Treatment challenges in the management of complicated skin and soft-tissue infections B. I. Eisenstein

REVIEW Treatment challenges in the management of complicated skin and soft-tissue infections B. I. Eisenstein Cubist Pharmaceuticals, Inc., Lexington, MA and Harvard Medical School, Boston, MA, USA ABSTRACT Complicated skin and soft-tissue infections (csstis) are a significant clinical problem, partially owing to increasing resistance of infecting bacteria to current antibiotic therapies. Two case studies that illustrate complications that can arise when treating csstis are outlined, and methods that can be used to address the problem and the final treatment outcome are detailed. Although these are specific examples, intolerance of and bacterial resistance to current antibacterial therapies are problems that are often seen in the clinical setting and must be addressed appropriately. The use of new antibiotic agents is one potential solution to these problems, and some of these agents are highlighted. Selecting the most appropriate therapy for an infection is often crucial for patient welfare. This article presents some potential approaches to the treatment of csstis. Keywords Antibiotic resistance, daptomycin, diabetic foot, Gram-positive infections, review, skin and soft-tissue infections, Staphylococcus aureus, ulceration Clin Microbiol Infect 2008; 14 (Suppl. 2): 17 25 INTRODUCTION Skin and soft-tissue infections (SSTIs; also known as skin and skin-structure infections, or SSSIs, in the USA) are defined as infections of the epidermis, dermis, or subcutaneous tissue. They are among the most common human bacterial infections and are frequently observed in clinical practice [1 3], accounting for c. 10% of hospital admissions for infections in the USA [1]. It has also been shown that the incidence of SSTIs in the USA is increasing [1]. This rise in incidence has been attributed to several factors, including increasing population age, surgical wounds related to more invasive surgery in the ageing population, obesity, diabetes, peripheral vascular disease and immunocompromised status [4]. SSTIs, particularly those caused by Staphylococcus aureus, can lead to bloodstream infections, which are often associated with the development Corresponding author and reprint requests: B. I. Eisenstein, Cubist Pharmaceuticals, Inc., 65 Hayden Ave., Lexington, MA 02421, USA E-mail: barry.eisenstein@cubist.com B. Eisenstein is a full-time employee of Cubist Pharmaceuticals, Inc., a company that sells and markets CUBICIN (daptomycin for injection), which is discussed in this review. of metastatic foci of infection. Thus, bacterial endocarditis and other infections, such as deepseated abscesses and or osteomyelitis, are wellknown complications of S. aureus bacteraemia [5]. An increase in the incidence of S. aureus endocarditis has been observed [6], which is probably partly due to the increased incidence of SSTIs, although the greater proportion is attributable to catheter-related infections [7 9]. The pathogenesis of SSTIs usually involves direct inoculation of pathogens through skin punctures or catheter insertions, but can also be associated with skin conditions such as eczema and dermatitis [2]. However, infections can also spread to the skin from deeper foci or distant sites [1 3]. Occasionally, there is no obvious source. Correctly diagnosing SSTIs, identifying the associated organism and addressing the focus are crucial for rapid treatment and resolution of the infection, and can also indicate appropriate treatment regimens. IDENTIFICATION, CLASSIFICATION AND TREATMENT OF SKIN AND SOFT-TISSUE INFECTIONS SSTIs are primarily diagnosed through clinical examination, which is combined with sample

18 Clinical Microbiology and Infection, Volume 14, Supplement 2, March 2008 Table 1. [4] Class Class 1 Class 2 Class 3 Class 4 Classification of skin and soft-tissue infections Clinical presentation of patient with skin infection culture identification and sensitivity testing to provide a definitive diagnosis [10]. Identification of the causative organism will also guide the choice of antibiotic therapy and can help to establish the prognosis for the infection [2]. Once diagnosed, SSTIs can be designated as one of four classes according to the severity of infection and the presence of systemic symptoms and co-morbidities (Table 1). Uncomplicated SSTIs are usually designated as class 1, whereas complicated SSTIs (csstis) are designated as classes 2 4 on the basis