CME Article Submitted: 22.3.2015 Accepted: 10.4.2015

DOI: 10.1111/ddg.12721

Frequent bacterial skin and soft tissue infections: diagnostic signs and treatment

Cord Sunderkötter 1, Karsten Becker2 (1) Department of Dermatology, ­University Hospital Münster and Division of Infectious Diseases in Dermatology, University of Münster (2) Institute for Medical Microbiology, University Hospital Münster Section Editor Prof. Dr. D. Nashan, Dortmund

Summary Skin and soft tissue infections rank among the most frequent infections worldwide. Classic erysipelas is defined as a non-purulent infection by beta-hemolytic streptococci. The typical signs are tender, warm, bright erythema with tongue-like extensions and early systemic symptoms such as fever or at least chills. Erysipelas always and best responds to penicillin. Limited soft tissue infection or limited cellulitis are the terms we have introduced for infections frequently caused by S. aureus and often originating from chronic wounds or acute trauma. Clinically, they are marked by tender, erythematous swelling which, unlike erysipelas, exhibit a darker red hue and is not always accompanied by fever or chills at onset. Severe cellulitis is a purulent, partially necrotic infection extending to the fascia, with general symptoms of infection, requiring surgical management in addition to antibiotics. It often fulfils criteria of so-called complicated soft tissue infections according to the definition of the FDA, due to their frequent association with e.g. severe diabetes mellitus, peripheral arterial occlusive disease or severe immunosuppression. In contrast, the rare necrotizing skin and soft tissue infections represent a distinct entity, characterized by rapid progression to ischemic necroses and shock due to special bacterial toxins. Limited cellulitis should be treated with cephalosporins group 1 or 2, or, when S.aureus is the isolated or highly likely causative agent, isoxazolyl-penicillins ­(exploiting their minimal selection pressure on other bacteria). For severe ­cellulitis, initial antibiotic treatment (mostly iv) includes – depending on the location agents also active against gram-negative and/or anaerobic bacteria. (e.g. clindamycine, aminopeniclilline with inhibitors of betalaktamase, fluochinolons, cephalosporines group 4). For cutaneous abscesses, drainage presents the therapy of choice. Only under ­certain conditions additional antibiotic therapy is required. Adherence to the diagnostic criteria and to evidence-based or consensus-derived treatment recommendations as presented herein should allow for an antibiotic therapy with a good balance of efficacy, tolerability by patients and low selection pressure for highly resistant bacteria.

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Introduction and fundamentals on antibiotic therapy

Unnecessary administration of broad-spectrum antibiotics (for example, group 3 cephalosporins, fluoroquinolones, or amoxicillin/ clavulanic acid) in soft tissue infections also accelerates the selection of highly resistant bacteria in tissues distant from the infection such as the intestines or the respiratory tract. The antibiotics administered should exhibit an efficacy spectrum which is as broad as necessary, but as narrow as possible; additionally, treatment should occur in a timely manner, for an adequate duration, and at a sufficiently high dosage.

Bacterial skin and soft tissue infections rank among the most frequent infections worldwide. In many cases, the portals of entry are chronic wounds, whose prevalence rises with increasing patient age, whereas others originate from small superficial lesions (impetigo or tinea pedis) as well as acute traumatic injuries or surgical wounds. Soft tissue infections include erysipelas, limited or severe cellulitis, abscesses, and acutely life-threatening necrotizing soft tissue infections. Correct definition and diagnosis of the respective soft tissue infection is crucial, for only this allows for adequate treatment with the most effective antibiotic in a given situation. Thus, classic erysipelas always and best responds to penicillin, whereas limited cellulitis does not. Aside from the correct clinical classification, rational handling of antibiotics is indispensable. As they are curative, they are particularly valuable drugs. Moreover, their effect is – unlike all other drugs – not targeted at the patient’s cells, but directly and causally at pathogens. However, at the same time – depending on the efficacy profile – they act against bacteria of the physiological flora (microbiota) in several organs and therefore exert selection pressure on many different bacteria, which facilitates the development and persistence of (multi-) resistant bacteria. Thus, unnecessary administration of group 3 cephalosporins, fluoroquinolones, or amoxicillin/clavulanic acid in soft tissue infections also accelerates the selection of highly resistant bacteria in tissues distant from the infection such as the intestines or the respiratory tract [1–3]. Through transposable genetic elements, these bacteria also enable an exchange of resistance mechanisms across strain and species borders. Therefore, when prescribing antibiotics, every physician bears a special responsibility not only for the individual patient, but also with respect to infection epidemiology and the resistance situation of the entire population [4]. As a general rule for the use of antibiotics, their efficacy spectrum should be as broad as necessary, but as narrow as possible. Additionally, treatment has to occur in a timely manner, for an adequate duration, and at a sufficiently high dosage (for an overview on the use of antibiotics in dermatology, see for example [5, 6]).

Impetigo

Impetigo is a primary, superficial infection of the skin (epidermis) caused by beta-hemolytic streptococci or S. aureus.

Of the superficial bacterial infections of the epidermis, only impetigo and ecthyma are to be discussed in this article. Impetigo is a primary, superficial infection of the skin (epidermis) caused by beta-hemolytic streptococci or S. aureus, which may lead to subcorneal acantholysis or even blistering, and to crusted erosions (Figure 1). It is not to be equated with secondary impetiginization of preexisting skin diseases, for example, in the context of various forms of eczema. In children, the delicate skin is more prone to microlesions that facilitate the penetration of the aforementioned bacteria; children therefore contract impetigo more frequently. Low socioeconomic status and a warm and humid climate are precipitating factors. Endemic outbreaks occur among children in kindergartens or schools, especially in late summer. Impetigo caused by Streptococcus pyogenes, especially serotypes 1, 4, 12, and 25, bears the risk of acute poststreptococcal glomerulonephritis.

Diagnosis Clinically, impetigo begins as a small, thin-walled blister on an erythematous base. The blisters quickly rupture and spread peripherally. The blister roof and the leaking

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Figure 1  Impetigo.

serum give rise to the characteristic honey-colored brown-yellow scabs that cover the polycyclic erosive lesions. Impetigo most frequently appears in the face or on the extremities. The lesions may be solitary or multiple, and have a slow tendency to heal. The diagnosis is made clinically. However, due to the high prevalence of macrolide-resistant Streptococcus pyogenes or S. aureus strains, or whenever methicillin-resistant S. aureus (MRSA) is suspected, isolation and susceptibility testing of the pathogens is recommendable. Molecular genetic detection (PCR) of Panton-Valentine leukocidin (PVL) should be performed if there is corresponding evidence for an infection with community-associated MRSA (cMRSA) such as recurrent furuncles in otherwise healthy children and adults, rapidly developing necroses, or progressive cutaneous abscesses, especially in returnees from endemic areas (USA, Pacific Asia) [7–10].

Differential diagnoses Herpes simplex infections: These can be distinguished, for, instead of multiple lesions, there is only one lesion with grouped blisters on an erythematous base, which does not exhibit the typical polycyclic borders. Inflammatory pustular tinea caused by zoophilic and geophilic fungi: They are characterized by folliculitis and highly inflammatory, partially purulent plaques, and usually also by a corresponding history. The diagnosis is confirmed by microbiological pathogen detection. Pemphigus foliaceus: It is rare in children and generally shows a more chronic clinical course. It lacks the honey-yellow scabs typical of impetigo. Bullous insect bite reaction: Usually following an initial urticarial reaction, it is characterized by a blister at the site of the insect bite, which is initially nonpurulent.

Therapy In case of only few impetigo lesions, topical therapy with retapamulin is the therapy of first choice.

