A 69-year-old woman presented to the hospital with a 3-month history of fever of unknown origin and dyspnea. Her medical history included diabetes mellitus and, many years ago, partially treated latent tuberculosis infection and pancreatic cancer, treated with Whipple surgery and chemotherapy.

Radiography (Figure 1) and computed tomography of the chest (Figure 2) revealed diffuse reticulonodular infiltrates. Initial cultures of blood and bronchoalveolar lavage fluid were negative for viral, fungal, bacterial, and mycobacterial infection. Transbronchial biopsy specimens showed necrotizing granulomas, which stained negative for acid-fast bacilli and fungus. Study of specimens obtained via open lung biopsy showed granulomatous infiltration with no yeast, fungal elements, or acid-fast bacilli. An interferon-gamma-release assay for Mycobacterium tuberculosis and serologic testing for human immunodeficiency virus (HIV) were negative.

Glucocorticoid treatment was started for presumed sarcoidosis, and a broad-spectrum antibiotic was also started; however, her condition deteriorated, and she developed seizures. Magnetic resonance imaging of the brain showed widespread 2- to 5-mm enhancing lesions (Figure 3). Cerebrospinal fluid studies revealed lymphocytic pleocytosis with a low level of glucose (34 mg/dL) and a high level of protein (174 mg/dL). She was subsequently transferred to our tertiary care center.

Q: What is the most likely diagnosis?

• Sarcoidosis of the lungs and central nervous system
• Hypersensitivity pneumonitis
• Miliary tuberculosis
• Cancer with pulmonary and brain metastases
• Disseminated fungal infection

A: The correct diagnosis is miliary tuberculosis, ie, progressive and widely disseminated hematogenous tuberculosis infection. Granulomas involving multiple organs suggested a broad differential diagnosis. The negative workup for infectious disease initially supported sarcoidosis by exclusion, but her condition failed to respond to steroid treatment. Multiple organ involvement is atypical for hypersensitivity pneumonitis, and antibody panels were negative. The absence of malignant cells in multiple biopsy specimens made metastasis unlikely.

Her remote history of partially treated latent tuberculosis infection raised our clinical suspicion and prompted mycobacterial antibiotic coverage. Three weeks after the initial sample collection, results from an independent laboratory revealed the presence of acid-fast bacilli in cultures of bronchoalveolar lavage fluid, cerebrospinal fluid, and blood, which were confirmed to be M tuberculosis. Despite treatment, the patient died of multiple organ failure.

Tuberculosis is rare in the United States, with 11,181 reported cases in 2010.¹ Miliary tuberculosis is associated with malnutrition, HIV infection, AIDS, alcoholism, diabetes, chronic kidney failure, immunosuppressive drugs, and organ transplantation.² Acid-fast bacilli smears and cultures confirm the diagnosis but have low sensitivity.³ Granulomas characterize miliary tuberculosis histopathologically. They may be present in sarcoidosis, hypersensitivity pneumonitis, and fungal infection but are not specific for these conditions. Tuberculin skin testing² and interferon-gamma-release assay can be falsely negative in immunosuppressed patients,⁴ highlighting the emphasis on clinical suspicion. The estimated death rate is 20%,^3,5 with central nervous system involvement being an independent predictor.⁵ Empiric therapy should not be delayed, as culture results may not be available for 6 to 8 weeks.

A 69-year-old woman presented to the hospital with a 3-month history of fever of unknown origin and dyspnea. Her medical history included diabetes mellitus and, many years ago, partially treated latent tuberculosis infection and pancreatic cancer, treated with Whipple surgery and chemotherapy.

Radiography (Figure 1) and computed tomography of the chest (Figure 2) revealed diffuse reticulonodular infiltrates. Initial cultures of blood and bronchoalveolar lavage fluid were negative for viral, fungal, bacterial, and mycobacterial infection. Transbronchial biopsy specimens showed necrotizing granulomas, which stained negative for acid-fast bacilli and fungus. Study of specimens obtained via open lung biopsy showed granulomatous infiltration with no yeast, fungal elements, or acid-fast bacilli. An interferon-gamma-release assay for Mycobacterium tuberculosis and serologic testing for human immunodeficiency virus (HIV) were negative.

Glucocorticoid treatment was started for presumed sarcoidosis, and a broad-spectrum antibiotic was also started; however, her condition deteriorated, and she developed seizures. Magnetic resonance imaging of the brain showed widespread 2- to 5-mm enhancing lesions (Figure 3). Cerebrospinal fluid studies revealed lymphocytic pleocytosis with a low level of glucose (34 mg/dL) and a high level of protein (174 mg/dL). She was subsequently transferred to our tertiary care center.

Q: What is the most likely diagnosis?

• Sarcoidosis of the lungs and central nervous system
• Hypersensitivity pneumonitis
• Miliary tuberculosis
• Cancer with pulmonary and brain metastases
• Disseminated fungal infection

A: The correct diagnosis is miliary tuberculosis, ie, progressive and widely disseminated hematogenous tuberculosis infection. Granulomas involving multiple organs suggested a broad differential diagnosis. The negative workup for infectious disease initially supported sarcoidosis by exclusion, but her condition failed to respond to steroid treatment. Multiple organ involvement is atypical for hypersensitivity pneumonitis, and antibody panels were negative. The absence of malignant cells in multiple biopsy specimens made metastasis unlikely.