of additional diagnostic factors [4]. Examples of csstis include infected ulcer with associated cellulitis, necrotising fasciitis and surgical site infections (Table 2). Because most csstis involve deep soft tissues or complicating factors, initial hospitalisation is often required to perform surgery and administer systemic antimicrobial therapy [4]. Empirical therapy with broad-spectrum antibiotic coverage usually follows diagnosis of a cssti; the therapy is determined according to knowledge of the most likely infecting pathogen(s) and local Common complicated skin and soft-tissue infec- Table 2. tions Localised infection, no signs or symptoms of systemic toxicity; afebrile and healthy, other than cellulitis Febrile and ill-appearing Toxic appearance or at least one unstable co-morbidity Sepsis syndrome or life-threatening infection Secondary infections of diseased skin Acute wound infections (traumatic, bite-related, post-operative) Chronic wound infections (diabetic foot infections, venous stasis ulcers, pressure sores) Perianal cellulitis with or without abscess Deeper soft-tissue infections, or those that require surgical intervention Infected ulcers, burns, major abscesses, and superficial infections or abscesses with a high risk of an anaerobic or Gram-negative pathogen susceptibility patterns, together with patient factors such as age, renal and hepatic function, and previous therapy. Broad-spectrum oral antibiotics, such as amoxicillin clavulanic acid, clindamycin, quinolones and linezolid, are frequently used for the treatment of uncomplicated infections; intravenous antibiotics, such as b-lactams (sometimes with b-lactamase inhibitors), broad-spectrum cephalosporins, carbapenem and linezolid, are generally used for more serious infections [2,4]. Choosing the correct empirical therapy following diagnosis is crucial in providing the best early care and to decrease the potential morbidity and mortality associated with incorrect treatment of SSTIs [11]. Most csstis are caused by Gram-positive bacteria, primarily S. aureus and group A streptococci; in addition, enterococci and various Gram-negative bacteria and anaerobes are found in mixed infections. Indeed, many bacteria are capable of causing these infections [12]. Several antibiotic classes and agents are frequently used to treat confirmed or likely Gram-positive csstis; these can include b-lactams, glycopeptides, oxazolidinones and clindamycin [4]. However, the decreasing susceptibility of some microorganisms (e.g., S aureus [13 15]) to these agents is a significant problem in treating SSTIs [16]; this problem has been further highlighted by a recent report demonstrating that invasive methicillinresistant S. aureus (MRSA) infections in the USA are not only an increasing problem in hospital settings, but are also a significant problem in community-acquired infections [17,18]. In addition, the frequent need for appropriate surgical drainage and or debridement must not be overlooked in treating csstis. CURRENT CHALLENGES IN THE TREATMENT OF COMPLICATED SKIN AND SOFT-TISSUE INFECTIONS Although many cases of SSTIs can be successfully treated using empirical antimicrobial therapy, the increasing prevalence of antibiotic resistance among some bacterial strains, particularly S. aureus, means that new treatment options must be sought [19,20]. In addition to the decreasing efficacy of antibiotics against the most resistant bacterial strains, the potential toxicity of many antibiotics is of clinical

Eisenstein Complicated skin and soft-tissue infections 19 concern. For example, treatment with vancomycin can lead to potentially serious disorders such as nephrotoxicity [21], and treatment with quinupristin dalfopristin is also problematic because of unfavourable adverse event profiles and high cost [22]. Therefore, new antibiotic classes without, or with minimal, potential for bacterial resistance, in addition to low-toxicity profiles, are needed for the treatment of serious bacterial infections. However, the need for surgical intervention, particularly in more complicated cases, is ever present [10]. In a recent observational study concerning abscesses caused by community-associated S. aureus strains [23] which are probably more virulent and invasive because of additional toxins, e.g., Panton Valentine leukocidin the authors concluded that most simple skin abscesses, even when caused by MRSA, can be cured with adequate drainage alone, and that drainage was more important than the initial