Antifungal resistance in mucorales Dannaoui, E.
International journal of antimicrobial agents,
November 2017, 2017-Nov, 2017-11-00, 20171101, 2017-11, Volume:
50, Issue:
5
Journal Article
Peer reviewed
•There is a great diversity among the order Mucorales.•Mucorales are characterised by their antifungal resistance to most commonly available antifungal drugs.•Amphotericin B, posaconazole and ...isavuconazole are the three drugs currently used for the treatment of mucormycosis.•Animal models are important to assess antifungal efficacy for this rare disease.
The order Mucorales, which includes the agents of mucormycosis, comprises a large number of species. These fungi are characterised by high-level resistance to most currently available antifungal drugs. Standardised antifungal susceptibility testing methods are now available, allowing a better understanding of the in vitro activity of antifungal drugs against members of Mucorales. Such tests have made apparent that antifungal susceptibility within this group may be species-specific. Experimental animal models of mucormycosis have also been developed and are of great importance in bridging the gap between in vitro results and clinical trials. Amphotericin B, posaconazole and isavuconazole are currently the most active agents against Mucorales; however, their activity remains suboptimal and new therapeutic strategies are needed. Combination therapy could be a promising approach to overcome resistance, but further studies are required to confirm its benefits and safety for patients.
The identification of Zygomycetes and diagnosis of zygomycosis are notoriously difficult. However, there have been recent advances, particularly in the availability and evaluation of new molecular ...approaches. Two main issues are of importance: the identification to species level of a strain isolated in culture, and the identification of a zygomycete in tissues. By using several molecular targets and by increasing the number of available DNA sequences in international databases, several studies have shown that accurate molecular identification of Zygomycetes to species level is feasible. The internal transcribed spacer (ITS) region may be used as a first-line molecular target for the identification of Zygomycetes in pure culture. However, cultures from infected tissues are often negative and the different Zygomycetes share similar morphology according to histopathology. Furthermore, differentiation of a zygomycete from another hyalohyphomycete can sometimes be difficult in histopathology. Thus, alternative methods for the diagnosis of zygomycosis and for species identification directly from tissues are needed. For this purpose, molecular methods have been recently evaluated, both on unfixed fresh/frozen material and on formalin-fixed, paraffin-embedded biopsies. This review discusses the molecular approaches currently available for the identification of Zygomycetes and the diagnosis of zygomycosis.
Background. Mucormycosis is a deadly invasive fungal infection whose characteristics are only partially understood. Methods. Data on mucormycosis obtained in France between 2005 and 2007 from 2 ...notification systems were merged. The 2008 European Organisation for Research and Treatment of Cancer/Mycoses Study Group definition criteria were applied and risk factors for death were analyzed by hazard ratios (HRs) calculated from the Cox proportional hazards regression model. Results. A total of 101 cases (60 proven, 41 probable), mostly in men (58%) > 50 years (mean age, 50.7 ± 19.9) were recorded. Hematological malignancies represented 50% (median time for occurrence, 8.8 months after disease onset), diabetes 23%, and trauma 18% of cases. Sites of infection were lungs (28%; 79% in hematology patients), rhinocerebral (25%; 64% in diabetic patients), skin (20%), and disseminated (18%). Median time between first symptoms and diagnosis was 2 weeks. The main fungal species were Rhizopus oryzae (32%) and Lichtheimia species (29%). In cases where the causative species was identified, R. oryzae was present in 85% of rhinocerebral forms compared with only 17% of nonrhinocerebral forms (P < .001). Treatment consisted of surgery in 59% and antifungals in 87% of cases (liposomal amphotericin B in 61%). Ninety-day survival was 56%; it was reduced in cases of dissemination compared with rhinocerebral (HR, 5.38 2.0-14.1; P < .001), pulmonary (HR, 2.2 1.0-4.7; P = .04), or skin localization (HR, 5.73 1.9-17.5; P = .002); survival was reduced in cases of hematological malignancies compared with diabetes mellitus (HR, 2.3 1.0-5.2; P < .05) or trauma (HR, 6.9 1.6-28.6, P = .008) and if ≥2 underlying conditions (HR, 5.9 1.8-19.0; P = .004). Mucormycosis localization remained the only independent factor associated with survival. Conclusions. This 3-year study performed in one country shows the diverse clinical presentation of mucormycosis with a high prevalence of primary skin infection following trauma and a prognosis significantly influenced by localization.
is an emerging, multidrug resistant pathogen, responsible for invasive hospital-acquired infections. Flucytosine is an effective anti-
drug, but which cannot be used as a monotherapy because of the ...risk of development of resistant mutants during treatment. It is therefore noteworthy to test possible combinations with flucytosine that may have a synergistic interaction. In this study, we determined the
interaction between flucytosine and amphotericin B, micafungin, or voriconazole. These combinations have been tested against 15
isolates. The MIC range (Gmean) of flucytosine, amphotericin B, micafungin and voriconazole were 0.125 to 1 μg/mL (0.42 μg/ml), 0.25 to 1 μg/ml (0.66 μg/ml), 0.125 to 0.5 μg/ml (0.3 μg/ml) and 0.03 to 4 μg/ml (1.05 μg/ml), respectively. When tested in combination, indifferent interactions were mostly observed with fractional inhibitory concentration index values from 0.5 to 1, 0.31 to 1.01 and 0.5 to 1.06 for the combination of flucytosine with amphotericin B, micafungin and voriconazole, respectively. A synergy was observed for the strain CBS 10913 from Japan. No antagonism was observed for any combination. Combination of flucytosine with amphotericin B or micafungin may be relevant for the treatment of
infections.