Her remote history of partially treated latent tuberculosis infection raised our clinical suspicion and prompted mycobacterial antibiotic coverage. Three weeks after the initial sample collection, results from an independent laboratory revealed the presence of acid-fast bacilli in cultures of bronchoalveolar lavage fluid, cerebrospinal fluid, and blood, which were confirmed to be M tuberculosis. Despite treatment, the patient died of multiple organ failure.

Tuberculosis is rare in the United States, with 11,181 reported cases in 2010.¹ Miliary tuberculosis is associated with malnutrition, HIV infection, AIDS, alcoholism, diabetes, chronic kidney failure, immunosuppressive drugs, and organ transplantation.² Acid-fast bacilli smears and cultures confirm the diagnosis but have low sensitivity.³ Granulomas characterize miliary tuberculosis histopathologically. They may be present in sarcoidosis, hypersensitivity pneumonitis, and fungal infection but are not specific for these conditions. Tuberculin skin testing² and interferon-gamma-release assay can be falsely negative in immunosuppressed patients,⁴ highlighting the emphasis on clinical suspicion. The estimated death rate is 20%,^3,5 with central nervous system involvement being an independent predictor.⁵ Empiric therapy should not be delayed, as culture results may not be available for 6 to 8 weeks.

A 69-year-old woman presented to the hospital with a 3-month history of fever of unknown origin and dyspnea. Her medical history included diabetes mellitus and, many years ago, partially treated latent tuberculosis infection and pancreatic cancer, treated with Whipple surgery and chemotherapy.

Radiography (Figure 1) and computed tomography of the chest (Figure 2) revealed diffuse reticulonodular infiltrates. Initial cultures of blood and bronchoalveolar lavage fluid were negative for viral, fungal, bacterial, and mycobacterial infection. Transbronchial biopsy specimens showed necrotizing granulomas, which stained negative for acid-fast bacilli and fungus. Study of specimens obtained via open lung biopsy showed granulomatous infiltration with no yeast, fungal elements, or acid-fast bacilli. An interferon-gamma-release assay for Mycobacterium tuberculosis and serologic testing for human immunodeficiency virus (HIV) were negative.

Glucocorticoid treatment was started for presumed sarcoidosis, and a broad-spectrum antibiotic was also started; however, her condition deteriorated, and she developed seizures. Magnetic resonance imaging of the brain showed widespread 2- to 5-mm enhancing lesions (Figure 3). Cerebrospinal fluid studies revealed lymphocytic pleocytosis with a low level of glucose (34 mg/dL) and a high level of protein (174 mg/dL). She was subsequently transferred to our tertiary care center.

Q: What is the most likely diagnosis?

• Sarcoidosis of the lungs and central nervous system
• Hypersensitivity pneumonitis
• Miliary tuberculosis
• Cancer with pulmonary and brain metastases
• Disseminated fungal infection

A: The correct diagnosis is miliary tuberculosis, ie, progressive and widely disseminated hematogenous tuberculosis infection. Granulomas involving multiple organs suggested a broad differential diagnosis. The negative workup for infectious disease initially supported sarcoidosis by exclusion, but her condition failed to respond to steroid treatment. Multiple organ involvement is atypical for hypersensitivity pneumonitis, and antibody panels were negative. The absence of malignant cells in multiple biopsy specimens made metastasis unlikely.

Her remote history of partially treated latent tuberculosis infection raised our clinical suspicion and prompted mycobacterial antibiotic coverage. Three weeks after the initial sample collection, results from an independent laboratory revealed the presence of acid-fast bacilli in cultures of bronchoalveolar lavage fluid, cerebrospinal fluid, and blood, which were confirmed to be M tuberculosis. Despite treatment, the patient died of multiple organ failure.

Tuberculosis is rare in the United States, with 11,181 reported cases in 2010.¹ Miliary tuberculosis is associated with malnutrition, HIV infection, AIDS, alcoholism, diabetes, chronic kidney failure, immunosuppressive drugs, and organ transplantation.² Acid-fast bacilli smears and cultures confirm the diagnosis but have low sensitivity.³ Granulomas characterize miliary tuberculosis histopathologically. They may be present in sarcoidosis, hypersensitivity pneumonitis, and fungal infection but are not specific for these conditions. Tuberculin skin testing² and interferon-gamma-release assay can be falsely negative in immunosuppressed patients,⁴ highlighting the emphasis on clinical suspicion. The estimated death rate is 20%,^3,5 with central nervous system involvement being an independent predictor.⁵ Empiric therapy should not be delayed, as culture results may not be available for 6 to 8 weeks.

A 21-year-old woman with Crohn disease presented to the hospital after 5 days of diffuse abdominal pain, nausea, vomiting, and watery diarrhea despite taking azathioprine (Imuran) 100 mg daily as maintenance therapy. She had been hospitalized 2 weeks previously at another hospital for a Crohn disease flare, which was treated with intravenous methylprednisolone (Solu-Medrol).

On admission to our hospital, her temperature was 38.4°C (101.1°F), heart rate 78 per minute, respiratory rate 18 per minute, blood pressure 110/50 mm Hg, and oxygen saturation 98% while breathing room air. She had diffuse abdominal tenderness without rebound tenderness.