choice of antibiotic in these cases. Thus, the administration of appropriate surgical care is critically important. Two case studies from Cubist Pharmaceuticals database of clinical experience illustrate some of these challenges in the clinical setting and provide examples of how these challenges can be addressed. ULCERATION AND CELLULITIS Cellulitis is an acute, spreading skin infection that penetrates the subcutaneous tissue layer. It can occur anywhere on the body [24] and is usually a complication of a wound or ulcer; oedema has also been shown to predispose patients to developing cellulitis [25]. Cellulitis of the skin and some subcutaneous tissues has been shown to account for a significant number of medical visits in both the USA and the UK; 2.2% of visits to a physician in the USA [26] and 158 medical visits per 10 000 person-years in the UK [27] have been attributed to cellulitis. Numerous factors have been shown to predispose patients to developing cellulitis, including skin trauma and underlying skin lesions, venous lymphatic compromise and a history of cellulitis [24,25]. The causative pathogens of cellulitis vary according to the site of infection, but are usually group A b-haemolytic streptococci, or S. aureus [25]. However, cultures from aspirates and lesions do not always reveal the causative organism(s) and, therefore, many diagnoses are based on the clinical presentation and morphology of the lesion [25], with the most appropriate empirical treatment being decided accordingly, and modified according to the response of the infection. CASE STUDY: INFECTED LEG ULCER Background A 48-year-old female with peripheral vascular disease, arterial insufficiency and occlusion, and a history of recurrent leg ulcer infections, had undergone an aorto bifemoral bypass. The patient presented with extreme pain and swelling in the left ankle and was admitted for treatment. Exudates from the ulcer yielded MRSA and Enterobacter spp., which were identified by day 3. Previous exposure to vancomycin had resulted in significant renal insufficiency and eosinophilia; thus, vancomycin could not be used to treat the patient, and the decision was made on day 3 to initiate treatment with daptomycin plus ceftriaxone. Treatment After initiation of intravenous daptomycin 4 mg kg once-daily with intravenous ceftriaxone 2 g day, the infection was monitored routinely. Less slough tissue was noted in the wound by day 5, and the wound appeared to be healing by day 7 (Fig. 1). Although antibiotic therapy was disrupted by the patient for 3 days and was recommenced on day 10, there was steady improvement during the course of the treatment. Following recommencement of antibiotic therapy on day 10, further wound healing was observed at day 12 and resolution of the infection occurred on day 14, when daptomycin and ceftriaxone administration was discontinued (Fig. 1). Assessment In this case, the previous history of side-effects from vancomycin was a significant factor in deciding the appropriate therapy. Current treatment guidelines for many countries (e.g., Australia [22]

20 Clinical Microbiology and Infection, Volume 14, Supplement 2, March 2008 Day 5 Day 12 Day 21 and the UK [28,29]) indicate that MRSA infection should be treated with vancomycin, but this was contraindicated in the case of this patient. Vancomycin therapy is associated with low rates of nephrotoxicity, which has been confirmed since the first clinical use of this drug [21], and the patient s renal function must be monitored during treatment with vancomycin to address any nephrotoxicities that may arise. However, the reported rates of nephrotoxicity associated with vancomycin vary significantly, and it has been demonstrated that the risk is increased if vancomycin is co-administered with aminoglycosides or when trough levels are high [30]. In addition to the potential for nephrotoxicity, vancomycin is not metabolised, and 90% of the infused drug is cleared through glomerular filtration and excretion into the urine; thus, dosage modification is necessary in patients with renal insufficiencies [31]. Because vancomycin therapy was not an option for this patient, daptomycin was chosen as the most appropriate agent for treating the infection. Daptomycin therapy resulted in significant improvements in the infection and wound healing within 2 weeks of initiating therapy, and complete resolution of the infection when the patient was seen at day 21 (Fig. 1). No complications resulting from ceftriaxone therapy