Learning Objectives

1. 1 Slide 1 _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 1 _________________ _________________ _______ _____ _______ _____ _______ _____ _______

2. 2 Learning Objectives A better understanding of the clinicalimportance of: The role of aerobic and anaerobic pathogens in complicated skin and soft-tissue infections Clinical evaluation and surgical/antimicrobial therapeutic approaches to complicated skin and soft-tissue infections Choices for empiric antimicrobial management of complicated skin and soft-tissue infections The challenging role of resistance in the treatment of complicated skin and soft-tissue infections Slide 2 Slide 2

3. 3 Skin and Soft-Tissue Infections Skin Epidermis Outermost, protective layer Dermis Blood vessels, nerves Subcutaneous tissue Fascia (adipose cells) Slide 3 Normal, intact skin is comprised of three anatomical layers; epidermis, dermis, and subcutaneous tissue. The epidermis is the outermost layer made up of tightly packed epithelial cells that protect the body from environmental insults. The dermis lies beneath the epidermis and contains blood vessels, nerves, hair roots, and sweat glands. The subcutaneous layer, or soft-tissue (superficial fascia and deep fascia), is located beneath the epidermis and is comprised primarily of adipose connective tissue, more commonly known as fat. The skin is one of the most important contributors to innate immunity in its protective role of controlling microbial populations colonizing the skin surface and preventing these microbes access to underlying soft-tissue layers. Its acidic pH and dryness, and the complex lipids present in the sebaceous secretions are inhibitory to most pathogenic bacteria. However, infection of the skin may occur when the integrity of the epidermis is disrupted allowing colonized microorganisms to invade and infect the underlying tissues. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 3 Normal, intact skin is comprised of three anatomical layers; epidermis, dermis, and subcutaneous tissue. The epidermis is the outermost layer made up of tightly packed epithelial cells that protect the body from environmental insults. The dermis lies beneath the epidermis and contains blood vessels, nerves, hair roots, and sweat glands. The subcutaneous layer, or soft-tissue (superficial fascia and deep fascia), is located beneath the epidermis and is comprised primarily of adipose connective tissue, more commonly known as fat. The skin is one of the most important contributors to innate immunity in its protective role of controlling microbial populations colonizing the skin surface and preventing these microbes access to underlying soft-tissue layers. Its acidic pH and dryness, and the complex lipids present in the sebaceous secretions are inhibitory to most pathogenic bacteria. However, infection of the skin may occur when the integrity of the epidermis is disrupted allowing colonized microorganisms to invade and infect the underlying tissues. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

4. 4 Skin and Soft-tissue Clinical Classification Mild-to-moderate Epidermal involvement Pyodermas Moderate-to-severe Involves dermis and subcutaneous tissue Secondary to pre-existing cutaneous lesions Severe or complicated Involves subcutaneous tissue, deep fascia and muscle Potential for deep necrotizing infections Slide 4 Bacterial infections of the skin and soft-tissue vary widely in severity and comprise a diverse spectrum of clinical findings. Many of these are readily recognized and easily treated, but there are those more severe infections that can manifest seemingly harmlessly early on causing a delay in diagnosis and treatment that may lead to poor patient outcome. Based on severity of disease, skin and soft-tissue infections can be classified into three main categories. Mild-to-moderately severe pyodermas, moderate-to-severe infections acquired secondary to pre-existing cutaneous lesions, and severe or complicated infections, which involve deep fascia and muscle and may manifest with a necrotizing process. Thus, it is important to have a clear understanding of the variety of infections and their clinical presentation in order to interpret the severity of disease. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 4 Bacterial infections of the skin and soft-tissue vary widely in severity and comprise a diverse spectrum of clinical findings. Many of these are readily recognized and easily treated, but there are those more severe infections that can manifest seemingly harmlessly early on causing a delay in diagnosis and treatment that may lead to poor patient outcome. Based on severity of disease, skin and soft-tissue infections can be classified into three main categories. Mild-to-moderately severe pyodermas, moderate-to-severe infections acquired secondary to pre-existing cutaneous lesions, and severe or complicated infections, which involve deep fascia and muscle and may manifest with a necrotizing process. Thus, it is important to have a clear understanding of the variety of infections and their clinical presentation in order to interpret the severity of disease. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

5. 5 Mild-to-Moderate Infections Focal, superficial � Epidermal involvement Impetigo, folliculitis, furunculosis, cutaneous abscesses, erysipelas, and cellulitis Bacterial causes Staphylococcus aureus Streptococcus pyogenes Gram-negative bacilli (immunocompromised patients) Slide 5 Mild-to-moderate skin infections include impetigo, folliculitis, furunculosis, cutaneous abscesses, erysipelas, and cellulitis. In most cases, these infections are monomicrobial with S. aureus, and S. pyogenes as the most common infecting organisms. In immunocompromised patients, it is not uncommon for gram-negative bacilli, such as P. aeruginosa, to cause infection. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 5 Mild-to-moderate skin infections include impetigo, folliculitis, furunculosis, cutaneous abscesses, erysipelas, and cellulitis. In most cases, these infections are monomicrobial with S. aureus, and S. pyogenes as the most common infecting organisms. In immunocompromised patients, it is not uncommon for gram-negative bacilli, such as P. aeruginosa, to cause infection. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

6. 6 Mild-to-Moderate Infections Slide 6 This slide provides an overview of mild-to-moderate skin and soft-tissue infections and the commonly-associated bacterial pathogens. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 6 This slide provides an overview of mild-to-moderate skin and soft-tissue infections and the commonly-associated bacterial pathogens. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