Results of laboratory studies, including a complete blood cell count, basic metabolic panel, and liver enzymes were within normal limits and had not changed from her usual values. Computed tomography of the abdomen and pelvis showed diffuse inflammation extending from the ileum to the proximal descending colon (Figure 1).

Because Clostridium difficile has a high prevalence in our hospital, treament for C difficile diarrhea was started empirically directly upon hospital admission; it was stopped 48 hours later when stool cultures came back negative for C difficile.

On colonoscopy, extensive mucosal ulcerations in the descending colon were noted (Figure 2). Biopsy specimens of the mucosal ulcers showed the characteristic “owl’s eye” inclusions of cytomegalovirus (CMV) infection on hematoxylin-eosin staining (Figure 3), and immunostaining confirmed it (Figure 4).

The patient was treated with intravenous ganciclovir (Cytovene), which resolved the colitis and the clinical symptoms after 2 weeks. Polymerase chain reaction testing of the blood confirmed the presence of CMV DNA.

At 1 year of follow-up, she had not had a relapse of infection despite long-term treatment with immunomodulators.

COLITIS AND CYTOMEGALOVIRUS INFECTION

CMV colitis is common in patients with inflammatory bowel disease (ie, Crohn disease or ulcerative colitis) who are on long-term immunosuppressive therapy. Heightened suspicion for it is needed when treating patients with inflammatory bowel disease, as they tend to present with atypical symptoms and signs.

It is also important to keep a wide differential diagnosis in mind, as acute fever and diarrhea in patients with inflammatory bowel disease are not always related to the underlying disease. In these patients, a variety of diagnostic tests may be necessary to exclude an opportunistic infection and an unrelated intercurrent illness.

Human CMV is a member of the family of herpes viruses, which persist for life after a primary infection. In exacerbations of inflammatory bowel disease, it is not clear whether CMV is a nonpathogenic bystander or a true pathogen.¹ Most CMV infections in patients with inflammatory bowel disease are due to reactivation of the virus, as levels of inflammatory cytokines such as tumor necrosis factor are increased in the intestinal mucosa in active inflammatory bowel disease, and these cytokines are known to trigger reactivation.²

In patients with chronic inflammatory bowel disease, CMV colitis usually presents with abdominal pain, diarrhea, intestinal bleeding, and fever. The gold standard for diagnosis is immunohistochemical testing of colon biopsy samples using monoclonal antibodies against CMV. Owl’s eye inclusion bodies on histopathologic sections are highly specific for CMV infection. Other diagnostic studies include endoscopy and serologic testing.

The gastrointestinal tract is thought to contain latent CMV after a primary infection, and long-term treatment with immunomodulatory drugs such as azathioprine and corticosteroids can cause local reactivation of the latent virus.³

CMV infection in patients with inflammatory bowel disease is associated with poor outcomes, such as the need for colectomy.⁴ The prevalence of CMV infection in patients with inflammatory bowel disease has been reported as 5% to 36%, and higher in patients with disease refractory to steroid therapy.^1,5

When a patient with inflammatory bowel disease is diagnosed with CMV infection, the immunomodulatory drugs should be stopped and the corticosteroids should be tapered to the lowest possible dose. Treatment of the infection is intravenous ganciclovir at 5 mg per kilogram of body weight twice daily for 14 days, followed by oral valacyclovir (Valtrex) 450 mg twice daily for 4 weeks.

After receiving intravenous ganciclovir for 14 days, our patient received oral valacyclovir (Valtrex) 450 mg twice daily for 4 weeks. Her azathioprine was stopped while she was taking the antivirals, and it was resumed the day after she completed the course of valacyclovir.

The response to treatment is monitored with a cytomegalovirus pp 65 antigenemia assay. Immunomodulatory therapy can be reintroduced slowly if needed.

A 21-year-old woman with Crohn disease presented to the hospital after 5 days of diffuse abdominal pain, nausea, vomiting, and watery diarrhea despite taking azathioprine (Imuran) 100 mg daily as maintenance therapy. She had been hospitalized 2 weeks previously at another hospital for a Crohn disease flare, which was treated with intravenous methylprednisolone (Solu-Medrol).

On admission to our hospital, her temperature was 38.4°C (101.1°F), heart rate 78 per minute, respiratory rate 18 per minute, blood pressure 110/50 mm Hg, and oxygen saturation 98% while breathing room air. She had diffuse abdominal tenderness without rebound tenderness.

Results of laboratory studies, including a complete blood cell count, basic metabolic panel, and liver enzymes were within normal limits and had not changed from her usual values. Computed tomography of the abdomen and pelvis showed diffuse inflammation extending from the ileum to the proximal descending colon (Figure 1).

Because Clostridium difficile has a high prevalence in our hospital, treament for C difficile diarrhea was started empirically directly upon hospital admission; it was stopped 48 hours later when stool cultures came back negative for C difficile.

On colonoscopy, extensive mucosal ulcerations in the descending colon were noted (Figure 2). Biopsy specimens of the mucosal ulcers showed the characteristic “owl’s eye” inclusions of cytomegalovirus (CMV) infection on hematoxylin-eosin staining (Figure 3), and immunostaining confirmed it (Figure 4).

The patient was treated with intravenous ganciclovir (Cytovene), which resolved the colitis and the clinical symptoms after 2 weeks. Polymerase chain reaction testing of the blood confirmed the presence of CMV DNA.