In case of only few impetigo lesions, topical therapy with retapamulin is a therapy of first choice, because it is efficacious, against the causative bacteria, not intended for systemic use and has not yet revealed marked cross resistance with or allergic

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cross sensitivity to other antibiotics. Yet, as soon as one these criteria loses validity, this recommendation for a topical antibiotic needs to be revised. This antibiotic is not intended for systemic use. Not only is this recommendation derived from available evidence [11], but also from the reasonable and cautious use of valuable reserve antibiotics [5, 6, 12]. Although topical application of mupirocin and fusidic acid has proven to be equally or even more effective than systemic antibiotic therapy in the treatment of impetigo [13], broad topical application of these antibiotics verifiably increases the risk of resistance development [15]. We therefore do not recommend it as therapy of first choice in impetigo, and thus hope to longer maintain their efficacy against MRSA. Topical therapy with newer antiseptic agents (e.g. octenidine, polyhexanide) may be the better alternative to topical application of antibiotics, but is not yet based on the same level of evidence [16]. In case of incrusted impetigo lesions, antiseptics should be applied if possible, in gel form. There is still a need for the development of antiseptic products with galenic formulations suitable for impetigo. Indications for the additional use of antibiotics would be multiple lesions without a quick response to topical therapy, or evidence of hemolytic streptococci. In the latter case, phenoxymethylpenicillin (penicillin V) 1.2–1.5 mil. IU 3 times daily is the systemic therapy of choice. The risk of a possible poststreptococcal disease is thereby not definitively reduced; thus, repeated urine analysis is indicated. Regarding calculated oral therapy in case of pending or missing pathogen isolation, cefadroxil (1 g once daily) or cefalexin (1 g 3–4 times daily) – due to its longer half-life, we prefer cefadroxil -, roxithromycin (0.3 g once daily) or clarithromycin (0.5 g twice daily) are recommendable [11, 12, 16]. If S. aureus is the probable or isolated pathogen, flucloxacillin (1 g 3 times daily, one hour before or two hours after a meal) may be given; its slightly poorer bioavailability compared to the antibiotics above-mentioned must be weighed against its efficacy spectrum tailored towards S. aureus. In case of penicillin allergy, clindamycin (0.6–1.8 g daily) represents an alternative. In case of strong suspicion or evidence of MRSA, especially CA-MRSA, trimethoprim/sulfamethoxazole (cotrimoxazole) (0.08/0.4 g twice daily) [12, 17] may initially be given, followed by treatment according to antibiogram. In addition, the respective recommendations for MRSA decolonization should be followed [9, 18]. Concomitantly, thorough personal hygiene and the cleaning of clothing and bed linen at least at 60°C is recommended in impetigo as well as ecthyma.

Ecthyma Ecthyma is the ulcerating form of impetigo. It occurs under humid and warm climatic conditions and also affects adults.

Ecthyma is the ulcerating form of impetigo, which primarily occurs under humid and warm climatic conditions and also affects adults. Here, the causative pathogens are usually beta-hemolytic streptococci, although S. aureus is also frequently isolated from the ulcers. In temperate zones, the defense mechanisms of the innate immune response in adults are often sufficient to prevent infections caused by the moderate amount of the aforementioned bacteria on the skin. However, in a humid and warm climate, the bacteria obviously multiply quickly enough to cause deeper infections in the soaked, more easily penetrable skin (Figure 2). Immunosuppression, poor hygienic conditions, or edema constitute further precipitating factors.

Diagnosis Ecthyma is a shallow ulcer extending into the dermis, typically characterized by sharply demarcated, evenly punched-out borders (Figure 2), with surrounding

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Figure 2  Ecthyma.

erythema, and an occasionally slightly necrotic purulent base or hemorrhagic crusts. The initial lesion may be a pustule. Usually, pus initially accumulates under a gray-yellow scab before the lesion ruptures, thus giving rise to the typical ulcer. Ecthyma may also result from impetigo, folliculitis, an erosion (for example, due to scratching), or an insect bite. In that case, the ulcer grows up to 1–3 cm within a few days. Depending on the cause, there may be multiple ecthyma lesions. The healing process is slow, frequently leaving behind a scar [19]. The diagnosis is made clinically; regarding isolation and susceptibility testing, the same procedures apply as in impetigo.

Differential diagnoses Venous ulcer: The typical predilection site on the medial ankle, its chronic progression, and the typical signs of chronic venous insufficiency (CVI) are indicative. Pyoderma gangrenosum: Undermined and red-livid borders, necroses at the ulcer base, and severe pain are characteristic. Ecthyma gangrenosum: These ulcers occur in the context of bacteremia with Pseudomonas (P.) aeruginosa, thus in severely ill patients. Cutaneous leishmaniasis: Although it is a frequently mentioned differential diagnosis in returnees from endemic areas, following an infection with Leishmania species, originating from a papule, the ulcer develops only slowly, and earliest two to 15 weeks after the start of the journey.

Therapy From the outset, ecthyma should be treated topically as well as systemically. As it is frequently caused by streptococci, phenoxymethylpenicillin (penicillin V) PO, the best therapy in this case, may initially be given. Should this not prove effective, since S. aureus turns out to be the causative pathogen, switching to cefadroxil or cefalexin after two days is early enough. If close follow-up is not feasible, cefalexin or cefadroxil may be given immediately. Further recommendations are the same as for impetigo, also with regard to personal hygiene and cleaning of clothing and bed linen at least at 60°C.

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Erysipelas Erysipelas is defined as an acute bacterial, nonpurulent infection of the dermis caused by beta-hemolytic streptococci (Streptococcus pyogenes), which involves lymph clefts and lymph vessels (Figure 3). They are usually group A, but also group C, G, or B streptococci, whereas group B streptococci play a significant role after tumor surgery and radiation therapy in gynecological patients. In order to penetrate the soft tissue, streptococci require an epidermal injury as portal of entry. These are usually small lesions, such as interdigital tinea, erosions on eczema, excoriations through any kind of scratching, or impetigo, especially if

Figure 3  Erysipelas on the lower leg.

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caused by streptococci. Wounds colonized or even infected by S. aureus less frequently constitute portals of entry for classic erysipelas. Streptococci can be found transiently in the throats of young adults and children without symptoms (2–8 %), furthermore in 0.003 % of all vaginal swabs in pregnant women [20, 21], and may be spread, for example, by scratching. They do not persist on healthy skin. Insufficiently treated erysipelas or lack of treatment of the portals of entry lead to relapses. Recurrent erysipelas, in turn, causes increasingly irreversible lymph vessel damage, resulting in serum-rich edema, which lays the foundation for repeated recurrences.

Diagnosis Characteristic symptoms and parameters are:  Acute, warm, variably tender, bright red erythema with a shiny surface, sharply demarcated borders and tongue-shaped extensions, which usually develops at a distance of some centimeters from the portal of entry (Figure 3),  Already in the initial stages, a systemic inflammatory response with fever or at least shivers, less frequently chills, as well as  Elevated ESR, increased CRP, or neutrophilia Depending on the kind of bacterial toxins and the patient’s inflammatory response, blistering and hemorrhaging may occur (Figure 4). Progression to bacteremia and sepsis is also possible. Predilection sites are the lower legs or the face (Figure 5), but any skin area may be affected. The draining lymph nodes are swollen. The diagnosis is made clinically based on the aforementioned symptoms. Only if the skin is significantly altered by chronic stasis or other dermatoses, or in case of facial infections, the diagnosis becomes more difficult; apparently, the tissue structure of the face makes inflammatory reactions to S. aureus or Hemophilus influenzae infections clinically resemble those seen in beta-hemolytic streptococci. However, since these patients are usually hospitalized and rounded on daily, penicillin may initially be given in this case as well (see below), especially when the patient has the general symptoms characteristic for erysipelas. Pathogen detection by culture using material from aspirates or lesional biopsies is generally disappointing.

Differential diagnoses The most frequent misdiagnoses in case of suspected erysipelas are probably acute stasis dermatitis of the lower legs, a pronounced insect bite reaction, and limited cellulitis caused by other bacteria.

The most frequent misdiagnoses in medical practice are probably acute stasis dermatitis (occasionally also called hypodermitis) of the lower legs, a pronounced insect bite reaction, and limited cellulitis caused by other bacteria. Acute stasis dermatitis of the lower legs in chronic venous insufficiency (CVI): It usually also shows a bright red color, whereas chronic stasis dermatitis is rather dark to livid-red. Both forms are less shiny, and, due to the pronounced edema, the erythematous areas exhibit deeper indentations upon palpation than erysipelas. The acute variant is sharply demarcated, but shows fewer thin tongue-shaped yet rather wider extensions. Unlike erysipelas, they often develop on both legs (Figure 6). Acute and chronic stasis dermatitis are typically associated with palpable lipodermatosclerosis and improve with compression. Erythematous insect bite reaction: Usually caused by specific mosquito species, erythematous insect bite reactions primarily occur in late spring and summer. They also appear as bright erythema with tongue-shaped extensions, which however develop within hours and therefore, much faster than erysipelas. They are not necessarily associated with fever, and, considering the size of the erythema, only with minimal general symptoms.