7. 7 Erysipelas Slide 7 _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 7 _________________ _________________ _______ _____ _______ _____ _______ _____ _______

8. 8 Cellulitis Slide 8 _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 8 _________________ _________________ _______ _____ _______ _____ _______ _____ _______

9. 9 Staphylococcal Furuncle Slide 9 _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 9 _________________ _________________ _______ _____ _______ _____ _______ _____ _______

10. 10 Staphylococcal Carbuncle Slide 10 _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 10 _________________ _________________ _______ _____ _______ _____ _______ _____ _______

11. 11 Moderate to Severe Infections Involves epidermis subcutaneous tissue Occurs in areas of abnormal or damaged skin Pre-existing conditions trauma from surgical site or puncture wound, injection drug abuse, pressure ulcers, diabetic foot Polymicrobial often mixed aerobic and anaerobic pathogens Slide 11 Moderate-to-severe infections can develop from areas of abnormal or damaged skin and soft-tissue. Preexisting conditions associated with these infections include trauma from surgical sites or puncture wounds, injection drug abuse, pressure (decubitis) ulcers, and diabetes mellitus. The microbial profile of these infections is usually polymicrobial, mixed with aerobic and anaerobic pathogens. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 11 Moderate-to-severe infections can develop from areas of abnormal or damaged skin and soft-tissue. Preexisting conditions associated with these infections include trauma from surgical sites or puncture wounds, injection drug abuse, pressure (decubitis) ulcers, and diabetes mellitus. The microbial profile of these infections is usually polymicrobial, mixed with aerobic and anaerobic pathogens. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

12. 12 Moderate to Severe Infections Clinical Manifestations Cellulitis Symptoms: edema, warmth, pain Signs: fever, erythema, bullae Necrotizing process advanced from cellulitis devitalized tissue Slide 12 Clinically, mild-to-severe infections tend to present with cellulitis. Cellulitis is defined as a spreading infectious inflammatory process that involves the skin and the subcutaneous tissues, and presents as an area that is edematous, warm, erythematous, and tender. Many organisms can cause cellulitis in selected circumstances, which may become complicated by abscess formation or involvement of bone and joint areas. Several forms of cellulitis have specific etiologies, caused by single pathogens. However, in many cases these secondary infections are polymicrobial, and can further develop into a deep necrotizing infection. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 12 Clinically, mild-to-severe infections tend to present with cellulitis. Cellulitis is defined as a spreading infectious inflammatory process that involves the skin and the subcutaneous tissues, and presents as an area that is edematous, warm, erythematous, and tender. Many organisms can cause cellulitis in selected circumstances, which may become complicated by abscess formation or involvement of bone and joint areas. Several forms of cellulitis have specific etiologies, caused by single pathogens. However, in many cases these secondary infections are polymicrobial, and can further develop into a deep necrotizing infection. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

13. 13 Moderate to Severe Infections Slide 13 This slide provides an overview of common pathogens causing skin and soft-tissue infections in patients with pre-existing conditions or specific social history. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 13 This slide provides an overview of common pathogens causing skin and soft-tissue infections in patients with pre-existing conditions or specific social history. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

14. 14 Moderate to Severe Infections Slide 14 Some skin and soft-tissue infections are associated with specific environmental exposures or unique situations. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 14 Some skin and soft-tissue infections are associated with specific environmental exposures or unique situations. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

15. 15 Deep Cellulitis Slide 15 _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 15 _________________ _________________ _______ _____ _______ _____ _______ _____ _______

16. 16 Deep Cellulitis Slide 16 _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 16 _________________ _________________ _______ _____ _______ _____ _______ _____ _______

17. 17 Complicated Skin and Soft-tissue Infections (CSSI) Infectious process involving: Deep fascia and muscle layers Requires surgical and antimicrobial intervention Co-morbidities likely to compromise treatment response Superficial lesions in areas that allow bacterial spread to deeper tissues perineal region involving enteric and anaerobic pathogens Examples � post-traumatic or post-surgical infections, perineal cellulitis/abscess, lower extremity infections in diabetic patients Slide 17 Complicated skin and soft-tissue infections are a common reason for hospital admission. Skin and soft-tissue infections are considered complicated when the infectious process involves deeper skin structures such as fascia and muscle layers, or requires significant surgical intervention or when the patient has a significant co-morbid condition such as diabetes mellitus or HIV infection that may compromise the response to treatment. Superficial infections in areas at risk for gram-negative or anaerobic pathogen involvement (ie. rectal area) are also classified as complicated infections. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 17 Complicated skin and soft-tissue infections are a common reason for hospital admission. Skin and soft-tissue infections are considered complicated when the infectious process involves deeper skin structures such as fascia and muscle layers, or requires significant surgical intervention or when the patient has a significant co-morbid condition such as diabetes mellitus or HIV infection that may compromise the response to treatment. Superficial infections in areas at risk for gram-negative or anaerobic pathogen involvement (ie. rectal area) are also classified as complicated infections. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

