Editorial
The rising threat of intrinsically resistant Candida species in Argentina
El creciente riesgo de Candida spp. intrínsicamente resistentes en Argentina
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This alarming trend poses a significant challenge in the management of fungal infections and demands immediate attention and action. In this editorial, we shed light on the implications of intrinsic resistance in <span class="elsevierStyleItalic">Candida</span> species and emphasize the urgent need for enhanced strategies to combat this threat.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Understanding intrinsic resistance</span><p id="par0010" class="elsevierStylePara elsevierViewall">The 2022 document M27M44SEd3E from the Clinical and Laboratory Standards Institute (CLSI) defines intrinsic resistance (IR) as the “inherent or innate (not acquired) resistance to an antifungal, which is reflected in the non-wild-type susceptibility patterns of all or almost all representatives of a species”. This characterization implies that a correct taxonomical identification would be enough to classify an isolate as intrinsically resistant or not. As an important achievement, the first list of intrinsically resistant species was published in the same document. This list includes <span class="elsevierStyleItalic">Candida krusei</span> (also recognized under the taxonomic name <span class="elsevierStyleItalic">Pichia kudriavzevii</span>), showing intrinsic resistance (IR) to fluconazole, and three basidiomycetous fungi (<span class="elsevierStyleItalic">Cryptococcus</span> spp., <span class="elsevierStyleItalic">Rhodotorula</span> spp., and <span class="elsevierStyleItalic">Trichosporon</span> spp.)<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">6</span></a> that should be considered intrinsically resistant to echinocandins, with <span class="elsevierStyleItalic">Rhodotorula</span> also being resistant to fluconazole. In this list has disappointed a part of the scientific community since intrinsic resistance limits the effectiveness of standard treatment options from the onset.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Implications for Public Health</span><p id="par0015" class="elsevierStylePara elsevierViewall">The impact of intrinsic resistance in <span class="elsevierStyleItalic">Candida</span> species on public health cannot be overstated. Infections caused by these resistant species often result in prolonged hospital stays, increased healthcare costs, and elevated mortality rates. Deep-seated <span class="elsevierStyleItalic">Candida</span> spp. infections are associated with mortality rates of ∼50% and these ratios are higher in the context of infections with drug-resistant <span class="elsevierStyleItalic">Candida</span> spp. Patients with compromised immune systems, such as those with HIV/AIDS or undergoing chemotherapy, are particularly vulnerable to these infections. In addition, the limited arsenal of effective antifungal drugs against these resistant Candida strains leaves healthcare providers with few treatment options, making it challenging to achieve successful outcomes.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Contributing factors</span><p id="par0020" class="elsevierStylePara elsevierViewall">Several factors contribute to the emergence of intrinsic antifungal-resistant <span class="elsevierStyleItalic">Candida</span> spp. One key factor is the overuse and misuse of antifungal agents. Inappropriate prescribing practices, inadequate dosing, and failure to complete treatment regimens have fueled the selection pressure of <span class="elsevierStyleItalic">Candida</span> spp. populations, leading to the development and propagation of resistant species. Furthermore, it was proposed that the extensive use of antifungals in agriculture and animal husbandry has contributed to the creation of reservoirs of resistant strains, which can be transmitted to humans.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">The rise of <span class="elsevierStyleItalic">Candida auris</span> and the <span class="elsevierStyleItalic">Candida haemulonii</span> species complex</span><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Candida auris</span> has rapidly gained attention as an emerging global health threat and has recently been included as one of the four fungal pathogens of the critical priority group of the WHÓs fungal priority pathogens list due to its morbidity and mortality rate, antifungal resistance and major knowledge gaps on its global burden<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>. Although <span class="elsevierStyleItalic">C. auris</span> was proposed to be included as a fluconazole IR species in the aforementioned CLSI document, it does not strictly meet the inclusion criteria since not all but more than 93% of the studied <span class="elsevierStyleItalic">C. auris</span> strains show high fluconazole MICs (and some high voriconazole MICs). Moreover, more than 35% of the strains showed high MIC values for amphotericin B and over 10% of the strains exhibited high MIC values for echinocandins (multidrug resistant: non-susceptible to one or more drugs of two or more antifungal classes). Their antifungal susceptibilities, resistance mechanisms and other characteristics are linked to different clonal populations that were partially kept geographically restricted<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">5</span></a>. In Argentina, the first two <span class="elsevierStyleItalic">C. auris</span> isolates reported in October 2022 were classified as clade III (known as the South African clade) and showed high azole, polyene and echinocandin MICs. These strains were clonal, demonstrating that they were transmitted among patients<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">3,4</span></a>.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">Candida haemulonii</span> complex comprises four species that are considered human pathogens: <span class="elsevierStyleItalic">C. haemulonii</span>, <span class="elsevierStyleItalic">C. duobushaemulonii</span>, <span class="elsevierStyleItalic">C. pseudohaemulonii</span> and <span class="elsevierStyleItalic">C. vulturna</span>. These species showed high MIC values for multiple antifungals. In many cases, those MICs are higher than the ones shown by <span class="elsevierStyleItalic">C. auris</span>. For instance, the susceptibility profile of 25 Argentinian strains of this complex showed that all but two strains had high fluconazole MIC values, 13 strains exhibited cross-high MICs for all tested azole and echinocandin drugs, while 8 strains displayed pan-resistance (resistance to amphotericin B, echinocandins and azole drugs)<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">2</span></a>.