Managing skin and soft tissue infections: expert panel recommendations on key decision points

Transcription

1 Managing skin and soft tissue infections: expert panel recommendations on key decision points Edited by Kate Gould Freeman Hospital NHS Trust, Newcastle upon Tyne, UK David Reeves Journal of Antimicrobial Chemotherapy, Birmingham, UK This supplement has been sponsored by F. Hoffmann-La Roche Ltd The Expert Panel was supported by an unrestricted educational grant from F. Hoffmann-La Roche Ltd Material published in this supplement has been peer-reviewed under the supervision of the Editors in accordance with the guidelines published in the Advice to contributors and editorial statements published previously [Volume 19 (1987), pp and Volume 25 (1990), pp ].

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3 Journal of Antimicrobial Chemotherapy (2003) 52, Suppl. S1, i3 i17 DOI: /jac/dkg466 Managing skin and soft tissue infections: expert panel recommendations on key decision points Lawrence J. Eron 1 *, Benjamin A. Lipsky 2, Donald E. Low 3, Dilip Nathwani 4, Alan D. Tice 1 and Gregory A. Volturo 5 1 University of Hawaii, John A. Burns Medical School, Honolulu, HI; 2 University of Washington School of Medicine, Antimicrobial Research Clinic, Seattle, WA; 5 University of Massachusetts, Medical School, Worcester, MA, USA; 3 University of Toronto, Microbiology and Medicine, Toronto, Ontario, Canada; 4 Ninewells Hospital and Medical School, Dundee, UK Introduction Skin and soft tissue infections (SSTIs) are suppurative microbial invasions of the epidermis, dermis and subcutaneous tissues that induce a host response. They are characterized by induration, erythema, warmth, and pain or tenderness. Local manifestations may be accompanied by systemic signs and symptoms, such as fever, chills, malaise and, at times, haemodynamic instability. SSTIs can sometimes lead to disseminated infection via the circulatory and lymphatic systems, especially in patients with various forms of immune suppression. 1 These infections affect various tissues, are caused by a variety of microorganisms and present with wide-ranging clinical manifestations. By virtue of their incidence and severity, SSTIs represent a major clinical problem. While the majority of cases are mild and may be treated with oral drugs, moderate or severe cases of SSTI may require hospitalization and parenteral therapy. In 1995, an estimated patients in the USA and 4300 patients in Scotland required hospital treatment for SSTIs, representing about 0.1% of the adult population. 2,3 SSTIs can pose considerable diagnostic and therapeutic challenges. Culturing the causative organisms is often difficult and takes several days. Host factors that contribute to the development and recurrence of SSTIs may not be apparent initially. When parenteral therapy is utilized, patients are frequently hospitalized, making treatment costly from both personal and financial perspectives. 4 In February 2003, a panel of clinicians and researchers with interest and expertise in infectious diseases, microbiology and emergency medicine gathered to discuss the classification and optimal treatment of SSTIs. The aim of the meeting was to develop practical recommendations that aid the clinical decision-making process in dealing with these infections, and thus optimize patient care. Five key decision points in the handling of SSTI patients were identified and will be addressed: (1) whether to hospitalize or to treat in an outpatient setting; (2) which type and route of antimicrobial agents to use initially; (3) when to switch from parenteral to oral therapy; (4) when to discharge the hospitalized patient; and (5) when to discontinue antimicrobial treatment. In many areas of SSTI management, there is little in the way of high-level evidence available from randomized clinical trials. The recommendations and statements given in this document are therefore based on published clinical trials where available, and on consensus opinion based on the clinical experiences of the faculty. The systems of care delivery described here may appear to have a North American flavour. However, while regional variations in health care infrastructure and care delivery may alter the actual method or style of care delivery, we believe that the underlying philosophies and generic principles discussed are applicable globally. 5 8 Classification SSTIs can be divided into four classes according to the severity of local and systemic signs and symptoms of infection, and the presence and stability of any comorbidities (Table 1 and Figure 1). This classification system serves as a useful guide to admission and treatment decisions for patients with SSTIs. 9 Class 1 patients have no signs or symptoms of systemic toxicity, have no uncontrolled comorbidities that may complicate treatment, and usually can be managed with topical or oral antimicrobials on an outpatient basis. Class 2 patients are either systemically ill, but any comorbidities they may have are stable, or are systemically well, but have one or more comorbidities (e.g. peripheral vascular disease, diabetes mellitus, chronic venous insufficiency, morbid obesity) that may complicate or delay the resolution of their SSTI. Some class 2 patients may improve with a course of oral antimicrobials. For those requiring parenteral therapy, outpatient parenteral antimicrobial therapy (OPAT) has the potential to greatly reduce costs and improve patient satisfaction, with outcomes that are equivalent or superior to those of inpatient treatment Some class 2 patients may require short-term hospitalization or observation in an infusion centre or emergency department. Class 3 patients may appear toxic, e.g. having changes in mental status, tachycardia, tachypnoea or hypotension, or they may appear non-toxic but have unstable comorbidities that may interfere with their response to therapy. Class 3 patients usually require initial inpatient treatment with parenteral antimicrobials, but many can be quickly discharged on OPAT or oral therapy. Some class 3 patients with limb-threatening infections due to vascular compromise may need to be hospitalized for vascular evaluation and remediation. Class 4 patients have sepsis syndrome or serious lifethreatening infections, such as necrotizing fasciitis, and are always... *Corresponding author. Tel: ; Fax: ; lawrence.eron@kp.org... i3 The British Society for Antimicrobial Chemotherapy 2003; all rights reserved.

