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Clonal Lineages, Antimicrobial Resistance, and PVL Carriage Of antibiotics Article Clonal Lineages, Antimicrobial Resistance, and PVL Carriage of Staphylococcus aureus Associated to Skin and Soft-Tissue Infections from Ambulatory Patients in Portugal Carolina Ferreira 1 , Sofia Santos Costa 1, Maria Serrano 1, Ketlyn Oliveira 1, Graça Trigueiro 2, Constança Pomba 3,4 and Isabel Couto 1,* 1 Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa (UNL), Rua da Junqueira 100, 1349-008 Lisboa, Portugal; [email protected] (C.F.); [email protected] (S.S.C.); [email protected] (M.S.); [email protected] (K.O.) 2 Laboratório de Análises Clínicas Dr. Joaquim Chaves, Av. General Norton de Matos, 71 R/C, 1495-148 Algés, Portugal; [email protected] 3 CIISA, Centre of Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Avenida da Universidade Técnica, 1300-477 Lisboa, Portugal; [email protected] 4 GeneVet, Laboratório de Diagnóstico Molecular Veterinário, Rua Quinta da Nora Loja 3B, 2790-140 Carnaxide, Portugal * Correspondence: [email protected]; Tel.: +351-21-3652652; Fax: +351-21-3632105 Abstract: Staphylococcus aureus (S. aureus) is a leading cause of skin and soft-tissue infections (SSTIs) in the community. In this study, we characterized a collection of 34 S. aureus from SSTIs in ambulatory Citation: Ferreira, C.; Costa, S.S.; patients in Portugal and analyzed the presence of Panton–Valentine leucocidin (PVL)-encoding genes Serrano, M.; Oliveira, K.; Trigueiro, and antibiotic-resistance profile, which was correlated with genetic determinants, plasmid carriage, G.; Pomba, C.; Couto, I. Clonal and clonal lineage. Nearly half of the isolates (15, 44.1%) were methicillin-resistant Staphylococcus Lineages, Antimicrobial Resistance, aureus (MRSA) and/or multidrug resistant (MDR). We also detected resistance to penicillin (33/34, and PVL Carriage of Staphylococcus 97.1%), fluoroquinolones (17/34, 50.0%), macrolides and lincosamides (15/34, 44.1%), aminoglyco- aureus Associated to Skin and sides (6/34, 17.6%), and fusidic acid (2/34, 5.9%), associated with several combinations of resistance Soft-Tissue Infections from blaZ erm erm msr mph aacA-aphD aadD aph 0 IIIa fusC Ambulatory Patients in Portugal. determinants ( , (A), (C), (A), (C), , , (3 )- , ), or mutations Antibiotics 2021, 10, 345. https:// in target genes (fusA, grlA/gyrA). The collection presented a high genetic diversity (Simpson’s index doi.org/10.3390/antibiotics10040345 of 0.92) with prevalence of clonal lineages CC5, CC22, and CC8, which included the MRSA and also most MDR isolates (CC5 and CC22). PVL-encoding genes were found in seven isolates (20.6%), three Academic Editor: Giovanna Batoni methicillin-susceptible Staphylococcus aureus (MSSA) (ST152-agrI and ST30-agrIII), and four MRSA (ST8-agrI). Plasmid profiling revealed seventeen distinct plasmid profiles. This work highlights the Received: 19 February 2021 high frequency of antimicrobial resistance and PVL carriage in SSTIs-related S. aureus outside of the Accepted: 19 March 2021 hospital environment. Published: 24 March 2021 Keywords: Staphylococcus aureus; skin and soft-tissue infections; antibiotic resistance; clonal lineages; Publisher’s Note: MDPI stays neutral plasmids; Panton–Valentine leucocidin with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Staphylococcus aureus (S. aureus) is a major human pathogen responsible for a wide range of infections both in hospitals and in the community. It is one of the main causes Copyright: © 2021 by the authors. of severe nosocomial infections such as bacteremia and infective endocarditis and in the Licensee MDPI, Basel, Switzerland. community is a frequent cause of skin and soft-tissue infections (SSTIs) [1]. Besides their This article is an open access article potential severity, infections caused by S. aureus are usually difficult to treat due to the distributed under the terms and conditions of the Creative Commons frequent acquisition of antimicrobial resistance determinants. In the last decades, there has Attribution (CC BY) license (https:// been an emergence and dissemination of methicillin-resistant S. aureus (MRSA) as well as creativecommons.org/licenses/by/ of multidrug-resistant (MDR) strains [2,3]. Consequently, MRSA are now included in the 4.0/). Antibiotics 2021, 10, 345. https://doi.org/10.3390/antibiotics10040345 https://www.mdpi.com/journal/antibiotics Antibiotics 2021, 10, 345 2 of 15 World Health Organization (WHO) list of high-priority bacteria for development of new drugs [4]. S. aureus is the most frequent pathogen associated with SSTIs, which can range from minor or superficial infections such as impetigo to life-threating infections such as necrotiz- ing fasciitis [5]. Topical