18. 18 Severe Necrotizing CSSI Inflammation and necrosis of skin, subcutaneous tissue, and muscle Rapid onset of exquisite pain, fever and malaise Cellulitis, bullae, crepitus, possible discolouration NB: Superficial skin can appear completely normal Limb and life-threatening outcomes Often polymicrobial Mixed aerobic & anaerobic pathogens Slide 18 One of the more serious group of CSSIs are those that induce soft-tissue necrosis. Necrotizing soft-tissue infections can develop from a range of cutaneous infections and is characterized by progressive inflammation and necrosis of the skin, subcutaneous fat, fascia, and muscle. Necrotizing infections occur much less frequently than less severe skin and soft-tissue infections but can progress rapidly with profound and extensive damage, leading to increased morbidity and mortality. Clinically, these infections are classified as either necrotizing fasciitis, clostridial myonecrosis (classic gas gangrene), and synergistic necrotizing cellulitis. Most necrotizing infections are polymicrobial, consisting of both aerobic and anaerobic bacterial species, although two syndromes caused by single pathogens are clostridial myonecrosis, and necrotizing fasciitis associated with group A streptococci. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 18 One of the more serious group of CSSIs are those that induce soft-tissue necrosis. Necrotizing soft-tissue infections can develop from a range of cutaneous infections and is characterized by progressive inflammation and necrosis of the skin, subcutaneous fat, fascia, and muscle. Necrotizing infections occur much less frequently than less severe skin and soft-tissue infections but can progress rapidly with profound and extensive damage, leading to increased morbidity and mortality. Clinically, these infections are classified as either necrotizing fasciitis, clostridial myonecrosis (classic gas gangrene), and synergistic necrotizing cellulitis. Most necrotizing infections are polymicrobial, consisting of both aerobic and anaerobic bacterial species, although two syndromes caused by single pathogens are clostridial myonecrosis, and necrotizing fasciitis associated with group A streptococci. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

19. 19 Common Aerobic Pathogens in CSSI from Hospitalized Patients Slide 19 The frequency of major pathogens isolated from CSSI has recently been reported by North American (n = 1404) and European (n = 1013) studies from the SENTRY Antimicrobial Surveillance Programme. The rank order of major pathogens was similar in both studies with S. aureus and P. aeruginosa comprising more than 50% of total isolates. Less than 5% of isolates were ?-hemolytic streptococci. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 19 The frequency of major pathogens isolated from CSSI has recently been reported by North American (n = 1404) and European (n = 1013) studies from the SENTRY Antimicrobial Surveillance Programme. The rank order of major pathogens was similar in both studies with S. aureus and P. aeruginosa comprising more than 50% of total isolates. Less than 5% of isolates were ?-hemolytic streptococci. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

20. 20 Common Anaerobic Pathogens in CSSI from Hospitalized Patients Gram-positive Peptostreptococcus Clostridium Gram-negative Bacteroides fragilis group Porphyromonas Prevotella Slide 20 Anaerobic bacteria are commonly associated with CSSI, such as, deep soft-tissue abscesses, surgical or traumatic wound infections, and diabetic foot infections. Common genera include Peptostreptococcus, Clostridium, members of the Bacteroides fragilis group, Porphyromonas, and Prevotella. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 20 Anaerobic bacteria are commonly associated with CSSI, such as, deep soft-tissue abscesses, surgical or traumatic wound infections, and diabetic foot infections. Common genera include Peptostreptococcus, Clostridium, members of the Bacteroides fragilis group, Porphyromonas, and Prevotella. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

21. 21 Necrotizing Fasciitis Slide 21 _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 21 _________________ _________________ _______ _____ _______ _____ _______ _____ _______



24. 24 Microbiologic Diagnosis of CSSI Collect specimens for Gram stain and culture (ie. from exudate or abscess commonly associated with CSSI) Obtain deep intra-operative specimens during debridement for open wounds and infected ulcers Blood culture ~50% positive Cultures often polymicrobial, interpret with caution Monomicrobial infection facilitates targeted therapy Soft-tissue gas and foul smell � suggests anaerobes Slide 24 Whenever possible, specimens for Gram stain and culture should be obtained from CSSI. Most CSSI are associated with an exudate or an abscess, which can be drained for examination. For open wounds and infected ulcers, deep intra-operative specimens may be obtained during surgical debridement. Culture from aspiration of bullae or necrotic tissue may be useful, and blood cultures are positive in ~50% of patients. Necrotic infections are often polymicrobial and must be interpreted with caution to avoid the treatment of skin contaminating microbes. However, identification of a monomicrobial infection facilitates targeted treatment, thereby justifying the need for culture. The presence of soft-tissue gas and foul smell is indicative of anaerobes. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 24 Whenever possible, specimens for Gram stain and culture should be obtained from CSSI. Most CSSI are associated with an exudate or an abscess, which can be drained for examination. For open wounds and infected ulcers, deep intra-operative specimens may be obtained during surgical debridement. Culture from aspiration of bullae or necrotic tissue may be useful, and blood cultures are positive in ~50% of patients. Necrotic infections are often polymicrobial and must be interpreted with caution to avoid the treatment of skin contaminating microbes. However, identification of a monomicrobial infection facilitates targeted treatment, thereby justifying the need for culture. The presence of soft-tissue gas and foul smell is indicative of anaerobes. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