for treatment of the Enterobacter spp. were observed, and ceftriaxone treatment resulted in clearance of the infection and resolution by day 21. Although this Gram-negative organism was recovered from the infection, it was probably a secondary pathogen, because it rarely causes skin infection by itself. In addition, this co-pathogen was probably not an extended-spectrum b-lactamase producer, or else it would have been resistant to the ceftriaxone. COMPLICATIONS ASSOCIATED WITH DIABETES Fig. 1. Infected leg ulcer. The patient presented with an infected leg ulcer, the cause of which, methicillin-resistant Staphylococcus aureus, was identified on day 3. Daptomycin therapy was commenced on day 3, and less slough tissue was observed on day 5. Although the treatment was interrupted by the patient between days 7 and 10, recommencement of treatment on day 10 led to noticeable wound healing by day 12. Antibiotic therapy was stopped on day 14, and complete healing of the wound had occurred by day 21. Because of the associated peripheral neuropathy, ulceration of the feet is a frequent problem in diabetic patients, and infections of foot ulcers in these patients can be limb- and life-threatening [32]. Diabetic foot ulcers typically occur as a result of factors such as puncture wounds, poorly fitting shoes or the presence of foreign bodies, which exacerbate the underlying neurological or neurovascular pathologies [32]. Delayed wound healing in diabetic foot ulcers occurs frequently because of impaired sensation

Eisenstein Complicated skin and soft-tissue infections 21 resulting in a lack of protection and weight offloading of the diseased tissues. In those with more advanced disease, this situation is further compromised by impaired peripheral circulation, altered leukocyte function, a disturbed balance of cytokines and proteases, and chronic hyperglycaemia [32]. After an infection is established, it can spread rapidly and lead to complications such as sepsis and osteomyelitis, and the risk of amputation and mortality is increased [33]. It is estimated that 40 60% of all non-traumatic amputations involve diabetic patients, and more than 85% of those are necessitated by diabetic foot ulcers [34], which account for more hospitalisations than any other complication of diabetes. Overall, the estimated prevalence of foot ulcers among diabetics is c. 3 8% [34], and it is a significant problem in the management and treatment of SSTIs. Diabetic foot ulcers, which occur more frequently in men than in women, and also more frequently in patients aged 60 years, can occur in patients with either type 1 or type 2 diabetes [32]. Management of the disease incorporates clearance of the infecting pathogens and pressure relief, as well as clearing and debridement of the infected area if required. Diabetic foot ulcers are often polymicrobial [35] and can be caused by numerous Gram-positive and Gram-negative microbes (both aerobic and anaerobic). Thus, they may require complex treatment strategies involving administration of two or more antimicrobials as well as other therapy for the control of the diabetic condition itself. CASE STUDY: INFECTED DIABETIC FOOT Background A 63-year-old female with type 2 diabetes presented with an ulcer on the tip of the fourth toe of the left foot that had been present for c. 7 weeks, with increased reddening and swelling during the 2 3 days before presentation. The patient had severe diabetic polyneuropathy, obesity (body mass index 32.8 kg m 2 ), hypertension and dyslipidaemia, and had previously had an amputation due to osteomyelitis, but had no history of coronary artery disease, cardiovascular disease or peripheral arterial disease. Following initial assessment, the patient was referred to a diabetologist with a diagnosis of non-healing foot ulcer. Initial debridement was performed, and a culture yielded methicillin-susceptible S. aureus and group B b-haemolytic streptococci, sensitive to clindamycin. Rapid progression of the infection had occurred by the second visit 4 days later, and led to hospital admission. At that time, the infection had spread to the complete forefoot and to the depth of the bone in the wound centre (Fig. 2). The patient s medication consisted of normal insulin (14 14 14 IU day) and basal insulin (12 0 0 12 IU day) to control the diabetes, and clindamycin (300 mg four-times-daily), which she had received for 7 weeks. Treatment upon admission comprised wound debridement with removal of all necrotic tissue