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Transmission and clinical impact of <span class="elsevierStyleItalic">C. auris</span> and the <span class="elsevierStyleItalic">C. haemulonii</span> species complex</span><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">C. auris</span> has been associated with nosocomial outbreaks, as well as the potential for rapid dissemination and high mortality rates among affected patients. In addition, <span class="elsevierStyleItalic">C. auris</span> has the ability to persist better than other <span class="elsevierStyleItalic">Candida</span> spp. on environmental surfaces. These facts have led the CDC to recommend the isolation of the affected patients. In order to comply with these recommendations, the correct identification of this species in clinical laboratories is essential. However, both <span class="elsevierStyleItalic">C. auris</span> and the <span class="elsevierStyleItalic">C. haemulonii</span> species complex pose challenges to accurate species identification, which can hinder appropriate treatment and surveillance efforts. There are two unique recommended methods for unequivocal identification: molecular-based procedures and/or MALDI-TOF, since most of the phenotype-based methods misidentify these species.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The ability of the <span class="elsevierStyleItalic">C. haemulonii</span> species complex to persist and cause outbreaks has not been thoroughly studied as in the case of <span class="elsevierStyleItalic">C. auris</span>. Nevertheless, the fact that they are taxonomically related –they all belong to the yeast family <span class="elsevierStyleItalic">Metshnikowiaceae</span>– allows to infer that something similar could happen. In Argentina, the isolation of yeasts from the <span class="elsevierStyleItalic">C. haemulonii</span> species complex is relatively common. Taking into account only the published data from the Malbrán Institute group -25 strains- and the autochthonous isolates that we keep in our laboratory, we can count more than 40 strains in the last six years. This leads us to ponder why there is such an alarm for two <span class="elsevierStyleItalic">C. auris</span> isolates and not such a stir for the regular and constant isolation of multi- and pan-resistant yeast strains that have the potential to cause outbreaks.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Addressing the Challenge</span><p id="par0045" class="elsevierStylePara elsevierViewall">Addressing the emergence of yeasts of the <span class="elsevierStyleItalic">Metshnikowiaceae</span> family requires a multi-pronged approach. Enhanced surveillance and rapid identification methods are crucial for the early detection and containment of outbreaks. Constant training is needed in the techniques necessary for the identification of these species, including strict adherence to hand hygiene protocols and environmental decontamination procedures. Interdisciplinary collaboration among healthcare professionals, mycologists and other members of the infection control teams is vital to prevent and manage infections caused by these resistant species. Furthermore, research efforts should focus on exploring alternative treatment options.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclusion</span><p id="par0050" class="elsevierStylePara elsevierViewall">The emergence of these intrinsically resistant species represents a significant threat to global health. Immediate action is needed to prevent the further spread of these pathogens and mitigate their impact. Strengthened surveillance, including improving identification and antifungal susceptibility testing capability, is key to addressing this escalating challenge.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Understanding intrinsic resistance" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Implications for Public Health" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Contributing factors" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "The rise of Candida auris and the Candida haemulonii species complex" ] 4 => array:2 [ "identificador" => "sec0025" "titulo" => "Transmission and clinical impact of C. auris and the C. haemulonii species complex" ] 5 => array:2 [ "identificador" => "sec0030" "titulo" => "Addressing the Challenge" ] 6 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusion" ] 7 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:6 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Clinical and Laboratory Strandards Institute. 2022. Performance Standards for Antifungal Susceptibility testing of yeasts. 3rd Ed. CLSI standard M27M44S-Ed3. Wayne, PA.;1; 2022." ] ] ] 1 => array:3 [ "identificador" => "bib0020" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Dirección de epidemiología. Ministerio de Salud de Argentina. 2022. Boletín epidemiológico nacional. Semana epidemiológica 42 (N.° 624)." ] ] ] 2 => array:3 [ "identificador" => "bib0025" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Un patógeno fúngico emergente multirresistente en Argentina" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "N.B. Fernández" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Rev. argent. microbiol. [online]." "fecha" => "2022" "volumen" => "54" "numero" => "n.4." ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0030" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Candida haemulonii sensu lato: Update of the Determination of Susceptibility Profile in Argentina and Literature Review" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "G. Isla" 1 => "C.G. Taverna" 2 => "W. Szusz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s12281-017-0300-y" "Revista" => array:5 [ "tituloSerie" => "Curr Fungal Infect Rep" "fecha" => "2017" "volumen" => "11" "paginaInicial" => "203" "paginaFinal" => "208" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0015" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:19 [ 0 => "S.R. Lockhart" 1 => "K.A. Etienne" 2 => "S. Vallabhaneni" 3 => "J. Farooqi" 4 => "A. Chowdhary" 5 => "N.P. Govender" 6 => "A.L. Colombo" 7 => "B. Calvo" 8 => "C.A. Cuomo" 9 => "C.A. Desjardins" 10 => "E.L. Berkow" 11 => "M. Castanheira" 12 => "R.E. Magobo" 13 => "K. Jabeen" 14 => "R.J. Asghar" 15 => "J.F. Meis" 16 => "B. Jackson" 17 => "T. Chiller" 18 => "A.P. Litvintseva" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/cid/ciw691" "Revista" => array:6 [ "tituloSerie" => "Clin Infect Dis." "fecha" => "2017 Jan 15" "volumen" => "64" "paginaInicial" => "134" "paginaFinal" => "140" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27988485" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0010" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "World Health Organization. 2022. WHO fungal priority pathogens list to guide research, development and public health action. ISBN 978-92-4-006024-1 (electronic version) ISBN 978-92-4-006025-8.(print version)." ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/03257541/0000005500000003/v1_202309280755/S0325754123000810/v1_202309280755/en/main.assets" "Apartado" => array:4 [ "identificador" => "17600" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Editorial" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/03257541/0000005500000003/v1_202309280755/S0325754123000810/v1_202309280755/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0325754123000810?idApp=UINPBA00004N" ]
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