25. 25 Differential Diagnosis and Therapeutic Intervention Moderate to severe infection - superficial Differential diagnosis allergic reaction to wound dressing, venous thrombosis, erythema nodosum, or carcinomatous infiltrate Antibiotic treatment Severe infection - involving necrotizing process Differential diagnosis muscle strain, gout, herpes zoster reactivation, deep venous thrombosis, pyoderma gangrenosum Surgical intervention and antibiotic treatment Slide 25 Identifying a CSSI as localized or spreading is a critical first step towards the surgical and antimicrobial management of the infection. For localized cellulitis or erysipelas with no evidence of necrosis, antibiotic therapy alone is indicated. If a spreading infection is diagnosed, the level of infection and the presence of necrotic tissue should be evaluated to direct the need for surgical intervention. For deep infections or those with tissue necrosis at any anatomic level, surgery is necessary. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 25 Identifying a CSSI as localized or spreading is a critical first step towards the surgical and antimicrobial management of the infection. For localized cellulitis or erysipelas with no evidence of necrosis, antibiotic therapy alone is indicated. If a spreading infection is diagnosed, the level of infection and the presence of necrotic tissue should be evaluated to direct the need for surgical intervention. For deep infections or those with tissue necrosis at any anatomic level, surgery is necessary. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

26. 26 Management of CSSI Meticulous physical examination of lesions Debridement of devitalized and necrotic tissue Drainage of abscess, removal of foreign debris Antibiotic therapy Supportive care Slide 26 Appropriate management of CSSI first involves taking a thorough medical and social history of the patient, and meticulous physical examination of skin and soft-tissue lesions. These severe infections often require surgical debridement of devitalized and necrotic tissue, drainage of subcutaneous abscesses, and removal of foreign debris. Prompt administration of appropriate antibiotics is also vital. Because of the polymicrobial nature of many of these infections, empirical treatment using broad-spectrum antibiotics is warranted. Compression dressings can be useful in resolving infections complicated by chronic venous insufficiency by reducing edema. Maintenance of organ system function via physiological support measures, and chemotherapeutic control of the inflammatory process may also be indicated. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 26 Appropriate management of CSSI first involves taking a thorough medical and social history of the patient, and meticulous physical examination of skin and soft-tissue lesions. These severe infections often require surgical debridement of devitalized and necrotic tissue, drainage of subcutaneous abscesses, and removal of foreign debris. Prompt administration of appropriate antibiotics is also vital. Because of the polymicrobial nature of many of these infections, empirical treatment using broad-spectrum antibiotics is warranted. Compression dressings can be useful in resolving infections complicated by chronic venous insufficiency by reducing edema. Maintenance of organ system function via physiological support measures, and chemotherapeutic control of the inflammatory process may also be indicated. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

27. 27 CSSI of the Diabetic Foot Peripheral neuropathy Feet prone to repeated trauma, leading to ulceration and secondary infection Peripheral vascular disease Autonomic neuropathy Motor neuropathy Polymicrobial infection involving anaerobes Management: diabetes control, abscess drainage, debridement of necrotic tissue, revascularization, antimicrobial therapy Slide 27 Peripheral neuropathy in the diabetic patient leaves the feet prone to repeated trauma, which often leads to ulceration and secondary infection. With concomitant peripheral vascular disease, healing is expected to be slow. Autonomic (vasomoter) neuropathy affects the peripheral nerve function, which controls the distribution of blood through arteriolar vessels. Motor neuropathy affects the muscles required for normal foot movement, altering the distribution of forces during walking and causing reactive thickening of skin at sites of abnormal load. Ischaemic necrosis of tissues beneath the callus then leads to breakdown of skin and subcutaneous tissue, resulting in a neuropathic ulcer. Diabetic foot infections are typically polymicrobial with anaerobic involvement. Antimicrobial treatment is adjunctive to diabetes control, drainage of the abscesses, debridement of necrotic tissue, and revascularization if vascular insufficiency is present. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 27 Peripheral neuropathy in the diabetic patient leaves the feet prone to repeated trauma, which often leads to ulceration and secondary infection. With concomitant peripheral vascular disease, healing is expected to be slow. Autonomic (vasomoter) neuropathy affects the peripheral nerve function, which controls the distribution of blood through arteriolar vessels. Motor neuropathy affects the muscles required for normal foot movement, altering the distribution of forces during walking and causing reactive thickening of skin at sites of abnormal load. Ischaemic necrosis of tissues beneath the callus then leads to breakdown of skin and subcutaneous tissue, resulting in a neuropathic ulcer. Diabetic foot infections are typically polymicrobial with anaerobic involvement. Antimicrobial treatment is adjunctive to diabetes control, drainage of the abscesses, debridement of necrotic tissue, and revascularization if vascular insufficiency is present. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

28. 28 CSSI of the Diabetic Foot Slide 28 _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 28 _________________ _________________ _______ _____ _______ _____ _______ _____ _______

29. 29 CSSI in Injection Drug Users Skin and soft-tissue abscesses common Polymicrobial infection eg. S. aureus, MRSA, Enterobacteriaceae, anaerobes Risk factors: Subcutaneous injection (skin-popping) Vasoconstrictive drugs (cocaine) Soft-tissue ischemia-inducing drugs (speedball) Slide 29 Skin and soft-tissue abscesses are a frequent complication of injection drug abuse. These infections are generally polymicrobial, involving Gram-positive pathogens such as S. aureus and S. pyogenes, and anaerobes such as Fusobacterium spp. and Peptostreptococcus spp. Risk factors for abscess formation are largely attributed to common practices used for drug injection. When vascular access becomes exhausted, drug users inject themselves subcutaneously (skin-popping), introducing bacteria into areas where immune defense is sub-optimal. Cocaine is a powerful vasoconstrictor that decreases oxygen tension in surrounding tissues, impairing phagocytic migration of immune cells. Abscess formation may also be influenced by injection of drugs that induce soft-tissue ischemia, such as cocaine and heroin combinations (speedball). _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 29 Skin and soft-tissue abscesses are a frequent complication of injection drug abuse. These infections are generally polymicrobial, involving Gram-positive pathogens such as S. aureus and S. pyogenes, and anaerobes such as Fusobacterium spp. and Peptostreptococcus spp. Risk factors for abscess formation are largely attributed to common practices used for drug injection. When vascular access becomes exhausted, drug users inject themselves subcutaneously (skin-popping), introducing bacteria into areas where immune defense is sub-optimal. Cocaine is a powerful vasoconstrictor that decreases oxygen tension in surrounding tissues, impairing phagocytic migration of immune cells. Abscess formation may also be influenced by injection of drugs that induce soft-tissue ischemia, such as cocaine and heroin combinations (speedball). _________________ _________________ _______ _____ _______ _____ _______ _____ _______