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Figure 4  Hemorrhagic erysipelas.

Buccal cellulitis caused by Hemophilus influenzae in children and limited facial cellulitis caused by other bacteria: Clinically, they are frequently indistinguishable from facial erysipelas, likely due to an inflammatory response taking a similar course in facial issue. Early fever is usually a sign for erysipelas. Limited cellulitis in other areas: They are not as shiny, darker red or livid-red, more edematous, and originate from an ulcer or a wound. Differential diagnostic difficulties will be discussed below. Erysipeloid (swine erysipelas): This zoonosis, caused by Erysipelothrix rhusiopathiae, presents as tender limited cellulitis usually on the hands or fingers of persons who work with marine animals, pigs, or poultry. After an incubation

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Figure 5  Impetigo and erysipelas on the face.

Figure 6  Acute stasis dermatitis on both lower legs.

period of 2–7 days, a shallow, red-livid plaque develops at the inoculation site, which spreads centrifugally with sharply demarcated, usually livid, raised borders under central clearing. Concomitant regional lymphadenopathy and lymphangitis are possible. The diagnosis is confirmed microbiologically through isolation of the pathogen or, almost as effectively, histologically by detecting long, thin, gram-positive rods in the biopsy specimen from deeper skin layers. In case of fever, blood cultures should be taken. Thrombophlebitis: It can be differentiated by history and clinical signs such as palpable, painful, cord-like, vessel-associated induration, and by Duplex sonography. The fact that erysipelas may cause thrombophlebitis ought to be considered. Phlebothrombosis: Erythema and swelling usually affect the entire leg circumference and are more livid as well as less well-defined than erysipelas.

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Acute contact dermatitis: In its acute form, mainly acute toxic contact dermatitis may present with sharply demarcated erythema, however, without general symptoms; in addition, it quickly reaches its final size, and a trigger may frequently be identified. Combustio, 1st degree burning or congelatio Periodic Mediterranean fever: The concomitant erythema can strongly resemble erysipelas, but, similar to the fever, it recurs, and is accompanied by arthritic, peritonitic (pseudo-peritonitis) and pleuritic symptoms. Erythema migrans: This typical manifestation of stage I borreliosis is characterized by a sharply demarcated erythema which spreads centrifugally. However, it is painless, of a paler red color, does not have tongue-shaped extensions, and takes a less acute course than erysipelas. If there is also a history of a tick bite, the lesion is very likely caused by Borrelia species. Borrelia serology is not required for diagnosis. SLE, lupus tumidus, erythmatous rosacea or Morbus Morbihan erythema in the face.

Therapy All beta-hemolytic streptococci are sensitive to penicillin. Therefore, the prompt administration of penicillin G or V is the therapy of choice and also sufficient in hemorrhagic erysipelas.

All beta-hemolytic streptococci are sensitive to penicillin. Therefore, the prompt administration of penicillin G or V is the therapy of choice and also sufficient in hemorrhagic erysipelas. For uncomplicated erysipelas, e.g. on the lower leg in otherwise healthy adults, systemic therapy with phenoxymethylpenicillin (penicillin V), 1.2–1.5 mil. IU, 3 times daily for 7–14 days is sufficient [12, 23–25]. For other occasionally given antibiotics, the following should be considered:  Aminopenicillins are 2 to 4 times less effective than penicillin, and group 1 or 2 cephalosporins are also slightly inferior with respect to desirable and adverse effects. Newer macrolides are characterized by their potential for interactions with other drugs, including antiarrhythmics.  Moxifloxacin shows an unfavorable risk-benefit ratio (see under limited cellulitis), especially in older patients with classic erysipelas. When given orally, it is similarly available as in its parenteral form [22], but the approved dose (400 mg daily) may not always suffice in overweight or tall patients.  We have pointed out the risk for resistance development in bacteria in other “locations” (intestines, urinary tract) as collateral damage. Treatment duration should be governed by the clinical response. In respective studies, various treatment regimens were used, frequently time spans between either 7–10 days or 10–14 days. Depending on clinical severity, we prefer treatment for at least 7–10 days and, within this scope, 1–2 days beyond the resolution of clinical symptoms in order to minimize the risk for persisting streptococci in the tissue [12, 23–25]. Severe, hemorrhagic or bullous erysipelas with pronounced general symptoms, as well as complex erysipelas in venous or arterial vessel disease are an indication for parenteral, at best sequential (that is, primarily intravenous and subsequently oral) administration of penicillin: penicillin G 10 mil. IU IV, 3 times daily, or 5 mil. IU IV, 4 times daily for 7–14 days (see above) or for approximately 5–7 days with subsequent oral administration of penicillin V (1.2–1.5 mil. IU, 3 times daily). In case of penicillin allergy, clarithromycin (0.25 to 0.5 twice daily) or roxithromycin (0.3 g every day) for 7–14 days, or clindamycin 0.2 to 0.6 g 3 times daily for 7–14 days are recommended. In case of chronically recurrent erysipelas, it is best to initially treat the acute relapse with, for example, high doses of penicillin G (see above; total of 20–30 mil.

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The treatment of chronic recurrent erysipelas with phenoxymethylpenicillin (penicillin V) for 12 months significantly decreased the number of relapses.

IU IV every day) with subsequent long-term therapy with phenoxymethylpenicillin (penicillin V) 250 mg twice daily or 0.4 mega IU twice daily for 12 months [26, 27]. An alternative, especially in case of lacking compliance, but less evidencebased, is the permanent prophylaxis with depot penicillin (benzathine penicillin 2.4 mil. U IM every two to three weeks (according to an acceptable study [28] and a meta-analysis [27]). Recently, there have been supply shortages for benzathine penicillin in Germany; if this is the case, it can be obtained via wholesale; as the therapeutic procedure is similar to the one used in syphilis, it is explained on the websites of the German Society for the Promotion of Sexual Health and of the Study Group Dermatological Infectious Diseases and Tropical Dermatology. Retarpen Trstamp 2.4 Mega can be ordered via wholesale through local pharmacies (www. koelsche-blister.de), for this purpose, an order form is retrievable from http://dstig. de/aktuellespressekalender/146-empfehlung-alternative-syphilis-therapie.html). In case of a penicillin allergy, we recommend clarithromycin 250 mg every day for a period of 12 months. Although this recommendation lacks a high evidence level due to a lack of studies, it was derived by the authors of the recommendations by the Paul-Ehrlich Society [12] analogous a) to oral penicillin prophylaxis and b) to studies conducted with erythromycin, which itself could not be recommended due to its poorer tolerability. Prior to this, clindamycin should be considered for the treatment of the acute relapse, since it has been shown to be effective in case of intercellular persistence of hemolytic streptococci, at least in tonsillitis; however, assessment of its efficacy has been inconsistent in case series [29]. If limited soft tissue infections (see below) cannot be ruled out in the above-mentioned situations (skin already altered by other dermatoses, facial infection), we recommend the following course of action: Since these patients are usually hospitalized and rounded on daily, and since penicillin is the most effective weapon – marked by the fewest side effects – in case of a streptococcal infection, penicillin should initially be given preferentially. It should only be switched in favor of the therapy suggested for limited cellulitis (see below), if there is no response after 1–2 days, for example, oral therapy with cefadroxil or cefalexin or parenteral treatment with cefuroxime [13, 25, 30]. Especially in facial infections, we would give cefuroxime IV, as it is significantly more effective against Hemophilus influenzae (see differential diagnoses) and generally characterized by a broader efficacy spectrum towards gram-negative rods. Possible portals of entry should also always be treated (e.g. interdigital tinea).

Limited cellulitis/limited soft tissue infection Limited cellulitis is a skin infection frequently caused by S. aureus, which is neither a bright red, sharply demarcated erysipelas nor a purulent necrotic infection extending to the fascia (severe cellulitis).

Limited cellulitis is defined by us as an infection of the dermis and subcutis, which is neither erysipelas caused by streptococci nor a purulent necrotic infection extending to the fascia (severe cellulitis), and therefore usually requires no surgical intervention. It primarily develops around a larger wound and is frequently caused by S. aureus. In the German terminology, there is no generally accepted term for an infection of the dermis, which originates from ulcers or wounds, but is neither streptococcal erysipelas nor cellulitis in the stricter sense, meaning a severe, deep, purulent soft tissue infection. However, referring to such limited soft tissue infections as erysipelas, on the one hand, leads to inadequate treatment of a limited soft tissue infection with penicillin and, on the other hand, to the inadmissible conclusion that not all erysipelas are treatable with penicillin. It is questionable whether, on otherwise healthy unaltered skin, the classic clinical presentation of erysipelas can also be caused by other gram-positive bacteria that cause soft tissue infections, such as S. aureus, S. lugdunensis or Hemophilus influenzae; exceptions may occur with respect to such infections in the face.