At 1 year of follow-up, she had not had a relapse of infection despite long-term treatment with immunomodulators.

COLITIS AND CYTOMEGALOVIRUS INFECTION

CMV colitis is common in patients with inflammatory bowel disease (ie, Crohn disease or ulcerative colitis) who are on long-term immunosuppressive therapy. Heightened suspicion for it is needed when treating patients with inflammatory bowel disease, as they tend to present with atypical symptoms and signs.

It is also important to keep a wide differential diagnosis in mind, as acute fever and diarrhea in patients with inflammatory bowel disease are not always related to the underlying disease. In these patients, a variety of diagnostic tests may be necessary to exclude an opportunistic infection and an unrelated intercurrent illness.

Human CMV is a member of the family of herpes viruses, which persist for life after a primary infection. In exacerbations of inflammatory bowel disease, it is not clear whether CMV is a nonpathogenic bystander or a true pathogen.¹ Most CMV infections in patients with inflammatory bowel disease are due to reactivation of the virus, as levels of inflammatory cytokines such as tumor necrosis factor are increased in the intestinal mucosa in active inflammatory bowel disease, and these cytokines are known to trigger reactivation.²

In patients with chronic inflammatory bowel disease, CMV colitis usually presents with abdominal pain, diarrhea, intestinal bleeding, and fever. The gold standard for diagnosis is immunohistochemical testing of colon biopsy samples using monoclonal antibodies against CMV. Owl’s eye inclusion bodies on histopathologic sections are highly specific for CMV infection. Other diagnostic studies include endoscopy and serologic testing.

The gastrointestinal tract is thought to contain latent CMV after a primary infection, and long-term treatment with immunomodulatory drugs such as azathioprine and corticosteroids can cause local reactivation of the latent virus.³

CMV infection in patients with inflammatory bowel disease is associated with poor outcomes, such as the need for colectomy.⁴ The prevalence of CMV infection in patients with inflammatory bowel disease has been reported as 5% to 36%, and higher in patients with disease refractory to steroid therapy.^1,5

When a patient with inflammatory bowel disease is diagnosed with CMV infection, the immunomodulatory drugs should be stopped and the corticosteroids should be tapered to the lowest possible dose. Treatment of the infection is intravenous ganciclovir at 5 mg per kilogram of body weight twice daily for 14 days, followed by oral valacyclovir (Valtrex) 450 mg twice daily for 4 weeks.

After receiving intravenous ganciclovir for 14 days, our patient received oral valacyclovir (Valtrex) 450 mg twice daily for 4 weeks. Her azathioprine was stopped while she was taking the antivirals, and it was resumed the day after she completed the course of valacyclovir.

The response to treatment is monitored with a cytomegalovirus pp 65 antigenemia assay. Immunomodulatory therapy can be reintroduced slowly if needed.

A 21-year-old woman with Crohn disease presented to the hospital after 5 days of diffuse abdominal pain, nausea, vomiting, and watery diarrhea despite taking azathioprine (Imuran) 100 mg daily as maintenance therapy. She had been hospitalized 2 weeks previously at another hospital for a Crohn disease flare, which was treated with intravenous methylprednisolone (Solu-Medrol).

On admission to our hospital, her temperature was 38.4°C (101.1°F), heart rate 78 per minute, respiratory rate 18 per minute, blood pressure 110/50 mm Hg, and oxygen saturation 98% while breathing room air. She had diffuse abdominal tenderness without rebound tenderness.

Results of laboratory studies, including a complete blood cell count, basic metabolic panel, and liver enzymes were within normal limits and had not changed from her usual values. Computed tomography of the abdomen and pelvis showed diffuse inflammation extending from the ileum to the proximal descending colon (Figure 1).

Because Clostridium difficile has a high prevalence in our hospital, treament for C difficile diarrhea was started empirically directly upon hospital admission; it was stopped 48 hours later when stool cultures came back negative for C difficile.

On colonoscopy, extensive mucosal ulcerations in the descending colon were noted (Figure 2). Biopsy specimens of the mucosal ulcers showed the characteristic “owl’s eye” inclusions of cytomegalovirus (CMV) infection on hematoxylin-eosin staining (Figure 3), and immunostaining confirmed it (Figure 4).

The patient was treated with intravenous ganciclovir (Cytovene), which resolved the colitis and the clinical symptoms after 2 weeks. Polymerase chain reaction testing of the blood confirmed the presence of CMV DNA.

At 1 year of follow-up, she had not had a relapse of infection despite long-term treatment with immunomodulators.

COLITIS AND CYTOMEGALOVIRUS INFECTION

CMV colitis is common in patients with inflammatory bowel disease (ie, Crohn disease or ulcerative colitis) who are on long-term immunosuppressive therapy. Heightened suspicion for it is needed when treating patients with inflammatory bowel disease, as they tend to present with atypical symptoms and signs.

It is also important to keep a wide differential diagnosis in mind, as acute fever and diarrhea in patients with inflammatory bowel disease are not always related to the underlying disease. In these patients, a variety of diagnostic tests may be necessary to exclude an opportunistic infection and an unrelated intercurrent illness.