30. 30 Empiric Antibiotic Therapy for Polymicrobial CSSI Amoxicillin/clavulanate Imipenem Meropenem Ertapenem Piperacillin/tazobactam Ticarcillin/clavulanate Vancomycin - indicated for suspected nosocomial MRSA Slide 30 Antimicrobial management of CSSI should be administered promptly with broad-spectrum empiric coverage due to the often polymicrobial (aerobic and anaerobic organisms) nature of these infections. Appropriate antibiotics recommended for single agent therapy include ?-lactam/?-lactamase inhibitors (piperacillin/ tazobactam and ticarcillin/clavulanate), and carbapenems (imipenem/cilastatin or meropenem). Combination therapy options include penicillin and aminoglycoside, a third generation cephalosporin, or a fluoroquinolone, combined with an antianaerobic agent (clindamycin or metroanidazole). Penicillin combination therapy has largely been displaced by newer single agents with gram-positive activity, similar to penicillin, that also have potent gram-negative and anaerobic activity. It is important to note that these recommendations are largely based on limited control trials and historical practice because of the paucity of data available from clinical trials. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 30 Antimicrobial management of CSSI should be administered promptly with broad-spectrum empiric coverage due to the often polymicrobial (aerobic and anaerobic organisms) nature of these infections. Appropriate antibiotics recommended for single agent therapy include ?-lactam/?-lactamase inhibitors (piperacillin/ tazobactam and ticarcillin/clavulanate), and carbapenems (imipenem/cilastatin or meropenem). Combination therapy options include penicillin and aminoglycoside, a third generation cephalosporin, or a fluoroquinolone, combined with an antianaerobic agent (clindamycin or metroanidazole). Penicillin combination therapy has largely been displaced by newer single agents with gram-positive activity, similar to penicillin, that also have potent gram-negative and anaerobic activity. It is important to note that these recommendations are largely based on limited control trials and historical practice because of the paucity of data available from clinical trials. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

31. 31 Antibiotics and Spectrum of Activity for CSSI Slide 31 _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 31 _________________ _________________ _______ _____ _______ _____ _______ _____ _______





36. 36 Antimicrobial Resistance and CSSI Inappropriate treatment of polymicrobial infections may promote selection of resistant microbes S. aureus (MRSA) P. aeruginosa Enterobacteriaceae (?-lactamase-producing) Slide 36 According to recent SENTRY data, antimicrobial resistance rates, with the exception of MRSA, remains seemingly minor for the treatment of skin and soft-tissue infections. However, appropriate antimicrobial treatment of these infections is still warranted. Many skin and soft-tissue infections are polymicrobial and inappropriate broad-spectrum antimicrobial therapy could promote the selection of resistant pathogens. S. aureus, P. aeruginosa, and members of the Enterobacteriaceae (ie. E. coli and K. pneumoniae) are commonly associated with severe skin and soft-tissue infections and highly resistant strains exist. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 36 According to recent SENTRY data, antimicrobial resistance rates, with the exception of MRSA, remains seemingly minor for the treatment of skin and soft-tissue infections. However, appropriate antimicrobial treatment of these infections is still warranted. Many skin and soft-tissue infections are polymicrobial and inappropriate broad-spectrum antimicrobial therapy could promote the selection of resistant pathogens. S. aureus, P. aeruginosa, and members of the Enterobacteriaceae (ie. E. coli and K. pneumoniae) are commonly associated with severe skin and soft-tissue infections and highly resistant strains exist. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

37. 37 The Downside to ?-Lactam Monotherapy-?-Lactam Resistance- Gram-positive bacteria ?-lactamase enzymes Low-affinity penicillin-binding proteins (PBP) Gram-negative bacteria ?-lactamase enzymes Altered porin channels Slide 37 The potential for infection by antibiotic-resistant bacteria is an important concern during the treatment of an infection in neutropenic patients. Resistance to ?-lactam antibiotics can occur by a couple of different mechanisms. Namely, ?-lactamase production in gram-negative and gram-positive pathogens, and low-affinity penicillin-binding proteins in gram-positive pathogens. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 37 The potential for infection by antibiotic-resistant bacteria is an important concern during the treatment of an infection in neutropenic patients. Resistance to ?-lactam antibiotics can occur by a couple of different mechanisms. Namely, ?-lactamase production in gram-negative and gram-positive pathogens, and low-affinity penicillin-binding proteins in gram-positive pathogens. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