antibiotics that are often used for the prevention or treatment of milder infections include mupirocin, fusidic acid, neomycin, and bacitracin [6,7]. The use of some of these topical antibiotics is particularly relevant in the community/ambulatory settings, where they may not require medical prescription. Other antibiotics for systemic use, such as clindamycin, trimethoprim-sulfamethoxazole, tetracyclines, and linezolid, are also indicated for treatment of severe forms of SSTIs caused by S. aureus [6,8]. The frequency of antibiotic-resistant S. aureus isolates associated with SSTIs is rising worldwide [9–12], particularly to fusidic acid and mupirocin, which is probably linked with the widespread use of these antibiotics [3]. Resistance to antibiotics in S. aureus can be mediated by several mechanisms, such as antibiotic modification or degradation, target mutation, or antibiotic efflux. Resistance to penicillins can occur by inactivation of the antibiotic molecule through the action of the β-lactamase BlaZ. The blaZ gene occurs frequently in S. aureus clinical isolates. Resistance to penicillins and other β-lactams, with the exception of fifth-generation cephalosporins, is mediated by the acquisition of the mecA gene, which is part of the mobile genetic element SCCmec (staphylococcal cassette chromosome mec) and encodes for an additional penicillin- binding protein, PBP2a, with low affinity for the β-lactam antibiotics [3]. Resistance to macrolides and lincosamides can occur through several mechanisms, including the acquisition of rRNA methylases-encoding erm genes that methylate the binding site of the antibiotics [3]. Resistance to aminoglycosides is associated with acquisition of several genes, like aacA-aphD or aadD that encode enzymes that modify the antibiotic molecule rendering it inactive [3]. Resistance to fluoroquinolones is usually linked to the occurrence of mutations in the quinolone-resistant determining region (QRDR) of the grlA/B and gyrA/B genes that encode the DNA topoisomerase IV and DNA gyrase, respectively. Fluoroquinolone resistance can also be conveyed by overexpression of chromosomally-encoded efflux pump genes such as norA/B/C and mepA [13]. Resistance to fusidic acid can be achieved by the acquisition of the fusB/C genes that encode ribosomal protection proteins or by mutations in the fusA gene [3]. S. aureus produces several virulence factors, including toxins, proteins associated with immune evasion, and tissue-degrading enzymes [1]. The cytotoxin Panton–Valentine leucocidin (PVL), encoded by the genes lukF-PV and lukS-PV carried on bacteriophage 'Sa2, is a two-component pore-forming protein that has been strongly associated with S. aureus isolates causing skin infections in the community and with necrotizing pneumo- nia [1]. Nevertheless, the role of PVL in S. aureus infection pathogenesis is still not fully elucidated [14]. The S. aureus accessory gene regulator (agr) locus regulates the expression of several virulence factors like cell-wall-associated and extracellular proteins, contributing to infection severity and persistence. The polymorphism of the agr locus allows the clas- sification of S. aureus in four predominant agr types (I to IV), that may differ in terms of infection type, carriage of virulence factors, and temporal patterns of autoinduction [15]. Most antimicrobial resistance and virulence genes of S. aureus are located on mo- bile genetic elements (MGEs) such as plasmids, bacteriophages, pathogenicity islands, transposons, integrative conjugative elements (ICEs), integrons, and staphylococcal chro- mosome cassettes (SCCs), which make up to 15–20% of its genome [16]. The acquisition of antimicrobial resistance by S. aureus is mostly due to horizontal gene transfer (HGT), and plasmids have been identified as one of the main responsible for the dissemination of resistance genes [17]. Several studies have evaluated the main clones of MRSA circulating both in hospitals and in the community in Portugal, a country with a high prevalence of MRSA [18–22]. However, there have been fewer studies focusing on S. aureus, both methicillin-susceptible Staphylococcus aureus (MSSA) and MRSA causing SSTIs. The aim of this work was to per- Antibiotics 2021, 10, 345 3 of 15 form a phenotypic and genotypic characterization of a collection of S. aureus isolated from SSTIs in ambulatory patients and to assess their virulence determinants and susceptibility to the main antibiotics used in SSTI therapeutics, correlating their resistance profile to genetic determinants and identifying their main mechanisms of dissemination among S. aureus strains. 2. Results 2.1. Antimicrobial Susceptibility Profile and Correlation with Resistance Determinants
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