4 L. J. Eron et al. Table 1. Eron 9 classification system for patients with SSTIs Class Patient criteria 1 afebrile and healthy, other than cellulitis 2 febrile and ill appearing, but no unstable comorbidities 3 toxic appearance, or at least one unstable comorbidity, or a limb-threatening infection 4 sepsis syndrome or life-threatening infection, e.g. necrotizing fasciitis admitted, often to the intensive care unit or a critical care facility. Many class 4 patients will require surgical intervention. Once class 4 patients are stabilized, they may also be candidates for OPAT or oral therapy. 9 Examples of cases from each of these classes are presented in Figure 1, and the treatment pathways are summarized in Figure 2. This manuscript focuses on the management and treatment of patients with class 2 and 3 SSTIs. Microbiology The majority of SSTIs are caused by aerobic Gram-positive cocci, specifically Staphylococcus aureus and streptococci. In specific clinical or epidemiological circumstances, a number of other infectious agents also cause infection (Table 2). 13 Owing to the difficulties of isolating organisms from cellulitis cases, most of which are caused by streptococci, these agents may be under-represented in published data. Streptococci can be classified into several groups; those causing SSTIs are predominantly of groups A and B. Group A streptococci are particularly associated with necrotizing fasciitis, while group B streptococci are often the causative agents of infections in diabetic patients. Necrotizing soft tissue infections and wounds due to human bites are more often caused by a mixture of aerobic and anaerobic microorganisms; in the case of animal bite wounds, these are caused most frequently by Pasteurella multocida and rarely by Capnocytophaga. 13 Vibrio vulnificus infections, acquired from sea water, often occur in patients with cirrhosis or other deficiencies. 14 Pseudomonas aeruginosa is often isolated from lower extremity infections, 13 particularly in patients who sustain nail puncture injuries of the plantar surfaces of their feet, but may also be seen in patients with comorbidities, such as peripheral vascular disease, chronic renal insufficiency or diabetes. P. aeruginosa infection is often associated with preceding hydrotherapy. Synergic gangrene in diabetic patients is caused by polymicrobial flora, including S. aureus, group B streptococci, anaerobes and Gram-negative bacilli. Decision point 1: assessment, classification and admission decision The first decision point is whether or not to hospitalize a patient with an SSTI. Financially, this is by far the most important decision. It depends largely on the severity of the illness at presentation and the Figure 1. Examples of typical cellulitis case presentations according to class. Class 1: (a) Carbuncle. A 48-year-old man with no history of trauma developed a swelling in his lower leg over a 24 h period. He otherwise felt well and his temperature was 37.3 C (99.1 F). This is a class 1 patient. He was successfully treated with five days of oral dicloxacillin. (b) Infected insect bite. A 16-year-old boy presented 5 days after an insect bite. Immediately after the bite there was 1 cm of erythema and the area was pruritic. Now the area is swollen and tender with lymphangitic streaking. There are no systemic signs or symptoms of infection. This class 1 case can be treated with oral outpatient antibiotic therapy active against aerobic Gram-positive cocci. Class 2: (c) Erysipelas. A 72-year-old man presented with a swollen leg for the past 4 days. He has been on cefalexin for 3 days with continued worsening of the infection. His temperature is 39.2 C (102.6 F), blood pressure is 100/70 mm Hg (normally 130/85 mm Hg), heart rate 120 beats/min. Laboratory tests showed a white blood cell count of cells/mm 3 ; the haematocrit, platelet count, renal function and other tests were within normal limits. This is a class 2 patient. Because of the severity of the infection and failure to respond to oral antibiotic therapy, he could be managed on OPAT following an observation period in the hospital. A skin aspiration culture of the leading edge of his cellulitis was sterile, but there was a 4-fold rise in convalescent titres of his streptococcal DNAase B antibodies, suggesting group A streptococci as the causative organism. (d) Leg wound. A 23-year-old woman with a history of substance abuse who presented about 30 hours after sustaining an injury to her right leg. No care has been provided to the wound. Her entire lower leg was oedematous with erythema from mid calf to approximately 8 cm above the knee, and she had a fever of 38.7 C (101.6 F). This class 2 patient was discharged on OPAT after drainage of her abscess. (e) Recurrent cellulitis. An 82-year-old diabetic woman with chronic venous stasis and recurrent cellulitis of the lower extremities presented with a fever, increased erythema and bullae on the lower extremities. Her diabetes is well controlled and she is eating. Because of her systemic signs and co-morbidities, she is a class 2 patient. She was discharged to stay with her family on OPAT with compressive dressings covering her infected areas, with follow-up scheduled in 3 days. Class 3: (f) Haemorrhagic bullae. A 34-year-old man sustained a bite to his index and middle finger while playing with a dog. On presentation, he was stable and had haemorrhagic bullae on his index finger. Laboratory tests revealed leucocytosis with a left shift, evidence of disseminated intravascular coagulation, elevated creatine kinase levels, and abnormal liver function studies. Blood cultures were later positive for Capnocytophaga canimorsus. He has a severe bacteraemic cellulitis and should be hospitalized for observation of his Class 3 sepsis syndrome. (g) Diabetic foot infection. This 62-year-old man with diabetes, peripheral neuropathy and peripheral vascular disease, stepped on a tack one week