoformans from the Asia-Pacific, Africa/Middle East, and Latin American regions but not among isolates from Europe or North America. This survey documents the continuing broad spectrum of activity of voriconazole against opportunistic yeast pathogens but identifies several of the less common species with decreased azole susceptibility. These organisms may pose a future threat to optimal antifungal therapy and emphasize the importance of prompt and accurate species identification.
The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on ...diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.
EUCAST has revised the definition of the susceptibility category I from ‘Intermediate’ to ‘Susceptible, Increased exposure’. This implies that I can be used where the drug concentration at the site ...of infection is high, either because of dose escalation or through other means to ensure efficacy. Consequently, I is no longer used as a buffer zone to prevent technical factors from causing misclassifications and discrepancies in interpretations. Instead, an Area of Technical Uncertainty (ATU) has been introduced for MICs that cannot be categorized without additional information as a warning to the laboratory that decision on how to act has to be made. To implement these changes, the EUCAST-AFST (Subcommittee on Antifungal Susceptibility Testing) reviewed all, and revised some, clinical antifungal breakpoints.
The aim was to present an overview of the current antifungal breakpoints and supporting evidence behind the changes.
This document is based on the ten recently updated EUCAST rationale documents, clinical breakpoint and breakpoint ECOFF documents.
The following breakpoints (in mg/L) have been revised or established for Candida species: micafungin against C. albicans (ATU = 0.03); amphotericin B (S ≤/> R = 1/1), fluconazole (S ≤/> R = 2/4), itraconazole (S ≤/> R = 0.06/0.06), posaconazole (S ≤/> R = 0.06/0.06) and voriconazole (S ≤/> R = 0.06/0.25) against C. dubliniensis; fluconazole against C. glabrata (S ≤/> R = 0.001/16); and anidulafungin (S ≤/> R = 4/4) and micafungin (S ≤/> R = 2/2) against C. parapsilosis. For Aspergillus, new or revised breakpoints include itraconazole (ATU = 2) and isavuconazole against A. flavus (S ≤/> R = 1/2, ATU = 2); amphotericin B (S ≤/> R = 1/1), isavuconazole (S ≤ /> R = 1/2, ATU = 2), itraconazole (S ≤/> R = 1/1, ATU = 2), posaconazole (ATU = 0.25) and voriconazole (S ≤/> R = 1/1, ATU = 2) against A. fumigatus; itraconazole (S ≤/> R = 1/1, ATU = 2) and voriconazole (S ≤/> R = 1/1, ATU = 2) against A. nidulans; amphotericin B against A. niger (S ≤/> R = 1/1); and itraconazole (S ≤/> R = 1/1, ATU = 2) and posaconazole (ATU = 0.25) against A. terreus.
EUCAST-AFST has released ten new documents summarizing existing and new breakpoints and MIC ranges for control strains. A failure to adopt the breakpoint changes may lead to misclassifications and suboptimal or inappropriate therapy of patients with fungal infections.
Summary
Invasive fungal infections (IFI) of the Central Nervous System (IFI‐CNS) and Paranasal Sinuses (IFI‐PS) are rare, life‐threatening infections in haematologic patients, and their management ...remains a challenge despite the availability of new diagnostic techniques and novel antifungal agents. In addition, analyses of large cohorts of patients focusing on these rare IFI are still lacking. Between January 2010 and December 2016, 89 consecutive cases of Proven (53) or Probable (36) IFI‐CNS (71/89) and IFI‐PS (18/89) were collected in 34 haematological centres. The median age was 40 years (range 5‐79); acute leukaemia was the most common underlying disease (69%) and 29% of cases received a previous allogeneic stem cell transplant. Aspergillus spp. were the most common pathogens (69%), followed by mucormycetes (22%), Cryptococcus spp. (4%) and Fusarium spp. (2%). The lung was the primary focus of fungal infection (48% of cases). The nervous system biopsy was performed in 10% of IFI‐CNS, and a sinus biopsy was performed in 56% of IFI‐PS (P = 0.03). The Galactomannan test on cerebrospinal fluid has been performed in 42% of IFI‐CNS (30/71), and it was positive in 67%. Eighty‐four pts received a first‐line antifungal therapy with Amphotericine B in 58% of cases, Voriconazole in 31% and both in 11%. Moreover, 58% of patients received 2 or more lines of therapy and 38% were treated with a combination of 2 or more antifungal drugs. The median duration of antifungal therapy was 60 days (range 5‐835). A surgical intervention was performed in 26% of cases but only 10% of IFI‐CNS underwent neurosurgical intervention. The overall response rate to antifungal therapy (complete or partial response) was 57%, and 1‐year overall survival was 32% without significant differences between IFI‐CNS and IFI‐PS. The overall mortality was 69% but the IFI attributable mortality was 33%. Mortality of IFI‐CNS/PS remains high but, compared to previous historical data, it seems to be reduced probably due to the availability of newer antifungal drugs. The results arising from this large contemporary cohort of cases may allow a more effective diagnostic and therapeutic management of these very rare IFI complications in haematologic patients.
The emergence of azole-resistant Aspergillus fumigatus isolates is a matter of significant concern in Europe, with countries reporting resistance rates (which can be as high as 30%) in hospitalized ...patients. Consequently, the treatment guidelines in The Netherlands, the country with the highest documented prevalence of azole-resistant A. fumigatus, has just been revised to now recommend initial therapy with combination therapy until the susceptibility pattern is known. Therefore, susceptibility testing of clinically relevant isolates has been strongly recommended in the ESCMID-EFISG aspergillosis guidelines. Furthermore, mixed azole-susceptible and azole-resistant (isogenic as well as non-isogenic) infections have been reported to occur, which implies that colonies of clinical cultures may harbour various phenotypes of azole susceptibility.
The EUCAST-AFST (European Committee on Antimicrobial Susceptibility Testing Subcommittee on Antifungal Susceptibility Testing) has released a new screening method document (E.Def 10.1) for the detection of azole-resistant A. fumigatus isolates and updated the QC tables for antifungal susceptibility testing with associated QC endpoints. This review described in detail how to perform the screening test.
This “How to document” is based on the EUCAST azole agar screening method document E.Def 10.1 and the QC tables for antifungal susceptibility testing document, v 2.0 (available at http://www.eucast.org/ast_of_fungi/qcafsttables/)
The method is based on the inoculation of azole-containing and azole-free agars and visual determination of fungal growth after one and two days of incubation. It can easily be implemented in routine laboratories of clinical microbiology and has been validated for simultaneous testing of up to five A. fumigatus colonies using itraconazole and voriconazole (mandatory), and posaconazole (optional).
This easy-to-use screening procedure for the detection of azole resistance in clinical A. fumigatus isolates will allow rapid testing in the daily routine of the microbiology laboratory and thus facilitate earlier appropriate therapy.
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