Human CMV is a member of the family of herpes viruses, which persist for life after a primary infection. In exacerbations of inflammatory bowel disease, it is not clear whether CMV is a nonpathogenic bystander or a true pathogen.¹ Most CMV infections in patients with inflammatory bowel disease are due to reactivation of the virus, as levels of inflammatory cytokines such as tumor necrosis factor are increased in the intestinal mucosa in active inflammatory bowel disease, and these cytokines are known to trigger reactivation.²

In patients with chronic inflammatory bowel disease, CMV colitis usually presents with abdominal pain, diarrhea, intestinal bleeding, and fever. The gold standard for diagnosis is immunohistochemical testing of colon biopsy samples using monoclonal antibodies against CMV. Owl’s eye inclusion bodies on histopathologic sections are highly specific for CMV infection. Other diagnostic studies include endoscopy and serologic testing.

The gastrointestinal tract is thought to contain latent CMV after a primary infection, and long-term treatment with immunomodulatory drugs such as azathioprine and corticosteroids can cause local reactivation of the latent virus.³

CMV infection in patients with inflammatory bowel disease is associated with poor outcomes, such as the need for colectomy.⁴ The prevalence of CMV infection in patients with inflammatory bowel disease has been reported as 5% to 36%, and higher in patients with disease refractory to steroid therapy.^1,5

When a patient with inflammatory bowel disease is diagnosed with CMV infection, the immunomodulatory drugs should be stopped and the corticosteroids should be tapered to the lowest possible dose. Treatment of the infection is intravenous ganciclovir at 5 mg per kilogram of body weight twice daily for 14 days, followed by oral valacyclovir (Valtrex) 450 mg twice daily for 4 weeks.

After receiving intravenous ganciclovir for 14 days, our patient received oral valacyclovir (Valtrex) 450 mg twice daily for 4 weeks. Her azathioprine was stopped while she was taking the antivirals, and it was resumed the day after she completed the course of valacyclovir.

The response to treatment is monitored with a cytomegalovirus pp 65 antigenemia assay. Immunomodulatory therapy can be reintroduced slowly if needed.

The New Year prompts us to think about where we are going and where we have come from. Our thoughts of the future of medicine in the United States are dominated by rancorous debates about health care delivery and alternative payment schemes. Some dialogues are between serious students of health care systems, but the most audible are between self-declared pundits, many with limited practical knowledge of the physician’s perspective, doctor-patient relationships, or the complicated and cascading ways that federally funded medical education directly affects health care. Discussions about the future of medicine, even among physicians, are often filled with sound bites rather than citation of solid data.

The article on soft-tissue infections in this issue of the Journal by Dr. Sabitha Rajan made me reflect on the relentless march of biology. Pathogens continue to evolve, influenced by human behavior but untouched by self-promoting and partisan dialogue and undaunted by doubting politicians. Several years ago, we could assume that most skin pathogens would readily be controlled by normal body defenses, a few requiring cephalosporin therapy and even fewer needing surgical intervention. But now, environmental pressures, including the zealous use of antibiotics, have altered the microbiology of skin infections. This requires new choices for empiric antibiotic therapy of these infections. With more than just altered susceptibility profiles, these bugs exhibit biologic behaviors distinct from their historic predecessors. The “spider bite” lesion of MRSA and the scarily rapid advance of certain streptococcal infections across tissue planes mandate prompt recognition by astute clinicians—the physical examination still matters.

The brisk evolutionary pace of this new range of infections stokes the urgent need to rapidly develop novel antibiotics, a process caught smack in the middle of our pundits’ political debates. Will the development of drugs for uncommon but serious infections be underwritten by the government, or will companies be required to bear the full expense of developing drugs under the scrutiny of the FDA? Will they then be pressed to price them “affordably” or price them to recoup estimated development costs, only to have payors list them as “third-tier” on the formulary, thus making them unaffordable to many patients? Our ability to medically confront this evolution will be directly affected by the outcome of the current political debate. Will all patients be able to easily access medical care so that early significant infections are recognized for what they are, and will the new antibiotics required for appropriate treatment be affordable? This year is going to be an interesting one.

So, as empiric therapy with cephalexin changes to clindamycin and 2011 rolls into 2012, I and our editorial staff offer our sincere wishes for a healthy, happy, and especially a peaceful New Year.

The New Year prompts us to think about where we are going and where we have come from. Our thoughts of the future of medicine in the United States are dominated by rancorous debates about health care delivery and alternative payment schemes. Some dialogues are between serious students of health care systems, but the most audible are between self-declared pundits, many with limited practical knowledge of the physician’s perspective, doctor-patient relationships, or the complicated and cascading ways that federally funded medical education directly affects health care. Discussions about the future of medicine, even among physicians, are often filled with sound bites rather than citation of solid data.

The article on soft-tissue infections in this issue of the Journal by Dr. Sabitha Rajan made me reflect on the relentless march of biology. Pathogens continue to evolve, influenced by human behavior but untouched by self-promoting and partisan dialogue and undaunted by doubting politicians. Several years ago, we could assume that most skin pathogens would readily be controlled by normal body defenses, a few requiring cephalosporin therapy and even fewer needing surgical intervention. But now, environmental pressures, including the zealous use of antibiotics, have altered the microbiology of skin infections. This requires new choices for empiric antibiotic therapy of these infections. With more than just altered susceptibility profiles, these bugs exhibit biologic behaviors distinct from their historic predecessors. The “spider bite” lesion of MRSA and the scarily rapid advance of certain streptococcal infections across tissue planes mandate prompt recognition by astute clinicians—the physical examination still matters.