and infected bone, local disinfection of the wound with polyhexanide-soaked gauze, and removal of pressure from the infected area by complete bed rest. In addition, the patient received low molecular weight heparin and intensive insulin therapy. The antibiotic coverage against Gram-negative anaerobes was provided by clindamycin. Treatment was initiated with amoxicillin clavulanic acid (1.2 g three-times-daily), but was changed to vancomycin 1 g day after 2 days on the basis of the results of a resistogram. The patient also received metronidazole (500 mg three-times-daily). The plan was to amputate the toe, with wound closure after complete control of the infection. Treatment After 5 days of treatment with vancomycin, clinical signs of regression of the infection were insufficient; there was a persistent putrid secretion and the level of C-reactive protein was not normalised (26.2 mg L) (Fig. 2a). Antibiotic therapy was thus changed to daptomycin (6 mg kg). After 2 days of therapy, the putrid secretion had cleared, there was regression of reddening with persistent swelling of the toe and the C-reactive protein was normalised (5 mg L) (Fig. 2b). Amputation of the fourth toe was performed on day 10 after admission (day 3 of therapy with daptomycin), and this was followed by uncomplicated primary wound healing. Daptomycin was discontinued after 7 days (Fig. 2c). Although the S. aureus isolates from the ulcer were classified as susceptible to vancomycin treatment on the basis of results of the microbial

22 Clinical Microbiology and Infection, Volume 14, Supplement 2, March 2008 (a) Fig. 2. Infected diabetic foot. The patient presented with an infected ulcer on the tip of the fourth toe of the left foot. The patient was hospitalised following assessment by a diabetologist, and initial wound debridement and cultures revealed methicillin-susceptible Staphylococcus aureus and group B b-haemolytic streptococci. Initial antibiotic treatment of the ulcer had no effect on the infection, and further treatment with vancomycin also resulted in insufficient regression of the infection (a). Treatment with daptomycin was commenced and resulted in reduction in the swelling and absence of putrid secretions after 2 days (b). Amputation of the fourth toe was performed on day 10 after admission (day 3 of therapy with daptomycin), and uncomplicated primary wound healing occurred after amputation; daptomycin was discontinued after 7 days (c). (b) (c) susceptibility tests, treatment with vancomycin was ineffective in clearing the infection. Treatment with daptomycin led to a rapid resolution of the infection, allowing the planned surgery to be undertaken. Assessment: empirical therapy and vancomycin MIC creep As can be seen from this case, appropriate empirical therapy is important because administration of inappropriate agents can have significant consequences for resolution of the infection. For example, it has been shown that inappropriate or delayed initial therapy for bloodstream infections is associated with an increased length of hospital stay and increased mortality [11,36,37]. Although bacterial isolates might be susceptible to vancomycin in vitro, this does not always predict the susceptibility of the infection in the patient [38]. Aside from the issue of strain susceptibility, vancomycin has a less than ideal pharmacokinetic pharmacodynamic profile; potentially, vancomycin s low concentrations at the infection site and slow bactericidal activity may have contributed to the failure of vancomycin therapy in this case [39,40]. The MIC is used to determine bacterial susceptibility to a chosen antibiotic [41]. However, with regard to S. aureus, the classification of susceptibility to vancomycin (S. aureus is deemed susceptible to vancomycin if concentrations 2 mg L inhibit growth in vitro) may not accurately predict efficacy in vivo [38]. For example, recent studies have shown that infections due to MRSA isolates with vancomycin MIC values of 0.5 mg L were associated with a 55.6% treatment success rate with vancomycin, whereas those with MIC values of 1 2 mg L were associated with a 9.5% treatment success rate [42]. These results demonstrate that, although the S. aureus isolates were initially deemed susceptible to vancomycin, the overall clinical response