previously. He has had increased swelling of his foot for the last 5 days. His temperature is 38.3 C (101 F), he was mildly tachycardic but normotensive, and he has no palpable foot pulses. His white blood cell count was cells/mm 3, and his blood glucose was 450 mg/dl, but other blood tests were normal. This is a class 3 patient who needs hospitalization for surgical debridement, blood sugar control, and vascular remediation. His deep wound tissue specimens grew S. aureus and group B streptococci. Class 4: (h) Necrotizing fasciitis. A 45-year-old man with diabetes presented with a painful, swollen foot that began 3 days ago several days after stubbing his toe. He complained of pain in his foot and was disoriented. His temperature was 39.9 C (103.8 F), he is hypotensive and tachycardic, his white blood cell count was cells/mm 3, his platelet count was platelets/mm 3, and his creatinine was 2.4 mg/dl. This is a class 4 patient who needs to be admitted to the hospital, probably to an ICU. Cultures of his foot grew only group A streptococci. i4

5 Managing skin and soft tissue infections i5

6 L. J. Eron et al. likelihood of disease progression. These factors are assessed on the basis of the history, the presence of comorbidities, the physical examination, and the results of laboratory studies and other tests. 15 This decision should also consider the patient s ability to understand their disease and comply with instructions, the amount of support they can expect at home from friends or family, their ability to return for outpatient visits, and the availability of home nursing services. Economic considerations may also influence the admission decision. In the UK, for example, SSTIs account for up to 10% of admissions to infection units and the mean length of hospital stay is 5 days. This represents a considerable occupancy of the unit s beds Figure 2. Algorithm for managing cellulitis: site of care and route of therapy. and generates substantial costs. 16 Furthermore, some data suggest that hospitalization may have other adverse consequences. Patients with community-acquired pneumonia treated as outpatients had similar clinical outcomes, yet returned to normal daily activities much sooner, than patients with similar severity of disease who were hospitalized (8 versus 25 days; P = ). 11 History Table 2. Risk factors for specific pathogens causing SSTIs 13,119 Risk factor Diabetes Cirrhosis Neutropenia Bite wounds human cat dog rat Animal contact Reptile contact Hot tub exposure/loofah sponges Fresh water exposure Sea (or fish tank) water exposure Drug abuse intravenous subcutaneous Clinicians should particularly seek concomitant medical conditions that may predict rapid disease progression or poor response to treatment. These include advanced age, chronic liver disease, chronic renal disease, asplenia, alcohol abuse or the use of an antimicrobial in the previous 2 weeks. 13,17 19 The risk of a poor outcome for chronic wounds, such as lower extremity ulcers, is greater in patients with reduced arterial perfusion or neuropathy. Chronic venous insufficiency, diabetes, obesity, malnutrition, advanced age and compromised immune function have also been reported to delay wound healing. 13 Information about underlying illnesses and vocational or avocational exposure may also help to determine the causative agent and thus the appropriate treatment (Table 2). In immunocompromised patients, Gram-negative bacteria and atypical mycobacteria are seen at higher incidences than in the general population. 20 Other factors, e.g. exposure to salt water, may predispose to less common infectious organisms, as listed in Table 2. Clinicians should inquire about factors such as hobbies, job duties and travel, because they may influence the aetiological agents, and thus the decision whether or not to culture the wound and the choice of an empirical antimicrobial regimen. The use of medications by the patient should also be considered. Recent antimicrobial therapy can alter the aetiological agents or their antimicrobial susceptibilities. High-dose corticosteroids can increase the risk, and alter the manifestations, of SSTIs. Tumour necrosis Characteristic pathogens S. aureus, group B streptococci, anaerobes, Gram-negative bacilli Campylobacter fetus, Klebsiella pneumoniae, Escherichia coli, Capnocytophaga canimorsus, other Gram-negative bacilli, V. vulnificus P. aeruginosa oral flora (Eikenella corrodens) P. multocida C. canimorsus, P. multocida Streptobacillus moniliformis Campylobacter spp. Salmonella spp. P. aeruginosa Aeromonas hydrophila V. vulnificus, Mycobacterium marinum MRSA, P. aeruginosa anaerobes, especially Eikenella corrodens i6

7 Managing skin and soft tissue infections factor inhibitors, such as infliximab, are associated with the reactivation of infections such as tuberculosis. 21,22 Physical examination The physical examination helps determine the severity of the infection. Local signs of serious SSTI include bullae, haemorrhagic lesions, and anaesthesia or pain out of proportion to the objective findings. Fluctuance suggests an abscess that may require drainage. Crepitus should raise concerns about a gas-forming infection that may require surgical intervention. With infections of extremities (especially the foot), severe ischaemia may mask erythema, and neuropathy may reduce tenderness. Systemic manifestations suggest a more severe infection. Specific features identified as predictors of outcome include hypotension, tachycardia, body temperature <35 C or >40 C, and confusion or decreased levels of consciousness. 15,17,19 The presence of two or more of these factors is associated with particularly poor outcome or response to treatment. 17 Extreme pain or tenderness, especially out of proportion to objective findings, may be a sign of necrotizing infection. 