The brisk evolutionary pace of this new range of infections stokes the urgent need to rapidly develop novel antibiotics, a process caught smack in the middle of our pundits’ political debates. Will the development of drugs for uncommon but serious infections be underwritten by the government, or will companies be required to bear the full expense of developing drugs under the scrutiny of the FDA? Will they then be pressed to price them “affordably” or price them to recoup estimated development costs, only to have payors list them as “third-tier” on the formulary, thus making them unaffordable to many patients? Our ability to medically confront this evolution will be directly affected by the outcome of the current political debate. Will all patients be able to easily access medical care so that early significant infections are recognized for what they are, and will the new antibiotics required for appropriate treatment be affordable? This year is going to be an interesting one.

So, as empiric therapy with cephalexin changes to clindamycin and 2011 rolls into 2012, I and our editorial staff offer our sincere wishes for a healthy, happy, and especially a peaceful New Year.

The New Year prompts us to think about where we are going and where we have come from. Our thoughts of the future of medicine in the United States are dominated by rancorous debates about health care delivery and alternative payment schemes. Some dialogues are between serious students of health care systems, but the most audible are between self-declared pundits, many with limited practical knowledge of the physician’s perspective, doctor-patient relationships, or the complicated and cascading ways that federally funded medical education directly affects health care. Discussions about the future of medicine, even among physicians, are often filled with sound bites rather than citation of solid data.

The article on soft-tissue infections in this issue of the Journal by Dr. Sabitha Rajan made me reflect on the relentless march of biology. Pathogens continue to evolve, influenced by human behavior but untouched by self-promoting and partisan dialogue and undaunted by doubting politicians. Several years ago, we could assume that most skin pathogens would readily be controlled by normal body defenses, a few requiring cephalosporin therapy and even fewer needing surgical intervention. But now, environmental pressures, including the zealous use of antibiotics, have altered the microbiology of skin infections. This requires new choices for empiric antibiotic therapy of these infections. With more than just altered susceptibility profiles, these bugs exhibit biologic behaviors distinct from their historic predecessors. The “spider bite” lesion of MRSA and the scarily rapid advance of certain streptococcal infections across tissue planes mandate prompt recognition by astute clinicians—the physical examination still matters.

The brisk evolutionary pace of this new range of infections stokes the urgent need to rapidly develop novel antibiotics, a process caught smack in the middle of our pundits’ political debates. Will the development of drugs for uncommon but serious infections be underwritten by the government, or will companies be required to bear the full expense of developing drugs under the scrutiny of the FDA? Will they then be pressed to price them “affordably” or price them to recoup estimated development costs, only to have payors list them as “third-tier” on the formulary, thus making them unaffordable to many patients? Our ability to medically confront this evolution will be directly affected by the outcome of the current political debate. Will all patients be able to easily access medical care so that early significant infections are recognized for what they are, and will the new antibiotics required for appropriate treatment be affordable? This year is going to be an interesting one.

So, as empiric therapy with cephalexin changes to clindamycin and 2011 rolls into 2012, I and our editorial staff offer our sincere wishes for a healthy, happy, and especially a peaceful New Year.

Skin and soft-tissue infections (SSTIs) are a common reason for presentation to outpatient practices, emergency rooms, and hospitals.^1–5 They account for more than 14 million outpatient visits in the United States each year,¹ and visits to the emergency room and admissions to the hospital for them are increasing.^2,3 Hospital admissions for SSTIs increased by 29% from 2000 to 2004.³

MORE MRSA NOW, BUT STREPTOCOCCI ARE STILL COMMON

The increase in hospital admissions for SSTIs has been attributed to a rising number of infections with methicillin-resistant Staphylococcus aureus (MRSA).^3–5

In addition, strains once seen mostly in the community and other strains that were associated with health care are now being seen more often in both settings. Clinical characteristics do not differ between community-acquired and health-care-associated MRSA, and therefore the distinction between the two is becoming less useful in guiding empiric therapy.^6,7

After steadily increasing for several years, the incidence of MRSA has recently stabilized. The US Centers for Disease Control and Prevention maintains a surveillance program and a Web site on MRSA.⁸

At the same time, infections with group A, B, C, or G streptococci continue to be common. The SENTRY Antimicrobial Surveillance Program for the United States and Canada collected data from medical centers in five Canadian provinces and 32 US states between 1998 and 2004. The data set represents mostly complicated infections (see below). Staphylococcus was the most commonly retrieved organism (Table 1).⁹ However, streptococci were likely underrepresented, since mild or superficial streptococcal cellulitis may not require hospital admission, and positive cultures can be difficult to obtain in streptococcal infection.