Eisenstein Complicated skin and soft-tissue infections 23 indicated otherwise. Vancomycin MIC creep (the gradual reduction in in-vitro susceptibility of S. aureus to vancomycin) has been observed in several hospitals [43], although other studies have indicated that there has been no decrease in susceptibility over recent years [38]. Undoubtedly, the clinical efficacy of vancomycin against S. aureus strains is increasingly being questioned. Underlying the debate are fundamental clinical issues with respect to the accurate laboratory identification of vancomycin-intermediate S. aureus and heteroresistant vancomycin-intermediate S. aureus strains, the potential need for a further reduction in vancomycin breakpoints, the presence of bacterial tolerance and the appropriate vancomycin dosing regimen issues that must be addressed to provide the best possible care for patients [44]. CONCLUSION The term SSTI covers several infections that can be caused by a variety of organisms [2]. Although uncomplicated SSTIs can usually be treated using oral antibiotics on an outpatient basis [4], most csstis involve deep soft tissues or have complicating factors and, therefore, initial hospitalisation is often required to perform surgery and administer systemic antimicrobial therapy [4]. Broadspectrum antibiotics are the mainstay of many cssti treatment regimens [2], but the efficacy and target range of these agents are constantly decreasing as a result of the development of resistance by microorganisms [16], in particular by S. aureus [13 15]. New agents with favourable safety and tolerability profiles are needed to overcome this problem. Daptomycin, a cyclic lipopeptide, is a particularly useful addition to currently available agents for treating csstis, particularly those caused by either methicillin-susceptible S. aureus or MRSA. In clinical trials, daptomycin was equivalent to standard-of-care treatment regimens such as vancomycin and penicillinase-resistant penicillins [45]. In addition to daptomycin, tigecycline (a broad-spectrum glycylcycline antibiotic that is effective against both Gram-positive and Gramnegative pathogens [46]) is also approved for the treatment of csstis, and dalbavancin (a lipoglycopeptide antibiotic that has shown efficacy against Gram-positive pathogens such as S. aureus [47]) is expected to be approved for the treatment of csstis in 2008 in both the USA and the EU. These new antibiotics are potentially alternative agents for tackling the problem of antibiotic resistance in SSTIs and other bacterial infections [45,47,48]. Although surgical intervention is one of the central strategies in the management of csstis [49], appropriate empirical antibiotic therapy at an early stage is important to provide the best possible patient care and to decrease the overall risk of mortality due to csstis. It has been demonstrated that incorrect empirical therapy is associated with a longer hospital stay, a higher overall mortality rate, and a higher risk of infection-related mortality [11]. However, in-vitro susceptibility does not always mean that the organism will be susceptible in vivo [38]; thus, constant monitoring of infections is required to ensure that the administered therapy is working as envisaged. As resistance to antibiotics such as vancomycin and b-lactam antibiotics continues to increase, new antibiotic agents will be central in providing the best possible care for patients and tackling the most problematic infections. Prompt clinical assessment and microbiological sampling is the key to a precise diagnosis of csstis [11], and new agents will provide further options for treating these infections and the complications that arise from them. ACKNOWLEDGEMENTS The author would like to thank R. Finch for his help in the preparation and presentation of materials and cases presented in this manuscript. The author would also like to thank P. A. McCormick of Chameleon Communications International for editorial assistance in the preparation of the manuscript, with funding from Novartis Pharmaceuticals. REFERENCES 1. Centers for Disease Control. Incidence of soft tissue infections: San Francisco General Hospital 1996 2000. MMWR 2001; 50: 381 384. 2. DiNubile MJ, Lipsky BA. Complicated infections of skin and skin structures: when the infection is more than skin deep. J Antimicrob Chemother 2004; 53 (suppl 2): ii37 ii50. 3. Nichols RL, Florman S. Clinical presentations of soft-tissue infections and surgical site infections. Clin Infect Dis 2001; 33 (suppl 2): S84 S93. 4. Eron LJ, Lipsky BA, Low DE et al. Managing skin and soft tissue infections: expert panel recommendations on key decision points. J Antimicrob Chemother 2003; 52 (suppl 1): i3 i17.

