Abstract
Erysipelas is a severe streptococcal infection of the skin primarily spreading through the lymphatic vessels. Penicillin is the treatment of choice. The most common complication consists in relapses which occur in up to 40% or more of patients despite appropriate antibiotic treatment. They cause lymphatic damage resulting in irreversible lymphedema and ultimately elephantiasis nostras and lead to major health restrictions and high socio-medical costs. Prevention of relapses is an unmet need, because even long-term prophylactic penicillin application does eventually not reduce the risk of recurrence. In this article we assess risk factors and causes of erysipelas recurrence. A systematic literature search for clinical studies addressing potential causes and measures for prevention of erysipelas recurrence was combined with a review of experimental and clinical data assessing the ability and clinical relevance of streptococci for intracellular uptake and persistence. The literature review found that venous insufficiency, lymphedema, and intertrigo from fungal infections are considered to be major risk factors for recurrence of erysipelas but cannot adequately explain the high recurrence rate. As hitherto unrecognized likely cause of erysipelas relapses we identify the ability of streptococci for intracellular uptake into and persistence within epithelial and endothelial cells and macrophages. This creates intracellular streptococcal reservoirs out of reach of penicillins which do not reach sufficient bactericidal intracellular concentrations. Incomplete streptococcal elimination due to intracellular streptococcal persistence has been observed in various deep tissue infections and is considered as cause of relapsing streptococcal pharyngitis despite proper antibiotic treatment. It may also serves as endogenous infectious source of erysipelas relapses. We conclude that the current antibiotic treatment strategies and elimination of conventional risk factors employed in erysipelas management are insufficient to prevent erysipelas recurrence. The reactivation of streptococcal infection from intracellular reservoirs represents a plausible explanation for the frequent occurrence erysipelas relapses. Prevention of erysipelas relapses therefore demands for novel antibiotic strategies capable of eradicating intracellular streptococcal persistence.
Highlights
Erysipelas is a severe infection of the skin mainly caused by β-hemolytic group A streptococci (S. pyogenes, Group A streptococci (GAS)) [1,2,3,4]
The terms erysipelas and cellulitis are often used interchangeably. They are commonly seen as manifestations of the same condition, whereby erysipelas is thought to primarily affect the superficial skin layers, i.e., epidermis, dermis, and upper subcutis, while cellulitis is considered a more diffuse skin infection extending from dermis deeper into subcutaneous tissue [8]
In searching for alternative explanations, we identify intracellular persistence of S. pyogenes as potential cause of relapses
Summary
Definition of ErysipelasErysipelas is a severe infection of the skin mainly caused by β-hemolytic group A streptococci (S. pyogenes, GAS) [1,2,3,4]. Persistent presence of entry sites for bacteria is considered a predisposing factor for recurrent erysipelas, and treatment of tinea is a recommended measure for reducing the risk of cellulitis. Entry into epithelial cells provides a robust rationale to explain the persistent pharyngeal colonization as it protects intracellular streptococci from immune effectors and antibiotics which are less membrane-permeable, in particular penicillin [43, 70].
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