COMPLICATED OR UNCOMPLICATED

Complicated skin and skin structure infections is a relatively new term coined in a 1998 US Food and Drug Administration (FDA) guideline for industry on developing antimicrobial drugs.¹⁰ Subsequent trials of antibiotics and reviews of skin infections used the guideline and its definitions. However, the category of complicated skin infections contained widely disparate clinical entities ranging from deep decubitus ulcers to diabetic foot infections (Table 2).¹⁰

The intent of the 1998 guideline was to provide not a clinical framework but rather a guide for industry in designing trials that would include similar groups of infections and therefore be relevant when compared with each other. In 2008, the Anti-Infective Drugs Advisory Committee was convened,¹¹ and subsequently, in August 2010, the FDA released a revision of the guide.¹²

The revised guidelines specifically exclude many diagnoses, such as bite wounds, bone and joint infections, necrotizing fasciitis, diabetic foot infections, decubitus ulcers, catheter site infections, myonecrosis, and ecthyma gangrenosum. Notably, the word “bacterial” in the title excludes mycobacterial and fungal infections from consideration. The diagnoses that are included include cellulitis, erysipelas, major cutaneous abscess, and burn infections. These are further specified to include 75 cm² of redness, edema, or induration to standardize the extent of the infection—ie, the infection has to be at least this large or else it is not “complicated.”

The terms “complicated” and “uncomplicated” skin and skin structure infections persist and can be useful adjuncts in describing SSTIs.^13–16 However, more specific descriptions of SSTIs based on pathogenesis are more useful to the clinician and are usually the basis for guidelines, such as for preventing surgical site infections or for reducing amputations in diabetic foot infections.

This review will focus on the general categories of SSTI and will not address surgical site infections, pressure ulcers, diabetic foot infections, perirectal wounds, or adjuvant therapies in severe SSTIs, such as negative pressure wound care (vacuum-assisted closure devices) and hyperbaric chambers.

OTHER DISEASES CAN MIMIC SSTIs

SSTIs vary broadly in their location and severity.

Although the classic presentation of erythema, warmth, edema, and tenderness often signals infection, other diseases can mimic SSTIs. Common ones that should be included in the differential diagnosis include gout, thrombophlebitis, deep vein thrombosis, contact dermatitis, carcinoma erysipeloides, drug eruption, and a foreign body reaction.^17,18

CLUES FROM THE HISTORY

Specific exposures. A detailed history can point to possible organisms and appropriate therapy. Table 3 lists several risk factors or exposures that may be elicited in the history and the pathogens they suggest.¹⁴

Wounds. Skin infections are usually precipitated by a break in the skin from a cut, laceration, excoriation, fungal infection, insect or animal bite, or puncture wound.

Impaired response. Patients with diabetes, renal failure, cirrhosis, chronic glucocorticoid use, history of organ transplantation, chronic immunosuppressive therapy, HIV infection, or malnourishment have impaired host responses to infection and are at risk for both more severe infections and recurrent infections. Immunocompromised hosts may also have atypical infections with opportunistic organisms such as Pseudomonas, Proteus, Serratia, Enterobacter, Citrobacter, and anaerobes. Close follow-up of these patients is warranted to ascertain appropriate response to therapy.¹⁹

Surgery that includes lymph node dissection or saphenous vein resection for coronary artery bypass can lead to impaired lymphatic drainage and edema, and therefore predisposes patients to SSTIs.

 

PHYSICAL EXAMINATION

The physical examination should include descriptions of the extent and location of erythema, edema, warmth, and tenderness so that progression or resolution with treatment can be followed in detail.

Crepitus can be felt in gas-forming infections and raises the concern for necrotizing fasciitis and infection with anaerobic organisms such as Clostridium perfringens.

Necrosis can occur in brown recluse spider bites, venous snake bites, or group A streptococcal infections.

Fluctuance indicates fluid and a likely abscess that may need incision and drainage.

Purpura may be present in patients on anticoagulation therapy, but if it is accompanying an SSTI, it also raises the concern for the possibility of sepsis and disseminated intravascular coagulation, especially from streptococcal infections.

Bullae can be seen in impetigo caused by staphylococci or in infection with Vibrio vulnificus or Streptococcus pneumoniae.¹⁹

Systemic signs, in addition to fever, can include hypotension and tachycardia, which would prompt closer monitoring and possible hospitalization.

Lymphangitic spread also indicates severe infection.

Depth of infection. Figure 1 depicts the possible depths of involvement of SSTIs and the accompanying diagnoses. Superficial infections such as erysipelas, impetigo, folliculitis, furuncles, and carbuncles are located at the epidermal layer, while cellulitis reaches into the dermis. Deeper infections cross the subcutaneous tissue and become fasciitis or myonecrosis.¹⁵ However, the depth of infection is difficult to discern on examination; laboratory studies can help with this assessment.²⁰

LABORATORY STUDIES

Simple, localized SSTIs usually do not require laboratory evaluation. Jenkins et al²¹ recently demonstrated that by using an algorithm for the management of hospitalized patients with cellulitis or cutaneous abscess, they could decrease resource utilization, including laboratory testing, without adversely affecting clinical outcome.

If patients have underlying disease or more extensive infection, then baseline chemistry values, a complete blood cell count, and the C-reactive protein level should be acquired.¹⁹ Laboratory findings that suggest more severe disease include low sodium, low bicarbonate (or an anion gap), and high creatinine levels; new anemia; a high or very low white blood cell count; and a high C-reactive protein level. A high C-reactive protein level has been associated with longer hospitalization.²²

A score to estimate the risk of necrotizing fasciitis

Laboratory values should be used to calculate the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score (Table 4).^20,23 Points are allocated for high C-reactive protein, creatinine, glucose, and white blood cell count values and for low red blood cell counts and sodium levels. Patients with a score of five points or less are considered at low risk, while those with six or more points are considered to be at least at intermediate risk of necrotizing fasciitis.