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Figure 7  Limited cellulitis with an ulcer as portal of entry.

In the research group SkinStaph, in quality standards for microbiology and infectious diseases (MiQ 6a and 6b), and for the current recommendations on skin and soft tissue infections by the Paul-Ehrlich Society for Chemotherapy [7, 8, 12, 31], we have therefore introduced the term “limited cellulitis.” In English, the term cellulitis is occasionally used in this context, but with similar frequency as a generic term for both erysipelas and the limited soft tissue infections referred to by us.

Diagnosis Clinically, a “limited soft tissue infection” presents with warm, edematous, tender, dark red or livid erythema or a pasty swelling surrounding a portal of entry (ulcer, wound). The lesion usually has a darker or more livid-red color, is less shiny and less sharply demarcated than classic erysipelas, probably because it involves deeper tissue layers (Figure 7). There is no evidence of a purulent infection extending to the fascia – this would rather correspond to severe cellulitis – or of toxinemia in the context of a necrotizing soft tissue infection. Systemic infection signs such as leukocytosis with neutrophilia, fever, elevated ESR or CRP are initially lacking. A microbiological workup of the wound base and edges is indicated if a) based on history or specific symptoms, unusual pathogens are suspected as infection cause, or b) multiresistant pathogens (especially MRSA) are suspected, or c) the limited cellulitis does not respond to antibiotics effective against S. aureus within 2–3 days. If fever or other signs of sepsis occur in soft tissue infections, blood cultures are appropriate. If S. aureus is isolated from the wounds, it is usually also the responsible pathogen in the infected dermis, regardless of the fact that other, for example, gram-negative bacteria may also have been isolated from the wound swab (Sunderkötter, Becker, Meyer et al., as yet unpublished results). If severe illnesses or other impairments of the immune system are present (PAD, poorly controlled diabetes mellitus, immunosuppression including neutropenia), other relevant bacteria may also be isolated from the soft tissue; in this case the infection no longer represents limited, but rather severe cellulitis.

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Differential diagnoses Erysipelas: Cellulitis and erysipelas can usually be distinguished on the basis of the aforementioned criteria. The differentiation may be difficult in the facial area or on previously pathologically altered skin, especially as the fever reaction typical for erysipelas may be missing in elderly patients or individuals on corticosteroids. For these cases, we have given a pragmatic treatment recommendation. Severe cellulitis: This is a purulent infection with diffuse progression within deep soft tissue, already affecting the fascia. It is also accompanied by necroses. Cutaneous abscesses: These are encapsulated, pus-filled hollow spaces in the dermis and subcutis that clinically appear as a fluctuating, dark red, tender, warm mass under a usually intact epidermis. Necrotizing skin and soft tissue infections (life-threatening): Necrotizing skin and soft tissue infections (necrotizing fasciitis; clostridial, necrotizing myositis; gas gangrene) are characterized by severe disease courses with fatal deterioration within hours, and violent pain, which initially cannot be reconciled with the visible cutaneous findings. Erysipeloid, thrombophlebitis, and phlebothrombosis were mentioned in the chapter on erysipelas.

Therapy

In orally treatable forms of limited cellulitis, cefadroxil (1–2 g twice daily) or cefalexin (1 g 3–4 times daily) are sufficient; by contrast, the bioavailability of cefuroxime is only adequate if given parenterally.

As mentioned before, in most cases, S. aureus (Sunderkötter, Becker, Meyer et al., unpublished data, manuscript in preparation) is the causative pathogen, even if the portal of entry is a wound additionally colonized by gram-negative pathogens. In orally treatable forms, cefadroxil (1–2 g twice daily) or cefalexin (1 g 3–4 times daily) [13, 25, 30] are sufficient (slight advantage for cefadroxil due to longer half-life). If involvement of gram-negative bacteria is ruled out or deemed improbable, but S. aureus (no MRSA), on the other hand, has been isolated or is very probable, first and second-generation cephalosporins such as cefadroxil or cefalexin [13, 25, 30] (for dosages, see above) or even isoxazolyl penicillin (in Germany, currently only flucloxacillin) are recommendable for oral therapy [32]. Flucloxacillin (1 g 3–4 times daily) exerts the lowest selection pressure due to its efficacy spectrum tailored towards S. aureus. Some prefer giving it intravenously, or even prefer giving the aforementioned cephalosporins, as flucloxacillin has a slightly lower bioavailability; however, its overall oral bioavailability is also acceptable, even in older patients [33] (in case of impaired creatinine clearance, it might be given every 12 hours instead of every 6–8 hours) [33]. Cefuroxime, though not quite as bioavailable in its oral form, shows excellent parenteral bioavailability and is marked by broader efficacy against gram-negative bacteria (dose: 750–1500 mg 2–3 times daily; if gram-negative pathogens are suspected, 1500 mg IV 2–4 times daily). In deeper wounds or portals of entry, especially in the face-neck area (anaerobic conditions and corresponding bacterial milieu), beginning abscess formation, or obvious general symptoms (toxin effect), clindamycin (0.6 g 3 times daily) would be recommendable. It inhibits bacterial protein and toxin synthesis and shows good efficacy against gram-positive cocci, nocardia, anaerobes, and diphtheria bacteria; however, with some exceptions (Bacteroides species), no activity against gram-negative pathogens is to be expected [13, 16, 34, 35]. Experience shows that in case of an infection of the genitoanal area, or a correspondingly infected wound, or a reduced immune response due to diabetes mellitus or severe PAD, anaerobic or gram-negative pathogens may be involved

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in the soft tissue infection. Therefore, the combination of an aminopenicillin plus a beta-lactamase inhibitor (e.g. amoxicillin/clavulanic acid 875 mg/125 mg twice daily) or also moxifloxacin is indicated [12, 36, 37]. In case of penicillin allergy, clindamycin 0.6 g 3 times daily or roxithromycin 0.3 g daily or clarithromycin 0.25–0.5 g twice daily for 7–10 days are indicated [12]. Indications for parenteral, at best sequential, therapy would be:  A critical location with the risk of severe sequelae (hand or facial area),  Relevant comorbidities (circulatory disorders, impaired absorption).

If antibiotic therapy is effective, a significant improvement with defervescence should occur within three days, and resolution within 7–10 days

For otherwise uncomplicated cases, flucloxacillin or first/second-generation cephalosporins (e.g. cefuroxime) are a reasonable choice [16]. If antibiotic therapy is effective, a significant improvement with defervescence should occur within three days, and resolution within 7–10 days. Concerning the aforementioned antibiotics, the following is to be considered (inter alia from [5, 6]):  Flucloxacillin, though effective if S. aureus has been isolated, has a slightly poorer bioavailability compared to the abovementioned cephalosporins and macrolides, as well as possibly a higher risk for hepatotoxicity (and adverse interactions, for example, with methotrexate). It should therefore not be given for more than 14 days.  Fluoroquinolones, such as moxifloxacin, show adverse effects in approximately 4–10 % of patients, most frequently in the gastrointestinal tract as well as in the form of CNS or skin reactions. In patients with electrolyte imbalances (hypokalemia) or simultaneous use of antiarrhythmics, there is an increased risk for torsade de pointes. Cases of hepatitis and also liver failure have also rarely been observed. Milk or milk products, or drugs with multivalent cations should be taken at sufficiently large intervals. In any case, there is an increased selection pressure. Evidence for these recommendations is limited. The recommendations mentioned herein have been compiled for the PEG recommendations [12], and are based on studies or case series, which especially included the soft tissue infections referred to here. Since there are as yet no fixed criteria for the group of limited soft tissue infections, although they occur frequently, barely any studies with corresponding inclusion criteria exist. This is in contrast to the situation for complicated soft tissue infections according to the FDA definition, which are, however, not referred to here. Thus there are no good comparative studies, either, let alone recommendations obtained from metaanalyses on the use of oral antibiotics. Even a 2010 Cochrane analysis on cellulitis and erysipelas [25] failed to provide conclusive recommendations for both erysipelas and the limited soft tissue infections subsumed under cellulitis. Overall, fluoroquinolones and beta-lactam antibiotics (excluding group 3 cephalosporins) have been shown to be similarly effective in mild to moderate infections [38].

