Staphylococcus Aureus Toxins and Diabetic Foot
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Staphylococcus aureus Toxins and Diabetic Foot Ulcers: Role in Pathogenesis and Interest in Diagnosis Catherine Dunyach-Remy, Christelle Ngba Essebe, Albert Sotto, Jean-Philippe Lavigne To cite this version: Catherine Dunyach-Remy, Christelle Ngba Essebe, Albert Sotto, Jean-Philippe Lavigne. Staphylococ- cus aureus Toxins and Diabetic Foot Ulcers: Role in Pathogenesis and Interest in Diagnosis. Toxins, MDPI, 2016, 8 (7), 10.3390/toxins8070209. hal-01903891 HAL Id: hal-01903891 https://hal.archives-ouvertes.fr/hal-01903891 Submitted on 27 May 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. 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Distributed under a Creative Commons Attribution| 4.0 International License toxins Review Staphylococcus aureus Toxins and Diabetic Foot Ulcers: Role in Pathogenesis and Interest in Diagnosis Catherine Dunyach-Remy 1,2, Christelle Ngba Essebe 1, Albert Sotto 1,3 and Jean-Philippe Lavigne 1,2,* 1 Institut National de la Santé Et de la Recherche Médicale U1047, Université de Montpellier, UFR de Médecine, Nîmes 30908, France; [email protected] (C.D.-R.); [email protected] (C.N.E.); [email protected] (A.S.) 2 Service de Microbiologie, Centre Hospitalo-Universitaire Carémeau, Nîmes 30029, France 3 Service des Maladies Infectieuses et Tropicales, Centre Hospitalo-Universitaire Carémeau, Nîmes 30029, France * Correspondence: [email protected]; Tel.: +33-466-683-202 Academic Editor: Vernon L. Tesh Received: 14 May 2016; Accepted: 1 July 2016; Published: 7 July 2016 Abstract: Infection of foot ulcers is a common, often severe and costly complication in diabetes. Diabetic foot infections (DFI) are mainly polymicrobial, and Staphylococcus aureus is the most frequent pathogen isolated. The numerous virulence factors and toxins produced by S. aureus during an infection are well characterized. However, some particular features could be observed in DFI. The aim of this review is to describe the role of S. aureus in DFI and the implication of its toxins in the establishment of the infection. Studies on this issue have helped to distinguish two S. aureus populations in DFI: toxinogenic S. aureus strains (harboring exfoliatin-, EDIN-, PVL- or TSST-encoding genes) and non-toxinogenic strains. Toxinogenic strains are often present in infections with a more severe grade and systemic impact, whereas non-toxinogenic strains seem to remain localized in deep structures and bone involving diabetic foot osteomyelitis. Testing the virulence profile of bacteria seems to be a promising way to predict the behavior of S. aureus in the chronic wounds. Keywords: diabetic foot infection; Staphylococcus aureus; toxins 1. Introduction Foot ulcers are common in diabetic patients. Its prevalence varies between 15% and 25% [1]. Infection of these ulcers is a frequent (40%–80%) complication representing a major cause of mortality and morbidity [2]. It is estimated to be the most common reason of lower-limb amputations [3–5]. The pathophysiology of diabetic foot infection (DFI) is quite complex. The prevalence and severity are a consequence of host-related processes (e.g., immunopathy, neuropathy and arteriopathy) and pathogen-related factors (e.g., virulence, antibiotic-resistance and microbial organization) (Figure1) [6–8]. DFI pose many problems in clinical practice in terms of both management and diagnosis [9]. Indeed, the presence of impaired leukocyte functions and/or peripheral arterial disease may reduce the local inflammatory response and classical signs or symptoms of local infection [10,11]. Moreover, systemic signs of toxicity (e.g., leukocytosis or fever) may be lacking or appear late, even in severe cases [12–14]. Microbiological diagnosis of these DFI also encounters many limitations. As microorganisms colonize all chronic wounds, the diagnosis of DFI should not be based only on the microbiological analysis of a wound culture, but also on clinical findings [5,9,15]. The Infectious Diseases Society of America (IDSA) and the International Working Group on the Diabetic Foot (IWGDF) have developed clinical criteria for classifying the severity of DFI (Table1)[15,16]. Toxins 2016, 8, 209; doi:10.3390/toxins8070209 www.mdpi.com/journal/toxins Toxins 2016, 8, 209 2 of 19 Toxins 2016, 8, 209 2 of 20 Diseases Society of America (IDSA) and the International Working Group on the Diabetic Foot (IWGDF) have developed clinical criteria for classifying the severity of DFI (Table 1) [15,16]. Figure 1.1. InteractionsInteractions