23 Anaesthesia around a wound may indicate tissue necrosis. The size and location of the lesion influence the severity, need for observation and surgical consultation, and thus the hospitalization decision; lesions on the thighs, digits, head or genitals are more likely to be serious. Large areas of infection (e.g. more than several centimetres) may warrant admission, especially in diabetic patients. Lymphangitis, or cellulitis with a raised indurated border (as in erysipelas), is usually caused by a more superficial group A streptococcus infection, and hospitalization may be unnecessary. A fetid odour suggests anaerobic infection, while greenish exudate is typical of Pseudomonas infection. Laboratory and ancillary studies A complete blood count (white blood cell count and differential, haematocrit, platelet count) may assist in assessing the severity of illness. Marked leucocytosis (or leucopenia), an extreme left shift in the white cell differential, new onset anaemia (caused by haemolysis) or thrombocytopenia may suggest sepsis syndrome. Elevated levels of blood urea nitrogen and creatinine suggest intravascular volume depletion or renal failure, while elevated creatine kinase levels may indicate myonecrosis caused by necrotizing fasciitis or a compartment syndrome Serological tests (streptozyme, anti-dnase B, anti-hyaluronidase) for streptococcal infection are generally not helpful except as paired acute and convalescent titres. Certain cases may warrant additional tests, such as X-rays (to look for foreign bodies or gas in the tissues), ultrasound or computed tomography (to look for drainable collections), or Doppler vascular exam (to rule out deep venous thrombosis or arterial insufficiency). Magnetic resonance imaging is useful to investigate suspected fasciitis or osteomyelitis. Radionuclide scans are generally not helpful in the acute situation, because they lack specificity. Obtaining culture specimens There has been considerable debate about the benefits, timing and methods used to sample a lesion for microbiological analysis. Culturing the skin in cases of cellulitis infrequently yields a pathogen. Obtaining specimens from other wounds for Gram-stained smear and culture is almost always useful, especially if there is reason to believe that the pathogen is methicillin-resistant S. aureus (MRSA). 13 The likelihood i7 of infection with MRSA depends largely on the local prevalence and previous antibiotic use by the patient. 27,28 Local antibiotic resistance patterns should be considered when deciding whether to obtain specimens for culture and sensitivity: the lower the prevalence of resistant strains, the less the need to culture. For cultures, tissue specimens are generally preferable to swabs, especially for open wounds. Depending on the type of wound, culture samples may be obtained by tissue biopsy or curettage (scraping with a dermal curette or scalpel blade) of ulcerated areas. If there is no open wound, needle aspiration of fluid from the skin at the leading edge of infection may be helpful. 13 Collection of an adequate aspirate is facilitated by using a large-bore needle (18 gauge) and drawing air into the barrel of the syringe before aspiration to later help expel any tissue fluid collected. 29 Blood cultures should be obtained from patients with a severe infection or sepsis syndrome, although the yield of a pathogen may be <10% Anaerobes are often difficult to culture, and require special handling (such as the use of anaerobic transport media). However, Gram-stained specimens may suggest their presence when analysed in conjunction with culture results. Anaerobes should be suspected if the wound is foul smelling or necrotic, even if they have not been recovered on culture. 13 Observation status In some hospitals, low-risk patients are treated initially in an observation unit, or are observed in the emergency department. This allows time (usually up to 24 h) to treat patients and observe their response to therapy. If a patient appears to be responding, then they may be treated as an outpatient, either at home or in an infusion centre. Patients whose symptoms do not improve are admitted for inpatient treatment. Observation units should follow standardized treatment protocols to maintain good clinical outcomes, as well as patient safety and satisfaction. 33 SSTIs are among the most frequently treated conditions in an observation setting. In one published study, SSTI was the third most common diagnosis (8% of patients), behind chest pain and asthma. 34 In this study, 85% of patients were discharged home from the observation unit within 23 h. 34 Similar results were seen in another study, in which 73% of patients were discharged from the observation unit, thus avoiding the need for admission. 35 The average length of stay in the observation unit was about 15 h. 35 Good candidates for observation status are patients who are likely to respond to empirical therapy, are expected to require a short stay, and have a low likelihood of infection with resistant organisms. Class 2 patients, who are moderately ill, often meet these criteria. Some class 1 patients may be suitable for observation, especially if they have a non-supportive home environment or require pain control. Although most class 3 patients require hospitalization, some (e.g. those who are not systemically toxic) may be adequately treated in an observation unit. Circumstances that would require hospitalization rather than an observational unit include the presence of tissue necrosis, sepsis, severe pain, altered mental status, immunocompromise (e.g. AIDS, cancer), or liver or renal failure. 34 Bite wounds and SSTIs on the hands, periorbital area, joints, scrotum and neck, which require careful observation or respond poorly to treatment, are not usually appropriate in an observation unit. 34 Successfully managing patients in an observation unit requires early consultation with primary care physicians and specialists, as well as with social services and visiting nurse associations.