Severe cellulitis In our understanding, severe cellulitis is a purulent infection with diffuse expansion into deep soft tissue, which may already involve the fascia. It is accompanied by significant purulence and frequently also by the formation of necroses, necessitating surgery or at least debridement (Figure 8). It is more often caused by other

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Figure 8  Severe cellulitis.

pathogens than limited cellulitis. It may develop from limited cellulitis if either a) no prompt treatment for e.g. S. aureus was initiated or b) complicating factors such as diabetes mellitus, PAD, edema, larger injuries exist; hence, severe cellulitis is often also a complicated soft tissue infection according to the original FDA definition. The preconditions apparently facilitate an infection by, among others, Enterobacteriaceae or P. aeruginosa. Severe cellulitis may also be directly caused by certain virulent bacteria that enter the soft tissue under certain conditions, such as, for example, infections by Aeromonas hydrophila after contact with contaminated fresh water and Vibrio spp. (Vibrio vulnificus, Vibrio alginolyticus, Vibrio parahaemolyticus) after corresponding saltwater exposure and diving injuries [19].

Differential diagnoses The differential diagnoses are similar to those for limited cellulitis (see above), and also include especially cutaneous abscesses and life-threatening necrotizing skin and soft tissue infections.

Diagnosis Although “severe cellulitis” – similar to “limited cellulitis” – clinically presents with a warm, edematous, tender, dark erythema or doughy swelling, it also exhibits significant accumulations of pus, as well as occasionally already necroses, and also includes deeper parts of soft tissues such as the fascia or possibly muscle layers. Patients experience fever, chills, and regional lymphadenopathy. Sampling [5, 7, 8]: Especially if a soft tissue infection progresses towards severe cellulitis or a complicated soft tissue infection, adequate sampling is indispensible (overview [5]). Other urgent indications for microbiological pathogen isolation include those types of limited cellulitis that do not respond to an antibiotic effective against S. aureus within 2–3 days, abscesses, skin infections after surgical procedures or after other iatrogenic procedures, infections in severe immunosuppression with the risk of exceptional causal pathogens such as fungi (Cryptococcus sp. and

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others), bite wounds, or skin lesions associated with systemic infections (endocarditis, sepsis, rickettsiosis, rat-bite fever, systemic mycoses and others) [7, 8]. With respect to pathogen isolation, tissue biopsies are better suited than swabs, as they allow for cultures as well as nucleic acid detection techniques such as PCR, and also a histological examination. Thus, sensitivity and specificity are increased. Careful harvesting of these biopsies is laborious, but justified. For this purpose, a tissue spindle of approximately 1 cm length, containing the subcutis, should be taken from the infected tissue at a distance of 1–2 cm from the wound edges. Beforehand, a reduction of superficial microorganisms must be ensured by thorough skin disinfection at the biopsy site. Following sterile removal of the biopsy, it is also recommended to separate its upper, epidermal part from the lower dermis and subcutis with another sterile scalpel. Thus, only pathogens in the soft tissue are identified, not any bacteria flushed onto the skin from the wound; for this separation, it is recommended to place the biopsy specimen on top of a sterile, solid pad (not fleece). Afterwards, the tissue sample to be evaluated is transferred into a sterile transport medium or a sterile liquid enrichment medium. This procedure is derived from the work instructions “Sampling in soft tissue infections” (C. Sunderkötter, R. Gläser, K. Becker) in the context of the BMBF joint project SkinStaph, and has been adopted for quality standards in microbiology and infectious diseases [7, 8]. Its advantages over swabbing are currently being further evaluated in comparative studies. In order to obtain a suitable smear from the portal of entry, Dacron tissue swabs for transfer media should be used, superficial secretions removed with a sterile swab, and fibrinous or necrotic coatings removed as well. The sample is taken from the wound base and from underneath the wound edges, if possible from various locations [7, 8]. Swabs covering an extensive area or those performed in a spiraling motion seem less suited, since they capture many clinically irrelevant microbes.

Therapy In severe cellulitis, parenteral, at best sequential, therapy is usually indicated. Selection principles are similar to those for limited cellulitis. Severe cellulitis usually requires – almost by definition – surgical intervention. In uncomplicated cases without severe symptoms, if no specific comorbidities or injury characteristics (no bite wounds, deep stab wounds with contaminated tools, or diving injuries) exist, and thus S. aureus (not MRSA) is the probable pathogen, intravenous cephalosporins (e.g. cefuroxime 750–1500 mg 2–3 times daily; if gram-negative pathogens are suspected, 1500 mg 2–4 times daily), alternatively flucloxacillin (1–2 g IV, 4 times daily) are recommended [31, 39]; flucloxacillin exerts the lowest selection pressure due to its efficacy spectrum tailored towards S. aureus, but exhibits slightly poorer pharmacokinetics. If complicated, chronic, possibly polymicrobial infections caused by gram-positive or gram-negative pathogens or also anaerobes are suspected, initial empirical therapy includes an aminopenicillin plus a beta-lactamase inhibitor or moxifloxacin, possibly plus clindamycin [36]; if such therapy is unsuccessful, treatment is adapted according to antibiogram. For quick empirical therapy of severe, possibly nosocomial soft tissue infections in patients with multiple comorbidities, reserve antibiotics are available (e.g. linezolid, tazobactam, ceftaroline, tigecycline, carbapenems, and others), which, however, should only be used after consultation with infectious disease specialists or microbiologists. A short description can be found after this paragraph. Foot infections in patients with severe diabetes mellitus should initially be classified

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­ ccording to severity, for example, according to one of the international classificaa tions such as PEDIS (acronym for Perfusion, Extent/size, Depth/tissue loss, Infection, and Sensation). Antibiotics are then selected according to recommendations of the International Working Group on Diabetic Foot from 2004 or 2007, which have been increasingly gaining acceptance. A differentiation between very superficial and deeper, but clinically moderate infections is reasonable, especially due to the different pathogen spectrum [40–43]. PEDIS 2 (superficial infection, ≤ 2 cm in diameter): While S. aureus and beta-hemolytic streptococci are the most frequent pathogens, an aminopenicillin plus a beta-lactamase inhibitor [40–43], moxifloxacin [44, 45], or cefalexin are recommended, in order to quickly cover other possible pathogens. PEDIS 3: (deep infection, moderate course): Enterobacteriaceae and anaerobes are the most frequent pathogens, aside from S. aureus and beta-hemolytic streptococci; therefore, an aminopenicillin plus a beta-lactamase inhibitor [45] or moxifloxacin are recommended; further combinations (such as ciprofloxacin or levofloxacin plus metronidazol, to cover anaerobes) should be used according to antibiogram and in consultation with infectious disease specialists or microbiologists. In severe infections, for example, initially carbapenems. In bite wounds, infections caused by Pasteurella multocida, Capnocytophaga spp., Bartonella spp., coagulase-positive staphylococci, beta-hemolytic streptococci, and anaerobes must be reckoned with. Therefore, depending on animal and severity, an aminopenicillin plus a beta-lactamase inhibitor, group 1/2 cephalosporins, moxifloxacin, or piperacillin/tazobactam are empirically recommendable. As soon as possible, the further course of action is to be determined by the antibiogram. Concerning the aforementioned antibiotics, the following is to be considered or to be observed [5]:  Amoxicillin/clavulanic acid (fixed combination) particularly effectively inhibits beta-lactamases of gram-positive pathogens such as methicillin-sensitive staphylococci, but also Hemophilus influenzae, Bacteroides fragilis, and some enterobacteria such as Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis and vulgaris, but not Enterobacter spp., Serratia marcescens, and Morganella (M.) morganii. The bioavailability of clavulanic acid, which is marked by pronounced individual variation, is approximately 60 %; intake immediately before meals increases absorption. It frequently causes, partly dose-dependent, gastrointestinal complaints, which are reduced by the simultaneous intake with meals, fractioning of high doses, and previous administration of metoclopramide. A frequent increase in transaminases, up to three or four times the normal values, may be tolerated, if there is no severe liver damage and no cholestasis or hepatocellular damage.  Sultamicillin (as fixed combination in ampicillin/sulbactam) has a lower hepatotoxicity than clavulanic acid, but is not practicable for oral use due to the many tablets required.  Piperacillin/tazobactam, fixed combination of the acylaminopenicillin piperacillin with the beta-lactamase inhibitor tazobactam, possesses a broader spectrum against beta-lactamases and is reserved for severe soft tissue infections where S. aureus, gram-negative pathogens, and anaerobes are suspected (thus in diabetes mellitus or PAD, also in bite wounds); against Pseudomonas spp., the dosage of piperacillin should be increased. It is not suited for immunosuppressed patients.  Metronidazol is given in combination with other antibiotics e.g. in the context of mixed aerobic-anaerobic infections, if clindamycin-resistant isolates are involved (especially Bacteroides fragilis).