between between metabolic, metabolic, anatomical anatomical and and bacteriological bacteriological factors factors in diabetic foot infection. Table 1. International Consensus on the Diabetic Foot classification of foot wound infections [3,15]. Table 1. International Consensus on the Diabetic Foot classification of foot wound infections [3,15]. Grades Symptoms GradesGrade 1 No symptoms, no signs of infection Symptoms Grade 1 No symptoms,Lesion no only signs involving of infection the skin (no subcutaneous tissue lesion or systemic Lesion onlydisorders) involving thewith skin at (noleast subcutaneous two of the following tissue lesion signs: or systemic disorders) with at least two of the‐ followinglocal warmth signs: - local‐ warmtherythema >0.5–2 cm around the ulcer - erythema >0.5–2 cm around the ulcer Grade 2 ‐local tenderness or pain Grade 2 - local tenderness or pain ‐local swelling or induration - local swelling or induration - purulent‐purulent discharge discharge (thick, opaque (thick, to opaque white or to sanguineous white or sanguineous secretion) secretion) Other causesOther of inflammation causes of inflammation of the skin must of bethe eliminated skin must (for be example: eliminated trauma, (for example: gout, acute Charcottrauma, foot, fracture,gout, acute thrombosis, Charcot venous foot, fracture, stasis) thrombosis, venous stasis) - Erythema‐Erythema >2 cm and>2 cm one and of the one findings of the describedfindings described above or above - Infectionor involving structures beneath the skin and subcutaneous tissue, Grade 3 Grade 3 such‐ asInfection deep abscess, involving lymphangitis, structures osteomyelitis, beneath the septic skin arthritis and subcutaneous or fasciitis tissue, There mustsuch not beas anydeep systemic abscess, inflammatory lymphangitis, response osteomyelitis, (see Grade septic 4) arthritis or fasciitis RegardlessThere of the must local infection, not be any in the systemic presence inflammatory of systemic signs response corresponding (see Grade to at least4) two of the followingRegardless characteristics: of the local infection, in the presence of systemic signs ˝ ˝ - temperaturecorresponding >39 C or to <36 at leastC two of the following characteristics: - pulse >90 bpm Grade 4 ‐temperature >39 °C or <36 °C - respiratory rate >0/min ‐pulse >90 bpm Grade -4 PaCO2 <32 mmHg - leukocytes‐respiratory >12,000 rate or <4000/mm > 0/min 3 - 10% of‐PaCO immature2 <32 leukocytesmmHg ‐leukocytes >12,000 or <4000/mm3 ‐10% of immature leukocytes For many decades, culturing wound specimens were the only way to determine the causative pathogen(s) in a DFI. As microorganisms are always present on every skin wound and the DFI are For many decades, culturing wound specimens were the only way to determine the causative often polymicrobial, the variability of bacterial virulence factors and the level of host resistance must pathogen(s) in a DFI. As microorganisms are always present on every skin wound and the DFI are also be taken into account. In fact, the different organisms isolated from infected wounds do not have often polymicrobial, the variability of bacterial virulence factors and the level of host resistance must a similar pathogenic impact, and evaluation of the intrinsic virulence potential of isolated bacteria also be taken into account. In fact, the different organisms isolated from infected wounds do not have to identify their real pathogenicity seems a promising way to best characterize the infection and to a similar pathogenic impact, and evaluation of the intrinsic virulence potential of isolated bacteria to distinguish infection from colonization [16]. identify their real pathogenicity seems a promising way to best characterize the infection and to Several studies have shown that DFI are polymicrobial, and Staphylococcus aureus is the pathogen distinguish infection from colonization [16]. most frequently isolated [17–22]. S. aureus is both a commensal bacterium and a human pathogen. Toxins 2016, 8, 209 3 of 20 Indeed, approximately 30% of the human population is colonized with S. aureus [23]. Importantly, this bacterium causes a wide range of clinical infections (e.g., bacteremia, endocarditis, skin and soft tissue, osteoarticular, pulmonary and device-related infections) [24]. The numerous virulence factors and toxins produced by S. aureus during infection are well characterized [22]. However, some specific features could be observed in DFI. The aim of this review is to describe the role of S. aureus in DFI and the implication of its toxins in the establishment of the infection. 2.