8 L. J. Eron et al. Table 3. Recommended drug therapy for outpatient oral treatment of uncomplicated SSTIs (excluding MRSA infections) Class Recommended antimicrobial agents Alternative antimicrobial agents Comments Class 1 dicloxacillin flucloxacillin taste or gastrointestinal disturbances cefalexin Indications for referral Certain cases require not only hospitalization, but also urgent referral for subspecialty consultation. Limb-threatening diabetic foot infections are best treated by a multidisciplinary team, including infectious disease, podiatry and/or surgical (e.g. orthopaedic, vascular) specialists. 13,36,37 Necrotizing fasciitis, synergic gangrene and sometimes osteomyelitis or septic arthritis require prompt surgical consultation. An infectious disease consultant may assist in discussing the choice of antimicrobial agents, adjunctive therapies and general patient care. Decision point 2: initial antimicrobial selection Once the severity of a patient s infection has been classified and a decision has been made about admission, the next step is to choose the initial antimicrobial regimen. Considerations in selecting an appropriate antimicrobial should include the spectrum of its antimicrobial activity, the route of delivery, antimicrobial resistance issues, side effects profile, drug interaction potential, patient allergies, pharmacodynamics and cost. Route and timing of administration benzyl penicillin (or phenoxymethyl penicillin) co-amoxiclav macrolides tetracyclines clindamycin The choice between oral and parenteral therapy is governed by many of the same factors that determine the class of the infection: the patient s clinical presentation, the results of laboratory analyses and the presence of comorbidities. There are, however, additional considerations. Many physicians prefer to prescribe oral therapy because of its greater patient convenience. Moreover, some studies have shown that clinical outcomes with oral therapy are not statistically worse than with parenteral therapy. However, such studies have not been sufficiently powered to show significant differences, nor have they stratified the patients according to disease severity. Furthermore, data from the OPAT Outcomes Registry (A. D. Tice & D. Nathwani, unpublished data) indicate that 22% of patients who were started on parenteral antimicrobial therapy had been treated initially with oral concurrent treatment with acid-suppressive therapy may cause failures for infection likely caused only by streptococci more expensive; diarrhoea often a problem; good choice for bite wounds; covers most anaerobes may be used in patients with penicillin allergies; however, resistance issues must be considered minocycline may be useful for some communityacquired MRSA strains for patients with severe penicillin allergies; covers anaerobes and some community-acquired MRSA antimicrobials and were switched because of treatment failure. Parenteral therapy is more likely to result rapidly in elevated serum (and thus tissue) antimicrobial levels than oral therapy, which is particularly important in seriously ill patients. Parenteral therapy is also preferred in patients for whom either gastrointestinal problems (e.g. nausea, vomiting, gastroparesis) or medication compliance is an issue. In general, outpatient oral therapy is most appropriate in the treatment of class 1 patients (Table 3), who are less likely to be infected with unusual or drug-resistant organisms. Some class 2 patients may respond well to oral therapy, but there is no reliable way to predict which ones. Therefore, parenteral therapy should be preferred, at least initially, for class 2 patients. In addition, most patients with more severe cases of SSTI (classes 3 and 4) require at least initial parenteral therapy. Parenteral antimicrobial therapy should be initiated in the hospital s emergency department, observation unit or infusion clinic. The first dose of antimicrobial is considered to be the most important one and should be administered without delay as soon as culture specimens are obtained. 38 Studies on patients with communityacquired pneumonia have shown that prompt antimicrobial administration reduces mortality, shortens the hospital stay and reduces costs. Substantial clinical benefits can result from saving just a few hours in time to drug delivery. 38,39 For patients in whom early or immediate discharge is anticipated, an initial dose of parenteral therapy with an antimicrobial that has an appropriate spectrum of activity against the commonly encountered organisms and a long half-life that provides 24 h coverage is ideal. 40 Dosing considerations Appropriate antimicrobial dosing requires an understanding of pharmacokinetics and pharmacodynamics. It is largely related to the drug concentration in tissues and body fluids and the MIC for the infecting organism. Dosing is also influenced by patient characteristics, such as body weight and renal or hepatic function. The most important factor in choosing an antimicrobial is the drug s activity against the targeted organism, but it must achieve levels at the i8

9 Managing skin and soft tissue infections Table 4. Recommended parenteral antimicrobial therapy for class 2 and 3 SSTIs (excluding MRSA infections) Class Recommended antimicrobial agents Alternative antimicrobial agents Comments Class 2 ceftriaxone appropriate range of antimicrobial activity, once-daily dosing cefazolin ± probenecid probenecid may be associated with adverse events flucloxacillin ± benzyl taste or gastrointestinal disturbances penicillin clindamycin for patients allergic to penicillin and for sensitive communityacquired MRSA strains Class 3 cefazolin semi-synthetic penicillins phlebitis may be a problem flucloxacillin ± benzyl penicillin taste or gastrointestinal disturbances may be a problem For additional information and special cases, see text. infected site exceeding the MIC for the infecting organism. Antimicrobial concentrations that kill the infecting organisms also prevent the selection of resistant mutants Tissue penetration of drugs has been measured in blister fluids and in interstitial fluids of muscle and fat using microdialysis techniques. The best predictor of the achievable drug concentration in these peripheral compartments appears to be free-drug concentration in serum. For most drugs, penetration into blister or interstitial fluid is delayed, and elimination from this compartment is slower than from the serum. The higher serum concentrations achieved with parenteral drugs ensures improved penetration compared with most oral agents In patients with impaired arterial supply, e.g. with diabetic limb infections, antimicrobial penetration is a particular problem. 