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Linezolid almost exclusively covers gram-positive bacteria, yet including MRSA, and should be reserved for infections caused by multiresistant pathogens. It is characterized by good distribution in cutaneous or soft tissue and is usable both orally and parenterally. Regular lab tests and adverse effects have to be observed. Group 5 cephalosporins (e.g. ceftaroline fosamil parenterally) possess a broad efficacy spectrum against gram-negative and gram-positive pathogens, including MRSA, but excluding extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, P. aeruginosa, or Acinetobacter baumannii. Group 2 fluoroquinolones (e.g. ciprofloxacin) show a good activity against Enterobacteriaceae, a moderate activity against P. aeruginosa, and an insufficient activity against staphylococci, streptococci, and enterococci. Group 3 fluoroquinolones (e.g. levofloxacin) exhibit a slightly better activity against gram-positive pathogens such as streptococci or staphylococci, but are less active against P. aeruginosa. Group 4 fluoroquinolones (e.g. moxifloxacin) possess a significantly higher efficacy against gram-positive pathogens (streptococci, staphylococci) and are also effective against other gram-positive and gram-negative anaerobes, but not against P. aeruginosa. Tigecycline has a broad efficacy spectrum against multiresistant gram-positive and gram-negative pathogens such as MRSA, Enterobacteriaceae, Acinetobacter baumannii, S. maltophilia, anaerobes, but not against P. aeruginosa, Proteus spp., and M. morganii. Carbapenems (all parenteral) are beta-lactam antibiotics with corresponding pharmacodynamic properties, but with a very broad antimicrobial spectrum. They cover most gram-positive pathogens, including penicillinase-producing staphylococci (but not MRSA), also many gram-negative bacteria, including anaerobes, and ESBL-producing pathogens, but Stenotrophomonas maltophilia, Clostridium difficile, and enterococci only insufficiently. They would by indicated in severe cellulitis with gram-negative pathogens in immunosuppressed patients, or in case of a deep, limb-threatening infections in the context of peripheral vasculopathy or severe diabetes (diabetic foot, see below). Glycopeptides (vancomycin, teicoplanin) or daptomycin should only be given if MRSA has been isolated and other substances are not suitable.

Abscesses Cutaneous abscesses are encapsulated, pus-filled hollow spaces in the dermis and subcutis. They form as a result of tissue damage caused by granulocytes and bacterial enzymes, and are clinically characterized by a fluctuating, dark red, painful, warm mass under a usually intact epidermis (Figure 9). Depending on their genesis, they are caused by either one or multiple bacterial species. Infection usually occurs through inoculation after injury, occasionally supported or facilitated by scratching, manipulation, or occlusion, but may also develop by hematogenous dissemination. In the former case, pathogens usually originate from the resident or transient skin flora (microbiota). In the dermatological patient population, S. aureus is frequently the only pathogen isolated.

Diagnosis In abscesses, a sufficient amount of sample material should be obtained prior to their opening or drainage. If this is not feasible, a sufficient amount of abscess content should be collected using a syringe or a surgical spoon during incision under

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Figure 9  Abscess.

aseptic conditions, and placed into a sterile receptacle for transport. If possible, additional tissue fragments should be obtained from the granulation tissue of the abscess wall in a separate transport receptacle for microbiological diagnostics. If tissue cannot be harvested, a swab should at least be taken from the edges of the abscess. Pus is microbicidal and mainly contains necrotic pathogens. Therefore, enough material must be obtained. When opening an abscess or in case of fistula canals, thin sterile catheters should be inserted as far as possible for sample collection; this should be preceded by cleansing and disinfection (here, residue-free disinfectants, e.g. 80 % ethyl alcohol, may be used) [7, 8].

Therapy For abscesses, adequate incision or opening with drainage followed by surgical care at regular intervals is the most important and primarily effective therapy.

According to studies and systematic overviews, adequate incision or opening with drainage followed by surgical care at regular intervals is the most important and primarily effective therapy for abscesses; this also prevents dissemination. If abscesses develop exceptionally fast in otherwise healthy patients, expand rapidly, quickly cause necroses, or recur, PVL-producing S. aureus should be suspected. Abscesses may have a high risk of complications and are among those compartments with fundamentally difficult accessibility for antibiotics. For the indications mentioned here and for the selection of systemic (oral) antibiotic therapy, few studies, at most case series on purulent skin infections, are available (16, 34, 46–49]. The following recommendations result:  Drainage and surgical care at regular intervals is the most important and frequently sufficient method. Depending on the size of the abscess, this may also be sufficient, if cMRSA is involved [34, 46].  Indications for additional antibiotic treatment are: - Location on the face, hands, and in the genitoanal region, - Difficulties in sufficient drainage, for example, in case of chambered abscesses (sufficient drainage should however take precedence whenever possible, and should not be replaced by the use of antibiotics),

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- Immunodeficiency, - Recurring abscesses [16] and - Diffuse expansion into soft tissues (cellulitis). Abscesses are difficult to access for antibiotics. There are specific indications for their use, in addition to opening and drainage.

Abscesses are difficult to access for antibiotics. There are specific indications for their use, in addition to opening and drainage. In these cases, the following antibiotics should be given:  If only gram-positive pathogens are suspected or have been detected and drainage has been adequate, oral cefadroxil or cefalexin [34] is often sufficient; in deep abscesses that have been drained, clindamycin (0.6 g 3 times daily) due to its good tissue penetration and efficacy against anaerobes [16, 34].  If the possibility of an infection with anaerobes and gram-negative pathogens exists, experience shows that amoxicillin plus clavulanic acid is an effective therapy of first choice (875 mg/125 mg twice daily or 500 mg/125 mg 3 times daily). Another recommendation would be moxifloxacin 400 mg daily, which, in studies, has proven equally effective, when given sequentially (first IV, then orally), as intravenous piperacillin/tazobactam followed by oral amoxicillin/ clavulanic acid [44].  If cMRSA, but also if hospital-acquired MRSA (hMRSA) [17] is suspected, the empirical use of trimethoprim/sulfamethoxazole is also recommended [12, 50]; the further course of action is adapted according to antibiogram as well as to recommendations for MRSA decolonization.

Severe necrotizing soft tissue infections Necrotizing soft tissue infections (e.g. necrotizing fasciitis) are rapidly progressive infections caused by specific toxin-producing bacteria and pose an immediate danger to life. They are an independent entity and can occur directly after minor trauma.

Severe necrotizing soft tissue infections (necrotizing skin and soft tissue infections) with an immediate danger to life (e.g. necrotizing fasciitis) are an independent entity with a specific toxin-mediated pathogenesis. They are not a direct continuum of the aforementioned soft tissue infections (cellulitis, abscesses). They affect the skin, the subcutaneous tissue, the fascia including the underlying muscle (necrotizing fasciitis) and the skeletal muscles (clostridial, necrotizing myositis = gas gangrene) or nonclostridial, usually streptococcal myonecrosis or pyomyositis. Pathophysiologically, they are characterized by the effects of bacterial toxins, intravascular thromboses, ischemic necroses, and by a disturbance of the host’s humoral and cellular immune response. The term “necrotizing fasciitis” is an inaccurate and trivializing misnomer, since the fascia may also present necrotic areas in severe cellulitis. Portals of entry for the pathogens are, aside from the hematogenous dissemination, usually minor traumas, infected surgery wounds and injection sites (injection abscess), less frequently inflamed periurethral glands or perianal infections (Fournier’s gangrene). Usually, these are monoinfections caused by toxin-producing hemolytic Group A streptococci equipped with specific M proteins, in recent years especially the hyperinvasive serotype M1T1, or less frequently by S. aureus (especially cMRSA). Mixed infections caused by gram-positive pathogens (streptococci, staphylococci), anaerobes (Bacteroides fragilis, Prevotella melaninogenica) and Enterobacteriaceae mainly occur in a nosocomial setting.