38. 38 ?-Lactamase Enzymes Hydrolyze ?-lactam ring and inactivate drug May cause resistance to penicillins, cephalosporins, monobactams, carbapenems Produced by gram-negative bacilli, staphylococci, and anaerobes Slide 38 ?-lactamase-mediated antibiotic degradation is the most common cause of resistance to ?-lactam antibiotics. Classically, these enzymes inactivate the drug by hydrolyzing the ?-lactam ring. Among gram-positive bacteria, S. aureus and coagulase-negative staphylococci are the only clinically relevant species that produce ?-lactamase, which is excreted extracellularly. ?-lactamase production is far more important as a mechanism of resistance in gram-negative bacteria, which produce a variety of ?-lactamases, generally located in the periplasmic space. Anaerobes may also produce penicillinases and/or cephalosporinases. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 38 ?-lactamase-mediated antibiotic degradation is the most common cause of resistance to ?-lactam antibiotics. Classically, these enzymes inactivate the drug by hydrolyzing the ?-lactam ring. Among gram-positive bacteria, S. aureus and coagulase-negative staphylococci are the only clinically relevant species that produce ?-lactamase, which is excreted extracellularly. ?-lactamase production is far more important as a mechanism of resistance in gram-negative bacteria, which produce a variety of ?-lactamases, generally located in the periplasmic space. Anaerobes may also produce penicillinases and/or cephalosporinases. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

39. 39 ?-Lactam Resistance in S. aureus ?-lactamase (penicillinase) Emergence attributed to introduction of penicillin Now present in majority of S. aureus isolates Low-affinity PBP (PBP 2a) Confers resistance to all ?-lactams ? Methicillin Resistant S. aureus (MRSA) MRSA: major pathogen in hospital & long-term care facilities Cross-resistant to macrolides, lincosamides, aminoglycosides, tetracyclines, chloramphenicol, and fluoroquinolones Vancomycin, linezolid, quinupristin/dalfopristin are effective Slide 39 Staphylococci are the only common gram-positive pathogens in which ?-lactamases have caused major resistance problems. Penicillinases, narrow-spectrum ?-lactamases, began to appear in S. aureus soon after penicillin was introduced, and are now present in the majority of S. aureus and coagulase-negative staphylococcal isolates. Penicillin resistance prompted the development of penicillinase-resistant beta-lactam antibiotics (ie. methicillin, cephalosporins), which ultimately gave rise to methicillin-resistant S. aureus (MRSA). Resistance is attributed to PBP 2a, encoded by the mecA gene, which has a low affinity for all ?-lactam agents. MRSA is a major nosocomial pathogen causing infection in hospitals and long-term care facilities, including bacteremia, surgical wound infections, and skin infections. MRSA isolates are resistant to all ?-lactam antibiotics, and exhibit cross-resistance to many other antibiotic classes; macrolides, lincosamides, aminoglycosides, tetracyclines, chloramphenicol, and most recently, fluoroquinolones. Vancomycin and newer agents, such as linezolid and quinupristin/dalfopristin, remain as effective agents. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 39 Staphylococci are the only common gram-positive pathogens in which ?-lactamases have caused major resistance problems. Penicillinases, narrow-spectrum ?-lactamases, began to appear in S. aureus soon after penicillin was introduced, and are now present in the majority of S. aureus and coagulase-negative staphylococcal isolates. Penicillin resistance prompted the development of penicillinase-resistant beta-lactam antibiotics (ie. methicillin, cephalosporins), which ultimately gave rise to methicillin-resistant S. aureus (MRSA). Resistance is attributed to PBP 2a, encoded by the mecA gene, which has a low affinity for all ?-lactam agents. MRSA is a major nosocomial pathogen causing infection in hospitals and long-term care facilities, including bacteremia, surgical wound infections, and skin infections. MRSA isolates are resistant to all ?-lactam antibiotics, and exhibit cross-resistance to many other antibiotic classes; macrolides, lincosamides, aminoglycosides, tetracyclines, chloramphenicol, and most recently, fluoroquinolones. Vancomycin and newer agents, such as linezolid and quinupristin/dalfopristin, remain as effective agents. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

40. 40 Incidence of MRSA in Canadian Hospitals Slide 40 This slide depicts the increasing incidence of MRSA colonization and infection in patients admitted to Canadian hospitals between 1995 and 1999. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 40 This slide depicts the increasing incidence of MRSA colonization and infection in patients admitted to Canadian hospitals between 1995 and 1999. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

41. 41 MRSA in CSSI Increasing prevalence in nosocomial-and community-acquired strains MRSA > 22% of skin and soft-tissue infections SENTRY data from North America and Europe North America - increased from 24% (1997) to 29.5% (2000) Significant problem in treating SSI Slide 41 Resistance to methicillin confers resistance to all penicillinase-resistant penicillins and cephalosporins. Surveillance reports indicate that at least 22% of skin and soft-tissue infections (hospital- or community-acquired) are caused by MRSA. Of note, the incidence of MRSA associated with skin and soft-tissue infections in North American hospitals has increased from 24% in 1997 to 29.5% in 2000. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 41 Resistance to methicillin confers resistance to all penicillinase-resistant penicillins and cephalosporins. Surveillance reports indicate that at least 22% of skin and soft-tissue infections (hospital- or community-acquired) are caused by MRSA. Of note, the incidence of MRSA associated with skin and soft-tissue infections in North American hospitals has increased from 24% in 1997 to 29.5% in 2000. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