Candida auris is an emerging fungal pathogen responsible for nosocomial invasive infection outbreaks on five continents. Large healthcare-related outbreaks of C. auris infection and colonization have ...been reported from different countries. Whole genome sequence analysis identified strong phylogeographic C. auris clades specific to particular geographical areas suggesting transmission of particular clades within countries. However, the mode of transmission within the healthcare environment is not clear and is likely to be multifactorial. The emergence of C. auris is alarming because this organism can harbor or develop multidrug resistance. This explains why C. auris infections are difficult to treat. In addition, difficulties in its identification in the routine diagnostic laboratory have a significant impact on outbreak detection and management. This mini-review highlights the available literature on C. auris, with particular insight into its epidemiology and the problems caused by its antifungal resistance.
•Candida auris is an emerging multiresistant pathogen.•Colistin alone has no antifungal activity.•The in vitro combination of colistin with caspofungin is strongly synergistic.
Antifungal combination ...is an interesting approach for the treatment of several fungal infections but there is currently little evidence to support combined therapy in Candida auris infections. The antibacterial colistin has recently been shown to interact synergistically with antifungals against Candida spp., including azole-resistant isolates. The current study evaluated the in vitro interaction between colistin and either caspofungin or micafungin against 15 C. auris isolates by a checkerboard methodology based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) reference method. Results were analysed by two approaches: calculation of the fractional inhibitory concentration index (FICI) and response surface analysis based on the Bliss model. The minimum inhibitory concentration (MIC) range (geometric mean Gmean) of caspofungin and micafungin was 0.25 to 1 µg/mL (0.691 µg/mL) and 0.03 to 0.125 µg/mL (0.114 µg/mL), respectively. No activity was observed for colistin alone with MIC of >64 µg/mL for all the isolates. When colistin was combined with caspofungin, synergistic interactions were observed for all strains with FICI values of 0.08 to 0.14. In contrast, indifferent interactions were observed for the combination of colistin with micafungin with FICI values of 0.51 to 1.01. Synergy was also demonstrated using the Bliss model against all isolates for the colistin-caspofungin combination and in 60% of isolates for the colistin-micafungin combination. Antagonism was not observed for any combination.
Clinical breakpoints (CBPs) have not been established for the Mucorales and any antifungal agent. In lieu of CBPs, epidemiologic cutoff values (ECVs) are proposed for amphotericin B, posaconazole, ...and itraconazole and four Mucorales species. Wild-type (WT) MIC distributions (organisms in a species-drug combination with no detectable acquired resistance mechanisms) were defined with available pooled CLSI MICs from 14 laboratories (Argentina, Australia, Canada, Europe, India, Mexico, and the United States) as follows: 10 Apophysomyces variabilis, 32 Cunninghamella bertholletiae, 136 Lichtheimia corymbifera, 10 Mucor indicus, 123 M. circinelloides, 19 M. ramosissimus, 349 Rhizopus arrhizus, 146 R. microsporus, 33 Rhizomucor pusillus, and 36 Syncephalastrum racemosum isolates. CLSI broth microdilution MICs were aggregated for the analyses. ECVs comprising ≥95% and ≥97.5% of the modeled populations were as follows: amphotericin B ECVs for L. corymbifera were 1 and 2 μg/ml, those for M. circinelloides were 1 and 2 μg/ml, those for R. arrhizus were 2 and 4 μg/ml, and those for R. microsporus were 2 and 2 μg/ml, respectively; posaconazole ECVs for L. corymbifera were 1 and 2, those for M. circinelloides were 4 and 4, those for R. arrhizus were 1 and 2, and those for R. microsporus were 1 and 2, respectively; both itraconazole ECVs for R. arrhizus were 2 μg/ml. ECVs may aid in detecting emerging resistance or isolates with reduced susceptibility (non-WT MICs) to the agents evaluated.
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.
combinations of isavuconazole with echinocandins were evaluated against 30
strains with a two-dimensional checkerboard microdilution method and an agar-based diffusion method. With the checkerboard ...method, the three combinations showed indifferent interactions for all strains. With the agar-based method, indifferent interactions were found for all strains for isavuconazole-micafungin and isavuconazole-anidulafungin. For the isavuconazole-caspofungin combination, indifference was found in 24/30 strains, synergism in 4/30 strains, and antagonism in 2/30 strains.
PDF