Diagnosis Necrotizing soft tissue infections are characterized by a foudroyant disease course with severe general symptoms and eventually shock. The extreme, ischemia-related, localized pain, which cannot be reconciled with the initially visible clinical findings, is simultaneously the leading and the only typical inaugural symptom.

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Timely diagnosis is difficult, but essential for the patient’s survival, since immediate surgical and antibiotic action must be taken.

Differential diagnoses Severe necrotizing soft tissue infections clinically differ from severe cellulitis or abscesses in their hyperacute progression (fatal deterioration within hours) and the severe pain. In uncertain cases, the decisive diagnostic procedure is an explorative incision in the suspicious area. On direct inspection, the fascia appears swollen and dark gray with necrotic areas. In addition to macroscopic and histological exploration, a sample should be taken for gram staining [7, 8]. The usefulness of MRT to confirm the diagnosis is not validated and may delay treatment; a cautious approach is inappropriate.

Therapy Radical surgical debridement has to be performed immediately, and antibiotic therapy must be initiated perioperatively at the latest. Post-op, the patient has to be monitored in an intensive care setting. Treatment with an acylaminopenicillin plus a beta-lactamase inhibitor (tazobactam) or a group 1 or 2 carbapenem is recommended. Alternatively, monotherapy with moxifloxacin or a combination of a group 3 cephalosporin with metronidazol may be given. For all therapeutic options, the additional use of clindamycin or linezolid is recommended in order to decrease toxin effects through inhibition of the protein biosynthesis of gram-positive bacteria. Thus, septic complications caused by exotoxins (e.g. superantigens) may be reduced.

Conclusion The term “skin and soft tissue infections” is a generic term that summarizes a broad spectrum ranging from superficial dermal infections to deeper infections that extend into the subcutis to toxin-mediated, life-threatening infections. Soft tissue infections include erysipelas, limited cellulitis or limited soft tissue infection, severe cellulitis, abscesses, and necrotizing ischemic toxin-mediated soft tissue infections. The most frequent pathogen in cellulitis is S. aureus, irrespective of other, e.g. gram-negative bacteria, which may have been isolated at the portal of entry. For many uncomplicated bacterial skin and soft tissue infections, benzyl or isoxazolyl penicillins or group 1 or 2 cephalosporins are exceedingly effective substances. Other antibiotics have a higher risk of side effects and increase selection pressure. They are indicated in complicated soft tissue infections with a different pathogen spectrum and/or with a risk of infections with (multi-)resistant pathogens.

Acknowledgments Special thanks is due to the coauthors of the chapter “skin and soft tissue infections, mastitis” in the PEG recommendations on initial empirical oral therapy of bacterial diseases in adults [12]: C. Eckmann, W. Kern, W. Graninger, P. Shah, W. Fritsche, R. Berner, A. Altiner, and G. Gross. The 2015 update has not yet been published, but much of the collaborative work has already been quoted in this article. The authors would also like to thank the photo department at the Department of Dermatology of the UKM for the photographic material. The article was in part supported by BMBF funds (SkinStaph in the joint project Susceptibility of Infections; K.B., 01Kl1009A and C.S., 01Kl7100).

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Correspondence to

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Prof. Dr. med. Cord Sunderkötter Klinik für Hautkrankheiten des Universitätsklinikums Münster Abteilung für translationale Dermatoinfektiologie Röntgenstraße 21 48149 Münster Germany E-mail: cord.sunderkö[email protected] ukmuenster.de

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23 Jorup-Ronstrom C, Britton S, Gavlevik A et al. The course, costs and complications of oral versus intravenous penicillin therapy of erysipelas. Infection 1984; 12: 390–4. 24 Tschachler E, Brockmeyer N, Effendy I et al. Streptococcal infections of the skin and mucous membranes. J Dtsch Dermatol Ges 2007; 5: 527–32. 25 Kilburn SA, Featherstone P, Higgins B, Brindle R. Interventions for cellulitis and erysipelas. Cochrane Database Syst Rev. 2010: CD004299. 26 Thomas KS, Crook AM, Nunn AJ et al. Penicillin to prevent recurrent leg cellulitis. N Engl J Med 2013; 368: 1695–703. 27 Oh CC, Ko HC, Lee HY et al. Antibiotic prophylaxis for preventing recurrent cellulitis: a systematic review and meta-analysis. J Infect 2014; 69: 26–34. 28 Chakroun M, Ben Romdhane F, Battikh R et al. Benzathine penicillin prophylaxis in recurrent erysipelas. Med Mal Infect 1994; 24: 894–7. 29 Koster JB, Kullberg BJ, van der Meer JW. Recurrent erysipelas despite antibiotic prophylaxis: an analysis from case studies. Neth J Med 2007; 65: 89–94. 30 Giordano PA, Elston D, Akinlade BK et al. Cefdinir vs. cephalexin for mild to moderate uncomplicated skin and skin structure infections in adolescents and adults. Curr Med Res Opin 2006; 22: 2419–28. 31 Kujath P, Eckmann C, Graninger W et al. Haut-und Weichgewebe-, Knochen- und Gelenkinfektionen. In: Bodmann KF, Grabein B, Expertenkommission der PaulEhrlich-Gesellschaft für Chemotherapie e.V. Empfehlungen zur kalkulierten parenteralen Initialtherapie bakterieller Erkrankungen bei Erwachsenen – Update 2010; Chemother J 2010; 19: 225–31. 32 Leman P, Mukherjee D. Flucloxacillin alone or combined with benzylpenicillin to treat lower limb cellulitis: a randomised controlled trial. Emerg Med J 2005; 22: 342–6. 33 Gath J, Charles B, Sampson J, Smithurst B. Pharmacokinetics and bioavailability of flucloxacillin in elderly hospitalized patients. J Clin Pharmacol 1995; 35: 31–6. 34 Chen AE, Carroll KC, Diener-West M et al. Randomized controlled trial of cephalexin versus clindamycin for uncomplicated pediatric skin infections. Pediatrics 2011; 127: e573–80. 35 Paganini H, Della Latta MP, Muller Opet B et al. [Community-acquired methicillinresistant Staphylococcus aureus infections in children: multicenter trial]. Arch Argent Pediatr 2008; 106: 397–403. 36 Vick-Fragoso R, Hernandez-Oliva G, Cruz-Alcazar J et al. Efficacy and safety of sequential intravenous/oral moxifloxacin vs intravenous/oral amoxicillin/clavulanate for complicated skin and skin structure infections. Infection 2009; 37: 407–17. 37 Aminzadeh A, Demircay Z, Ocak K, Soyletir G. Prevention of chronic furunculosis with low-dose azithromycin. J Dermatolog Treat 2007; 18: 105–8. 38 Falagas ME, Matthaiou DK, Vardakas KZ. Fluoroquinolones vs beta-lactams for empirical treatment of immunocompetent patients with skin and soft tissue infections: a meta-analysis of randomized controlled trials. Mayo Clin Proc 2006; 81: 1553–66. 39 Becker K. Staphylokokken. In: Rascher W: Therapie-Handbuch Infektionskrankheiten (Sonderedition). 1. Auflage. München: Elsevier, Urban & Fischer, 2013: 444–51. 40 Lipsky BA, Berendt AR, Deery HG et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2004; 39: 885–910. 41 Singer AJ, Dagum AB. Current management of acute cutaneous wounds. N Engl J Med 2008; 359: 1037–46. 42 Lipsky BA, Peters EJ, Berendt AR et al. Specific guidelines for the treatment of diabetic foot infections 2011. Diabetes Metab Res Rev 2012; 28 (Suppl 1): 234–5. 43 Peters EJ, Lipsky BA, Berendt AR et al. A systematic review of the effectiveness of interventions in the management of infection in the diabetic foot. Diabetes Metab Res Rev 2012; 28 (Suppl 1): 142–62. 44 Gyssens IC, Dryden M, Kujath P et al. A randomized trial of the efficacy and safety of sequential intravenous/oral moxifloxacin monotherapy versus intravenous piperacillin/tazobactam followed by oral amoxicillin/clavulanate for complicated skin and skin structure infections. J Antimicrob Chemother 2011; 66: 2632–42. 45 Schaper NC, Dryden M, Kujath P et al. Efficacy and safety of IV/PO moxifloxacin and IV piperacillin/tazobactam followed by PO amoxicillin/clavulanic acid in the treatment of diabetic foot infections: results of the RELIEF study. Infection 2013; 41: 175–86.