42. 42 MRSA in CSSI Widespread antibiotic cross-resistance Fluoroquinolones, clindamycin, aminoglycosides, Narrows treatment options Vancomycin resistance in S. aureus Newer effective agents Linezolid, quinupristin/dalfopristin, or daptomycin Slide 42 Widespread cross-resistance of MRSA strains to other antibiotic classes makes treatment that much more challenging. Vancomycin resistance in MRSA has also become an emerging concern. Newer agents, such as linezolid, quinupristin/dalfopristin, or daptomycin are effective and are indicated for the management of multi-resistant MRSA CSSI infections. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 42 Widespread cross-resistance of MRSA strains to other antibiotic classes makes treatment that much more challenging. Vancomycin resistance in MRSA has also become an emerging concern. Newer agents, such as linezolid, quinupristin/dalfopristin, or daptomycin are effective and are indicated for the management of multi-resistant MRSA CSSI infections. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

43. 43 MRSA and Fluoroquinolones Fluoroquinolone use associated with emergence of fluoroquinolone resistant MRSA Diminished role of oral ciprofloxacin for MRSA Ciprofloxacin has greater propensity to select for MRSA than newer quinolones Levofloxacin, moxifloxacin, and gatifloxacin also implicated Slide 43 Resistance to fluoroquinolones among MRSA is an increasing clinical problem as resistance develops in patients given a fluoroquinolone for the treatment of MRSA infection. However, not all of the fluoroquinolones have the same propensity to select for methicillin-resistant strains. Ciprofloxacin appears to select for MRSA at a far greater rate than the newer fluoroquinolones, but they are all implicated. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 43 Resistance to fluoroquinolones among MRSA is an increasing clinical problem as resistance develops in patients given a fluoroquinolone for the treatment of MRSA infection. However, not all of the fluoroquinolones have the same propensity to select for methicillin-resistant strains. Ciprofloxacin appears to select for MRSA at a far greater rate than the newer fluoroquinolones, but they are all implicated. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

44. 44 P. aeruginosa in CSSI 2nd most common SSI isolate Multi-drug resistance to anti-pseudomonal agents reported in SSI Anti-pseudomonal penicillins and cephalosporins, carbapenems, and fluoroquinolones Aminoglycosides � retain good in vitro activity Gentamicin (89.5%) Tobramycin (93.4%) Amikacin (98.0%) Slide 44 P. aeruginosa is a leading cause of nosocomial infections and is the second most common isolate from complicated skin and soft-tissue infections. There are a limited number of antimicrobial agents with reliable activity, including anti-pseudomonal penicillins and cephalosporins, carbapenems, and fluoroquinolones, particularly ciprofloxacin. Unfortunately, multidrug-resistant isolates of P. aeruginosa (resistant to ?-lactam and fluoroquinolone agents) have been reported in soft-tissue and lung infections. Interestingly, the aminoglycosides have retained good activity against P. aeruginosa associated with skin and soft-tissue infections in North America despite widespread use of these antibiotics. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 44 P. aeruginosa is a leading cause of nosocomial infections and is the second most common isolate from complicated skin and soft-tissue infections. There are a limited number of antimicrobial agents with reliable activity, including anti-pseudomonal penicillins and cephalosporins, carbapenems, and fluoroquinolones, particularly ciprofloxacin. Unfortunately, multidrug-resistant isolates of P. aeruginosa (resistant to ?-lactam and fluoroquinolone agents) have been reported in soft-tissue and lung infections. Interestingly, the aminoglycosides have retained good activity against P. aeruginosa associated with skin and soft-tissue infections in North America despite widespread use of these antibiotics. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

45. 45 P. aeruginosa in CSSI-North American & European SENTRY Data- Slide 45 The prevelance and antimicrobial susceptibility of P. aeruginosa isolates associated with skin and soft-tissue infections was recently described by the SENTRY Antimicrobial Surveillance Programme in separate North American and European reports. A total of 152 and 127 skin and soft-tissue associated isolates were evaluated, for the North American and European studies, respectively. In general, fluoroquinolones had markedly reduced activity against P. aeruginosa, in comparison to the activity of broad-spectrum ?-lactams. North American susceptibility data � ciprofloxacin (79.6%), levofloxacin (78.9%), piperacillin/tazobactam (87.5%), imipenem (91.4%), and amikacin (98.0%). European susceptibility data � ciprofloxacin (77.2%), levofloxacin (63%), piperacillin/tazobactam (91.3%), imipenem (95.3%), and amikacin (91.3%). _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 45 The prevelance and antimicrobial susceptibility of P. aeruginosa isolates associated with skin and soft-tissue infections was recently described by the SENTRY Antimicrobial Surveillance Programme in separate North American and European reports. A total of 152 and 127 skin and soft-tissue associated isolates were evaluated, for the North American and European studies, respectively. In general, fluoroquinolones had markedly reduced activity against P. aeruginosa, in comparison to the activity of broad-spectrum ?-lactams. North American susceptibility data � ciprofloxacin (79.6%), levofloxacin (78.9%), piperacillin/tazobactam (87.5%), imipenem (91.4%), and amikacin (98.0%). European susceptibility data � ciprofloxacin (77.2%), levofloxacin (63%), piperacillin/tazobactam (91.3%), imipenem (95.3%), and amikacin (91.3%). _________________ _________________ _______ _____ _______ _____ _______ _____ _______