24 Clinical Microbiology and Infection, Volume 14, Supplement 2, March 2008 5. Li JS, Sexton DJ, Mick N et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000; 30: 633 638. 6. Petti CA, Fowler VG Jr. Staphylococcus aureus bacteremia and endocarditis. Cardiol Clin 2003; 21: 219 233. 7. Fowler VG Jr, Olsen MK, Corey GR et al. Clinical identifiers of complicated Staphylococcus aureus bacteremia. Arch Intern Med 2003; 163: 2066 2072. 8. Fowler VG Jr, Miro JM, Hoen B et al. Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA 2005; 293: 3012 3021. 9. Fowler V Jr, Scheld W, Bayer A. Endocarditis and intravascular infections. In: Mandell GL, Douglas RG, Bennett JG, eds, Mandell, Douglas and Bennett s principles and practice of infectious diseases. Oxford: Churchill Livingstone, 2005; 975 1022. 10. Stevens DL, Bisno AL, Chambers HF et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 2005; 41: 1373 1406. 11. Bouza E, Sousa D, Munoz P et al. Bloodstream infections: a trial of the impact of different methods of reporting positive blood culture results. Clin Infect Dis 2004; 39: 1161 1169. 12. Moet GJ, Jones RN, Biedenbach DJ et al. Contemporary causes of skin and soft tissue infections in North America, Latin America, and Europe: Report from the SENTRY Antimicrobial Surveillance Program (1998 2004). Diagn Microbiol Infect Dis 2007; 57: 7 13. 13. Chambers HF. The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis 2001; 7: 178 182. 14. Johnson AP, Pearson A, Duckworth G. Surveillance and epidemiology of MRSA bacteraemia in the UK. J Antimicrob Chemother 2005; 56: 455 462. 15. Chopra I. Antibiotic resistance in Staphylococcus aureus: concerns, causes and cures. Expert Rev Anti Infect Ther 2003; 1: 45 55. 16. Tenover FC. Mechanisms of antimicrobial resistance in bacteria. Am J Infect Control 2006; 34: S3 S10. 17. Bancroft EA. Antimicrobial resistance: it s not just for hospitals. JAMA 2007; 298: 1803 1804. 18. Klevens RM, Morrison MA, Nadle J et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 2007; 298: 1763 1771. 19. EARSS. European Antimicrobial Resistance Surveillance System Annual Report. Bilthoven: EARSS Management Team, 2005. 20. Segreti J. Efficacy of current agents used in the treatment of Gram-positive infections and the consequences of resistance. Clin Microbiol Infect 2005; 11 (suppl 3): 29 35. 21. Finch RG, Eliopoulos GM. Safety and efficacy of glycopeptide antibiotics. J Antimicrob Chemother 2005; 55 (suppl 2): ii5 ii13. 22. Mitchell DH, Howden BP. Diagnosis and management of Staphylococcus aureus bacteraemia. Intern Med J 2005; 35 (suppl 2): S17 S24. 23. Moran GJ, Krishnadasan A, Gorwitz RJ et al. Methicillinresistant S. aureus infections among patients in the emergency department. N Engl J Med 2006; 355: 666 674. 24. Swartz MN, Pasternack MS. Cellulitis and subcutaneous tissue infections. In: Mandell GL, Douglas RG, Bennett JG, eds, Mandell, Douglas and Bennett s principles and practice of infectious diseases. Oxford: Churchill Livingstone, 2005; 1172 1194. 25. Swartz MN. Clinical practice. Cellulitis. N Engl J Med 2004; 350: 904 912. 26. Stulberg DL, Penrod MA, Blatny RA. Common bacterial skin infections. Am Fam Physician 2002; 66: 119 124. 27. Morris A. Cellulitis and erysipelas. Clin Evid 2002; 7: 1483 1487. 28. Coia JE, Duckworth GJ, Edwards DI et al. Guidelines for the control and prevention of methicillin-resistant Staphylococcus aureus (MRSA) in healthcare facilities. J Hosp Infect 2006; 63 (suppl 1): S1 S44. 