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46 Duong M, Markwell S, Peter J et al. Randomized, controlled trial of antibiotics in the management of community-acquired skin abscesses in the pediatric patient. Ann Emerg Med 2010; 55: 401–7. 47 Rajendran PM, Young D, Maurer T et al. Randomized, double-blind, placebo-controlled trial of cephalexin for treatment of uncomplicated skin abscesses in a population at risk for community-acquired methicillin-resistant Staphylococcus aureus infection. Antimicrob Agents Chemother 2007; 51: 4044–8. 48 Talan DA, Summanen PH, Finegold SM. Ampicillin/sulbactam and cefoxitin in the treatment of cutaneous and other soft-tissue abscesses in patients with or without ­histories of injection drug abuse. Clin Infect Dis 2000; 31: 464–71. 49 Schmitz GR, Bruner D, Pitotti R et al. Randomized controlled trial of trimethoprimsulfamethoxazole for uncomplicated skin abscesses in patients at risk for communityassociated methicillin-resistant Staphylococcus aureus infection. Ann Emerg Med 2010; 56: 283–7.

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Questions for certification by the DDA 1. a)

Which statement applies? Acute stasis dermatitis and ­acute insect bites can show ­similar m ­ anifestations on the skin as e ­ rysipelas and appear in ­combination with chills and fever or leukocytosis as frequently as ­erysipelas. b) S. aureus is the second most ­frequent cause of classical ­erysipelas. c) The causes of classical erysipelas are ususally beta-haemolytic group A streptococci (Streptococcus ­pyogenes). d) The causes of classical erysipelas can almost always be isolated from the possible ports of entry. e) Ulcers are frequent, foot mycoses rare ports of entry.

2. Which statement on phlegmons applies? a) A limited phlegmon or limited soft tissue infection is an infection of the skin frequently caused by S. aureus which often appears in combination with pale red swelling. b) A limited phlegmon is only ­distinguishable from pale red, ­sharply defined erysipelas or the purulent severe phlegmon which reaches the fascia through ­microbiological ­isolation of the ­pathogens. c) In case of insufficient treatment, a limited or severe phlegmon transforms into a necrotizing, ­toxin-­conveyed skin an soft tissue infection with vital danger (necrotizing fasciitis, gas gangrene). d) Flucloxacillin has a better ­pharmakocinetic and a broader e ­ fficacy spectrum against ­gram-­positive cocci than cefadroxil. e) Clindamycin is the additional ­substance of choice of aerobic gram-negative bacteria are also ­probable pathogens.

3. Which statement on impetigo, ­ cthyma and abscess applies? e a) In a two-day existant, expanded impetigo caused by beta-haemolytic group A streptococci in the face of a 4-year old boy, a systemic therapy with penicillin V is indicated. b) In impetigo caused by nephritogenic haemolytic group A streptococci, an acute poststreptococcal glomerulonephritis is always prevented reproducibly. c) Only children under 10 are endangered by impetigo and ecthyma. d) In case of impetigo and ecthyma, a localized therapy with penicillin is indicated. e) In abscesses, the application of S.-aureus effective antibiotics is the therapy of first choice: a correct incision or splitting with drainage should follow only in case of several risk factors.

4. Which statement on limited or s­ evere phlegmons applies? a) An adequate sample extraction in case of severe phlegmon is best conducted with a wooden swab which is transported in a small tube filled with distilled water. b) Sample extraction from infected wounds with soft tissue infection occurs from the secretions on the wound surface, not from the wound base or its edge. c) In severe phlegmons on the ­proximal thigh with suspicion of additional infection caused by gram-negative bacteria, a therapy with linezolid or group 5 cephalosporines is a method of choice. d) Amoxicillin/clavulanic acid is a ­possible alternative therapy in limited phlegmons in the buttocks area. e) In case of limited or severe ­phlegmons, only parenterally ­available cephalosporines have the most frequently suitable efficacy spectrum.

© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1306

5. Which statement applies? a) If a superheated erythema with ­shiny surface, sharply defined ­edges, and characteristic tongue-shaped extensions is present on the lower leg of an otherwise ­healthy young man, and S. aureus has been isolated from the port of entry in the interdigits, isoxozolylpenicillins are the substance of choice. b) If fever, paroxysmal arthralgia of the right knee, and abdominal pain are present in a patient of Turkish origin with sharply defined erythema of the thigh, the application of penicillin is sufficient. c) A red-livid plaque expanding from an erosion on the right thumb of a fisherman is typical for erysipelas. d) If a painful swelling of the complete right lower leg suddenly occurs in case of classical erysipelas on the lower leg of a bedridden patient three days prior to the start of a therapy with systemic penicillin V, and without indications to a gastrointestinal resorption disorder, this indicates that the penicillin is not sufficiently effective systemically and must be applied intravenously. e) In a dark-red swelling originating from an ulcer appears in a 50-year old patient with well-controlled ­diabetes mellitus and without ­serious general complaints, a limited phlegmon is probably present.

6. Which answer applies? In a child who is presented for the second time within seven months with flaccid ­blisters and yellow crusts on two ­gyrated erythemas each on the right cheek and under the chin... a) recurrent herpes simplex is probable. b) a therapy with cefadroxil should be started, and microbiological diagnostics for pathogen detection should occur. c) localized antiseptic therapy is not necessary.

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d) no erysipelas will develop. e) leukocytosis is always to be reckoned with.

7. Which statement does not apply? In a 50-year old female patient, a ­superheated, bright, sharply defined reddening occurs on the right lower

c)

If multiple sites of impetigo without ecthyma are present, ­systemic application of cefadroxil is appropriate and usually sufficient. d) If multiple ecthymas are present, flucoxacillin meets the bacterial spectrum as well as does cefadroxil. e) PVL-building cMRSA is not a pathogen of Impetigo.

leg within a few hours. The patient had been feeling unwell and suffering from 38.5°C fever from the start. a) In case of penicillin allergy, a ­fluorchinolon (gyrase inhibitor) is the therapy of choice. b) In blood tests, increased BSG and/or leukocytosis may be found. c) Increased streptolysin titer is not a confirmatory result. d) In these cases, mycosis of the ­interdigits is frequently to be found. e) In case of frequent relapses, a longterm prophylaxis with penicillin per os is recommended.

8. Which statement applies? a) Impetigo should always immediately be treated systemically and locally. b) For impetigo and ecthyma, mupirocin is the local treatment of choice.

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9. Which statement on diagnostics in case of impetigo or ecthyma is ­correct? a) Ecthyma is a pyoderma gangreanosum at the bottom of an ­I mpetigo. b) Prior to therapy, one should await the result of the microbiotical ­e xamination in order to simultaneously treat gram-negative ­bacteria. c) Differential diagnosis for cutaneous leishmaniasis is difficult and barely possible on the basis of family history. d) The most frequent pathogens are streptococci; S. aureus is also a ­possible pathogen. e) The most frequent pathogens of impetigo are Streptococcus viridans, and of ecthyma, S. aureus.

© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1306

10. Which statement applies? An application of group 3 fluorchinolons or amoxicillin/clavulanic acid in erysipelas... a) is an appropriate therapy in case of a penicillin allergy. b) is an appropriate therapy if erysipeloid is also considered from a ­differential diagnostic point of view. c) is an appropriate and sufficient ­t herapy if an abscess is present at the same time. d) accelerates the selection of hyperresistant bacteria, e.g. in the intestines or the respiratory tracts. e) is a good prophylaxis against ­recurring erysipelas.

Liebe Leserinnen und Leser, der Einsendeschluss an die DDA für diese Ausgabe ist der 18. June 2015. Die richtige Lösung zum Thema „Klinisches Management bei Pruritus“ in Heft 2 (­ February 2015) ist: (1c, 2a, 3a, 4d, 5e, 6b, 7a, 8c, 9d, 10d).

Bitte verwenden Sie für Ihre Einsendung das aktuelle Formblatt auf der folgenden Seite oder aber geben Sie Ihre Lösung online unter http://jddg. akademie-dda.de ein.

Frequent bacterial skin and soft tissue infections: diagnostic signs and treatment.

Skin and soft tissue infections rank among the most frequent infections worldwide. Classic erysipelas is defined as a non-purulent infection by beta-h...
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