46. 46 ?-Lactamases in Gram Negative Bacilli ?-Lactamases - AmpC and/or ESBL phenotype Outbreaks of infection in hospitals and long-term-care facilities Emergence of resistance is associated with increased use of extended-spectrum penicillins and cephalosporins Cephalosporin resistance may be associated with cross-resistance to aminoglycosides or fluoroquinolones Acquisition of AmpC chromosomal ?-lactamases coexisting with ESBLs ? resistance to ?-lactamase inhibitors Slide 46 Resistance due to ?-lactamase enzymes is difficult to detect, but the index of suspicion should be raised in situations and settings where increased use of extended-spectrum ?-lactam (ESBL) agents is known; hospitals and long-term-care facilities are at the highest risk of outbreaks due to these resistant organisms. Carbapenems are still effective against the vast majority of enzymes, but waning cephalosporin activity has been associated with treatment failure. Additionally, cross-resistance to aminoglycosides and fluoroquinolones may occur in cephalosporin-resistant isolates. In a proportion of AmpC isolates in Enterobacteriaceae, a genetic mutation may arise and cause stable derepression of the AmpC inhibitor. This results in over-expression of the ?-lactamase enzyme and is associated with an increased likelihood of resistance to cephalosporins, as well as cephamycins. Additionally, AmpC and ESBL ?-lactamases coexisting within a single organism may confer increased resistance to ?-lactamase inhibitors. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 46 Resistance due to ?-lactamase enzymes is difficult to detect, but the index of suspicion should be raised in situations and settings where increased use of extended-spectrum ?-lactam (ESBL) agents is known; hospitals and long-term-care facilities are at the highest risk of outbreaks due to these resistant organisms. Carbapenems are still effective against the vast majority of enzymes, but waning cephalosporin activity has been associated with treatment failure. Additionally, cross-resistance to aminoglycosides and fluoroquinolones may occur in cephalosporin-resistant isolates. In a proportion of AmpC isolates in Enterobacteriaceae, a genetic mutation may arise and cause stable derepression of the AmpC inhibitor. This results in over-expression of the ?-lactamase enzyme and is associated with an increased likelihood of resistance to cephalosporins, as well as cephamycins. Additionally, AmpC and ESBL ?-lactamases coexisting within a single organism may confer increased resistance to ?-lactamase inhibitors. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

47. 47 Enterobacteriaceae in CSSI E. coli, Enterobacter spp., and Klebsiella spp. Resistance rates for most agents remain unchanged in North America Imipenem, meropenem, cefepime ~100% activity Piperacillin/tazobactam exhibits excellent activity Fluoroquinolones exhibit great activity, but evidence of increasing resistance is apparent Slide 47 The three most common Enterobacteriaceae isolated from complicated skin and soft-tissue infections in North America are E. coli, and Enterobacter and Klebsiella species. Resistance rates for the majority of antimicrobial agents tested were similar to previous data, with the exception of an increased level of fluoroquinolone resistance. The ?-lactam agents, imipenem, meropenem, and cefepime were active against all isolates. Piperacillin/tazobactam also showed excellent activity against these pathogens, particularly North American isolates. Fluoroquinolones also remain relatively active, but increasing resistance is apparent, particularly in E. coli. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 47 The three most common Enterobacteriaceae isolated from complicated skin and soft-tissue infections in North America are E. coli, and Enterobacter and Klebsiella species. Resistance rates for the majority of antimicrobial agents tested were similar to previous data, with the exception of an increased level of fluoroquinolone resistance. The ?-lactam agents, imipenem, meropenem, and cefepime were active against all isolates. Piperacillin/tazobactam also showed excellent activity against these pathogens, particularly North American isolates. Fluoroquinolones also remain relatively active, but increasing resistance is apparent, particularly in E. coli. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

48. 48 Control Measures for Multidrug Resistance Judicious antibiotic use warranted to preserve activity Traditional infection-control measures Antibiotic-control measures Decrease use of 3rd-generation cephalosporins Decrease use of fluoroquinolones Limit carbapenem antibiotics to directed therapy Slide 48 The judicious use of antibiotics is warranted, in the hospital and community, to preserve their activity. The prevalence of MRSA in the community and hospital is increasing, as is the level of cross-resistance to non-?-lactam antibiotic classes like the fluoroquinolones, thereby limiting treatment options significantly. Several reports link increased use of third-generation cephalosporins and carbapenem antibiotics to outbreaks of multidrug-resistant K. pneumoniae and P. aeruginosa, respectively. In contrast, penicillin-based therapy combined with a reduction in third-generation cephalosporin use appears to limit infection with these antibiotic resistant organisms. _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 48 The judicious use of antibiotics is warranted, in the hospital and community, to preserve their activity. The prevalence of MRSA in the community and hospital is increasing, as is the level of cross-resistance to non-?-lactam antibiotic classes like the fluoroquinolones, thereby limiting treatment options significantly. Several reports link increased use of third-generation cephalosporins and carbapenem antibiotics to outbreaks of multidrug-resistant K. pneumoniae and P. aeruginosa, respectively. In contrast, penicillin-based therapy combined with a reduction in third-generation cephalosporin use appears to limit infection with these antibiotic resistant organisms. _________________ _________________ _______ _____ _______ _____ _______ _____ _______

49. 49 Conclusions Complicated skin and soft-tissue infections require appropriate antimicrobial therapy and adjunctive surgical debridement Appropriate antimicrobial regimens must be effective against aerobic and anaerobic pathogens Prevalence of resistance mechanisms may limit treatment options Slide 49 _________________ _________________ _______ _____ _______ _____ _______ _____ _______ Slide 49 _________________ _________________ _______ _____ _______ _____ _______ _____ _______

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