29. Gemmell CG, Edwards DI, Fraise AP et al. Guidelines for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the UK. J Antimicrob Chemother 2006; 57: 589 608. 30. Farber BF, Moellering RC Jr. Retrospective study of the toxicity of preparations of vancomycin from 1974 to 1981. Antimicrob Agents Chemother 1983; 23: 138 141. 31. Greenwood D. Glycopeptides. In: Finch RG, Greenwood D, Norrby SR, eds, Antibiotic and chemotherapy. Anti-infectives and their use in therapy, Vol. 8. Oxford: Churchill Livingstone, 2003; 300 304. 32. Rathur HM, Boulton AJ. The diabetic foot. Clin Dermatol 2007; 25: 109 120. 33. Jude EB, Unsworth PF. Optimal treatment of infected diabetic foot ulcers. Drugs Aging 2004; 21: 833 850. 34. Apelqvist J, Larsson J. What is the most effective way to reduce incidence of amputation in the diabetic foot? Diabetes Metab Res Rev 2000; 16 (suppl 1): S75 S83. 35. Bowler PG, Duerden BI, Armstrong DG. Wound microbiology and associated approaches to wound management. Clin Microbiol Rev 2001; 14: 244 269. 36. Khatib R, Saeed S, Sharma M et al. Impact of initial antibiotic choice and delayed appropriate treatment on the outcome of Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis 2006; 25: 181 185. 37. Lodise TP, McKinnon PS, Swiderski L et al. Outcomes analysis of delayed antibiotic treatment for hospitalacquired Staphylococcus aureus bacteremia. Clin Infect Dis 2003; 36: 1418 1423. 38. Jones RN. Microbiological features of vancomycin in the 21st century: minimum inhibitory concentration creep, bactericidal static activity, and applied breakpoints to predict clinical outcomes or detect resistant strains. Clin Infect Dis 2006; 42 (suppl 1): S13 S24. 39. Dykhuizen RS, Harvey G, Stephenson N et al. Protein binding and serum bactericidal activities of vancomycin and teicoplanin. Antimicrob Agents Chemother 1995; 39: 1842 1847. 40. Rybak MJ. The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis 2006; 42: S35 S39. 41. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing: sixteenth international supplement. M100-S16. Wayne, PA: Clinical and Laboratory Standards Institute, 2006. 42. Sakoulas G, Moise-Broder PA, Schentag J et al. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol 2004; 42: 2398 2402. 43. Wang G, Hindler JF, Ward KW et al. Increased vancomycin MICs for Staphylococcus aureus clinical isolates from a university hospital during a 5-year period. J Clin Microbiol 2006; 44: 3883 3886.

Eisenstein Complicated skin and soft-tissue infections 25 44. Gould IM. The problem with glycopeptides. Int J Antimicrob Agents 2007; 30: 1 3. 45. Arbeit RD, Maki D, Tally FP et al. The safety and efficacy of daptomycin for the treatment of complicated skin and skinstructure infections. Clin Infect Dis 2004; 38: 1673 1681. 46. Doan TL, Fung HB, Mehta D et al. Tigecycline: a glycylcycline antimicrobial agent. Clin Ther 2006; 28: 1079 1106. 47. Jauregui LE, Babazadeh S, Seltzer E et al. Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections. Clin Infect Dis 2005; 41: 1407 1415. 48. Breedt J, Teras J, Gardovskis J et al. Safety and efficacy of tigecycline in treatment of skin and skin structure infections: results of a double-blind phase 3 comparison study with vancomycin aztreonam. Antimicrob Agents Chemother 2005; 49: 4658 4666. 49. Napolitano LM, Lodise T. Strategies to manage serious skin and soft tissue infections. Health Care-Associated Infections: Strategies for Improving Patient Care 2007; 1: 1 10.