60 Fluoroquinolones, which have high bioavailability and tissue penetration, are therefore often used in such cases. All drugs require three to five half-lives to reach their steady state. Consideration should be given to the use of a loading dose (about twice the usual dose) for oral drugs with a long half-life in order to rapidly achieve serum levels above the MIC for the pathogen. Although azithromycin is the only oral antimicrobial with a loading dose approved by the US Food and Drug Administration, other drugs may be administered this way. It is also prudent to use a loading dose when treating a relatively resistant organism. A loading dose should be avoided if it is likely to cause nausea or vomiting. In such a case, or with agents with low bioavailability, a parenteral loading dose may be appropriate with a subsequent switch to oral therapy. Drug spectrum and activity ceftriaxone clindamycin The spectrum of the antimicrobial chosen for initial therapy must be broad enough to cover the suspected infecting organisms, but not overly broad such that it also kills normal colonizing flora. In communities where the rate of antimicrobial resistance is high, coverage ceftriaxone is recommended for class 3 patients on observation status who are subsequently admitted (for a short period of time) with the expectation that OPAT will be utilized upon discharge for patients allergic to penicillin and for sensitive community-acquired MRSA strains may need to account for strains with reduced antimicrobial susceptibility, such as MRSA. Because most cases of SSTI are caused by β-haemolytic streptococci and/or S. aureus, appropriate choices for empirical therapy include cephalosporins, semi-synthetic penicillins and clindamycin, or macrolides in penicillin-allergic patients. 13,15 Specific drug recommendations for SSTI classes 2 and 3 are shown in Table 4. For class 2 patients, ceftriaxone is commonly prescribed because of its appropriate antimicrobial spectrum and favourable pharmacokinetics, which allow once-daily infusion. 3,61,62 Moreover, adverse effects are relatively infrequent. 61 Ertapenem is a new once-daily carbapenem, for which limited clinical data are available. Its spectrum may be appropriate for complicated polymicrobial skin infections, such as diabetic foot infections or pressure ulcers, because it is active against most aerobic Gram-positive and Gram-negative pathogens, and also anaerobes. Unlike other carbapenems, it is not effective against Pseudomonas species and has decreased activity against staphylococci. 63 Nafcillin and cefazolin each have a more limited spectrum but excellent activity against S. aureus (non-mrsa strains) and streptococci. Nafcillin may cause phlebitis, and because it must be administered four times daily, it is limited to hospitalized patients. While cefazolin is normally administered three times daily, some studies have shown that it can be given once-daily when combined with probenecid to prolong its serum half-life. 62,64,65 Probenecid may cause various adverse events and should therefore be used with caution. Cefazolin and semi-synthetic penicillins are appropriate choices for class 3 patients. It is advisable to treat patients who are expected to be discharged early on OPAT with the same drug during their hospital stay. For patients in an observation unit, antimicrobials that may be administered once daily are particularly useful. If MRSA infection is suspected, several points must be considered (Table 5). First, community-acquired MRSA is typically susceptible to several classes of antimicrobials [clindamycin, quinolones, tetra- i9

10 L. J. Eron et al. Table 5. Recommended parenteral therapy for class 2 and 3 SSTIs caused by MRSA Recommended antimicrobial agent Alternative antimicrobial agents Comments Clindamycin Daptomycin Linezolid Teicoplanin Vancomycin quinupristin + dalfopristin fusidic acid + rifampicin minocycline rifampicin + For additional information and special cases, see text. cyclines and trimethoprim sulfamethoxazole (co-trimoxazole)] to which hospital-acquired MRSA strains are not. 27 Because of its potentially toxic side effects and the need to not overuse the drug, vancomycin should be reserved for MRSA acquired in health care facilities, or for infections associated with dialysis or intravenous drug use. Linezolid is virtually 100% bioavailable orally, can also be given parenterally and is highly active against MRSA. It has been shown to be effective in treating complicated skin infections, including diabetic foot infections. 66,67 However, linezolid is expensive, and has been associated with haematological toxicity, particularly when given for more than 2 weeks. 68,69 In patients who report serious allergies (e.g. hives or anaphylaxis) with β-lactam antimicrobials, clindamycin is an appropriate choice. For those with only a non-specific maculopapular eruption due to penicillin, cephalosporins can usually be used safely, provided that the patient is observed for a few hours thereafter. Fluoroquinolones (especially agents more active against Gram-positive cocci) have been used for SSTIs, but we discourage using them for this indication because of the potential for the development of resistance, except perhaps in diabetic foot infections. 70 They may be appropriate for patients with a penicillin allergy who cannot tolerate clindamycin. In class 4 patients with necrotizing fasciitis or sepsis syndrome, urgent surgical consultation and follow-up is paramount. These infections usually require debridement, and occasionally amputation. Because they can be caused by a variety of pathogens, and there is no time to correct errors, broad-spectrum antimicrobial therapy should be used initially in most cases. Depending on the type of infection, the patient may require coverage for group A streptococci only (necrotizing fasciitis) or for polymicrobial flora, including S. aureus, group B streptococci, anaerobes and Gram-negative bacilli (synergic gangrene in diabetic patients). Clindamycin is the drug of choice in most cases caused by group A streptococci. 71 When necrotizing fasciitis is complicated by toxic shock syndrome, many clinicians use intravenous gamma globulin to neutralize the causative streptococcal pyrogenic exotoxin. 72,73 Intravenous fluids and pressors are usually necessary, and drotrecogin alpha (activated) may be useful for severe sepsis suitable for certain community-acquired MRSA strains once daily; iv only; highly bactericidal suitable for hospital- or nursing-home-acquired MRSA; oral bioavailability almost 100% once-daily iv or im administration; loading doses may be necessary for severe infections appropriate for hospital- or nursing home-acquired MRSA must be administered with a peripherally inserted central catheter line, twice daily for class 1 patients paucity of data and experience; for class 1 patients only used in combination with other drugs syndrome. 74 For some anaerobic infections, especially those caused by Clostridium perfringens, hyperbaric oxygen may be useful. 75,76 Adjunctive procedures and medications Patients with necrotic tissue or an undrained abscess should be seen by a surgeon. Compression dressings can be useful for SSTIs complicated by chronic venous insufficiency. 77 Reducing oedema helps resolve the infection and prevent recurrences. In patients with a limb infection and peripheral vascular disease, revascularization procedures may be necessary. 78 In patients with SSTI on therapy with antimicrobials, concomitant corticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs) may shorten the intensity and duration of inflammatory signs and facilitate earlier discharge. A randomized study of 112 patients with erysipelas found that adding oral prednisolone to penicillin therapy significantly shortened the time to complete resolution of fever, as well as the duration of intravenous therapy and hospital stay (a difference of 1 day versus placebo for each measure). 79 There was also a non-significant trend towards fewer relapses of SSTIs in the prednisolone-treated group during a 1 year follow-up. 80 Because steroids (and to a lesser extent NSAIDs) are associated with various adverse effects, and may mask signs of worsening infection, further data are required before their routine use can be recommended. Similarly, other adjunctive therapies, such as hyperbaric oxygen and granulocyte colony-stimulating factor, 76,81,82 have shown promise, but these expensive therapies cannot be recommended routinely until further, properly conducted, supportive studies are available. Resistance patterns among SSTI pathogens Community-acquired MRSA is now the greatest antimicrobial problem in treating SSTIs. Although still infrequent in most locations, the prevalence is increasing in some areas of the world. 27,83 The average prevalence of methicillin resistance among community-acquired S. aureus isolated in the USA is at least 20%, and growing. Some i10

11 Managing skin and soft tissue infections Table 6. Factors increasing the likelihood of isolating MRSA in community-acquired SSTIs 27,28 Recent antimicrobial therapy Recent hospitalization or health care institutionalization Frequent device use in the community (e.g. home haemodialysis, intravenous catheters) High rates of MRSA in institution or community Previous MRSA colonization centres have reported rates as high as 50%. 27,83 Clinicians should be aware of the local community and hospital resistance trends, and consider the presence of risk factors associated with communityacquired MRSA (Table 6). 22,79 MRSA has been reported in some cases to be disseminated from the hospital to the community. 84 Macrolide resistance has risen rapidly among group A and B streptococci in the last few years, but they remain susceptible to penicillins and cephalosporins On the other hand, staphylococci have developed several types of resistance to β-lactams, glycopeptides and other antimicrobials. 27,83 Vancomycin should not be used empirically, except in the most seriously ill patients or when MRSA rates are high. Clindamycin is highly effective against most staphylococcal or streptococcal strains. However, it should not be used alone against strains that are resistant to erythromycin, even if they appear to be clindamycin susceptible, because this may induce resistance Reports of increasing resistance of MRSA strains to clindamycin have further complicated the antimicrobial selection process. 27 Where available, teicoplanin is a useful alternative to vancomycin for treating moderate to severe SSTIs due to MRSA infection. It offers the advantage of once daily intravenous or intramuscular therapy. Loading doses may be required in severe infections. 91 Agents active against MRSA may be associated with toxicity (vancomycin) or high costs (linezolid, quinupristin/dalfopristin). Thus, there is renewed interest in treating MRSA with older antimicrobials, such as minocycline, co-trimoxazole or doxycycline. 92 In a randomized double-blind trial of 101 intravenous drug users with S. aureus infections, co-trimoxazole showed similar efficacy to vancomycin against MRSA. 93 Minocycline has also been shown to be effective in treating MRSA, 94,95 but extensive studies with minocycline monotherapy have not been reported. Diabetic foot infections Foot ulcers in diabetic patients are usually caused by sensory and motor neuropathy and consequent excessive pressure or trauma. These ulcers often become infected, especially when complicated by arterial insufficiency. SSTIs can then extend to the skin surrounding the infected ulcer, to deep spaces, or to bone or joint. Most acute infections in patients not recently treated with antimicrobials are caused by S. aureus and/or β-haemolytic streptococci. In these cases, relatively narrow-spectrum therapy is sufficient. 96 However, in previously treated patients, or those with chronic or necrotic wounds, polymicrobial infections are more likely and require broad-spectrum antimicrobials (Table 7). Most cases also require adjunctive therapies, such as pressure relief, wound debridement or drainage, control of hyperglycaemia and vascular evaluation. 13,97 Granulocyte colonystimulating factor and hyperbaric oxygen may be useful in selected patients. Vacuum dressings may help the healing of uninfected wounds that do not show vascular compromise, but data on their safety or efficacy in treating infections are not yet available. Recurrent infections Recurrent bouts of SSTI are most commonly seen in patients with chronic lymphoedema, e.g. in those who have undergone saphenous venectomy for coronary artery bypass grafting, pelvic surgery or irradiation, lymphadenectomy, mastectomy, or node dissection. 98 Microbiologically, it is important to distinguish between persistent infection (i.e. not successfully eradicated), and a new infection due to either the same organism (relapse) or a different one (reinfection). Reducing or eliminating the predisposing conditions (e.g. oedema, dermatophytosis) is crucial to preventing relapse. Recurrent skin infection caused by S. aureus may be prevented by eradicating anterior nasal carriage with nasal mupirocin ointment. 99 Recurrent SSTI is often caused by β-haemolytic streptococci (groups A, B, C or G); long-term antimicrobial prophylaxis may reduce these recurrences. 100 In patients with recurrent leg cellulitis, the entry portal for bacteria may be sites of toe dermatophytosis. 101 Special attention should be paid to eradicating any coexistent tinea pedis. Safety and tolerability Although most antimicrobials are safe and well tolerated when given in proper dosage, adverse effects occur and may occasionally be serious. In patients with a history of drug allergies, it is usually safest to avoid using those agents. In patients with a questionable history of penicillin allergy, those at risk can usually be identified by antecedent penicillin skin testing with penicilloyl polylysine. 102,103 Crossreactivity between penicillins and cephalosporins is low (<5%), but cephalosporins should be avoided when a previous penicillin reaction was severe (e.g. anaphylaxis, laryngeal oedema or hives). 103 Data on antimicrobial side effects have been gathered by the OPAT Outcomes Registry from 44 centres in the USA, Canada, Italy and the UK on > courses of outpatient antimicrobial therapy. The most common antimicrobial used in the OPAT Outcomes Registry network is ceftriaxone (Figure 3). 104 In this database, drug discontinuation due to adverse effects was most common with piperacillin tazobactam, nafcillin and gentamicin, and least common with ceftriaxone (Figure 4). 105 Rash, diarrhoea, nausea/vomiting and fever are among the most common antimicrobial-related adverse events. Treating SSTIs with OPAT OPAT has the potential to greatly reduce costs and improve patient satisfaction, with outcomes that are equivalent or superior to those of inpatient treatment In the OPAT Outcomes Registry, SSTI is the most common infection treated, accounting for about 19% of diagnoses. 104 OPAT, however, remains under-utilized, and could benefit many more patients. Its advantages include documented excellent clinical and bacteriological outcomes in appropriately selected patients, reduced cost and length of stay for hospitalized patients, i11

12 L. J. Eron et al. Table 7. Recommended parenteral therapy for class 2 and class 3 diabetic limb infections Class Recommended antimicrobial agents Alternative antimicrobial agents Comments Class 2 ceftriaxone ± metronidazole add metronidazole if anaerobic infection suspected or confirmed fluoroquinolone + clindamycin broad spectrum coverage with easy oral switch Class 3 ceftriaxone ± metronidazole fluoroquinolone + clindamycin meropenem piperacillin/tazobactam semi-synthetic penicillins + metronidazole co-trimoxazole ± metronidazole fluoroquinolone ± metronidazole co-amoxiclav ertapenem fusidic acid cefepime ± metronidazole linezolid ± aztreonam vancomycin ± ceftriaxone For additional information, see text. Only add anti-anaerobic agents when anaerobic infection is suspected or proven. potential avoidance of nosocomial infections, improved patient and caregiver satisfaction, and earlier return to usual daily activities. 10,12,106 In the OPAT Outcomes Registry, 22% of patients are started on OPAT after oral therapy, the two most common reasons for this being failure of the patient to tolerate oral medication and progression of the infection despite the patient receiving oral therapy for several days. The reasons for the lack of efficacy of oral treatment may be inadequate drug levels due to dosing, absorption or compliance problems. Class 2 patients, who are moderately ill but do not require hospitalization, are ideal candidates for OPAT. Other candidates include class 3 patients for whom continued intravenous antimicrobial therapy is considered useful following a short stay in hospital or on observation status. For OPAT to succeed, there must be adequate home support, and an understanding of, and willingness to follow, the instructions. The patient must be able to return to the hospital or infusion centre when necessary, or otherwise access home health care or visiting nurse services. In hospitals or emergency departments without an OPAT system, patients can be instructed to return as frequently as necessary for continued injections/infusions. Alternatively, arrangements may be made for their own physicians to administer the antimicrobials in not recommended for observation patients; add metronidazole if anaerobic infection suspected or confirmed oral drugs with good bioavailability; can be given intravenously if the patient is vomiting; Staphylococcus and Streptococcus coverage may be suboptimal widely used drug with proven efficacy in clinical trials limited data available to date used in some countries due to perceived (but unconfirmed) high penetration into tissue must be administered multiple times daily; appropriate for community-acquired infections not previously treated with antimicrobial agents use for Pseudomonas infections linezolid is a useful alternative to vancomycin in the treatment of MRSA infection; aztreonam is a useful alternative to β-lactams in the treatment of Gram-negative infections when MRSA infection suspected or confirmed the office. In our experience, this is most easily accomplished with a once-daily drug that is well tolerated and can be administered by either an intramuscular or intravenous route. Decision point 3: antimicrobial switch Limited research and much clinical experience on the timing of the switch from parenteral to oral antimicrobial therapy suggest that most patients with uncomplicated SSTI may be safely switched to oral agents after 3 4 days. 10, The timing is guided by the patients response to parenteral antimicrobials, the culture and susceptibility results, and the patients readiness for oral therapy. Therefore, each case needs to be assessed on a daily basis. Signs and symptoms of infection should be improving, with decreases in erythema and induration. Skin wrinkling at the infected site suggests reduced swelling. Body temperature and white blood cell count and differential should show an improving trend, and comorbidities should have stabilized. A randomized, double-blind trial of hospitalized patients with complicated SSTIs demonstrated that switching from intravenous to i12