This tool was developed retrospectively but has been validated prospectively. It has a high sensitivity and a positive predictive value of 92% in patients with a score of six points or more. Its specificity is also high, with a negative predictive value of 96%.^20,24

Necrotizing fasciitis has a mortality rate of 23.5%, but this may be reduced to 10% with early detection and prompt surgical intervention.¹⁵ Since necrotizing fasciitis is very difficult to diagnose, clinicians must maintain a high level of suspicion and use the LRINEC score to trigger early surgical evaluation. Surgical exploration is the only way to definitively diagnose necrotizing fasciitis.

Blood cultures in some cases

Blood cultures have a low yield and are usually not cost-effective, but they should be obtained in patients who have lymphedema, immune deficiency, fever, pain out of proportion to the findings on examination, tachycardia, or hypotension, as blood cultures are more likely to be positive in more serious infections and can help guide antimicrobial therapy. Blood cultures are also recommended in patients with infections involving specific anatomic sites, such as the mouth and eyes.¹⁹

Aspiration, swabs, incision and drainage

Fluid aspirated from abscesses and swabs of debrided ulcerated wounds should be sent for Gram stain and culture. Gram stain and culture have widely varying yields, from less than 5% to 40%, depending on the source and technique.¹⁹ Cultures were not routinely obtained before MRSA emerged, but knowing antimicrobial susceptibility is now important to guide antibiotic therapy. Unfortunately, in cellulitis, swabs and aspirates of the leading edge have a low yield of around 10%.²⁵ One prospective study of 25 hospitalized patients did report a higher yield of positive cultures in patients with fever or underlying disease,²⁶ so aspirates may be used in selected cases. In small studies, the yield of punch biopsies was slightly better than that of needle aspirates and was as high as 20% to 30%.²⁷

 

IMAGING STUDIES

Imaging can be helpful in determining the depth of involvement. Plain radiography can reveal gas or periosteal inflammation and is especially helpful in diabetic foot infections. Ultrasonography can detect abscesses.

Both magnetic resonance imaging (MRI) and computed tomography (CT) are useful to image fascial planes, although MRI is more sensitive. However, in cases of suspected necrotizing fasciitis, imaging should not delay surgical evaluation and debridement or be used as the definitive study. Therefore, the practicality of CT and MRI can be limited.^15,16

ANTIMICROBIAL TREATMENT FOR SSTIs IN OUTPATIENTS

An electronic poll conducted by the New England Journal of Medicine in 2008 revealed broad differences in how physicians treat SSTIs.²⁸ The Infectious Diseases Society of America released guidelines for treating MRSA in SSTIs in January 2011 (Table 5).²⁷

For minor skin infections such as impetigo and secondarily infected skin lesions such as eczema, ulcers, or lacerations, mupirocin 2% topical ointment (Bactroban) can be effective.²⁷

For a simple abscess or boil, incision and drainage is the primary treatment, and antibiotics are not needed.

For a complicated abscess or boil. Patients should be given oral or intravenous antibiotic therapy to cover MRSA and, depending on the severity, should be considered for hospitalization if the abscess is associated with severe disease, rapid progression in the presence of associated cellulitis, septic phlebitis, constitutional symptoms, comorbidity (including immunosuppression), or an abscess or boil in an area difficult to drain, such as the face, hands, or genitalia.²⁷

For purulent cellulitis in outpatients, empiric therapy for community-acquired MRSA is recommended, pending culture results. Empiric therapy for streptococcal infection is likely unnecessary. For empiric coverage of community-acquired MRSA in purulent cellulitis, oral antibiotic options include clindamycin (Cleocin), trimethoprim-sulfamethoxazole (Bactrim), doxycycline (Doryx), minocycline (Minocin), and linezolid (Zyvox).

For nonpurulent cellulitis in outpatients, empiric coverage for beta-hemolytic streptococci is warranted. Coverage for community-acquired MRSA should subsequently be added for patients who do not respond to beta-lactam therapy within 48 to 72 hours or who have chills, fever, a new abscess, increasing erythema, or uncontrolled pain.

Options for coverage of both beta-hemolytic streptococci and community-acquired MRSA for outpatient therapy include clindamycin on its own, trimethoprim-sulfamethoxazole or a tetracycline in combination with a beta-lactam, or linezolid on its own.

Increasing rates of resistance to clindamycin, tetracycline, and trimethoprim-sulfamethoxazole in community-acquired MRSA may limit empiric treatment. In areas where resistance is prevalent, culture with antimicrobial susceptibility testing may be required before starting one of these antibiotics.

The use of rifampin (Rifadin) as a single agent is not recommended because resistance is likely to develop. Also, rifampin is not useful as adjunctive therapy, as evidence does not support its efficacy.^19,27,29

ANTIMICROBIAL TREATMENT FOR SSTIs IN HOSPITALIZED PATIENTS

For hospitalized patients with a complicated or severe SSTI, empiric therapy for MRSA should be started pending culture results. FDA-approved options are vancomycin, linezolid, daptomycin (Cubicin), tigecycline (Tygacil), and telavancin (Vibativ). Data on clindamycin are very limited in this population. A beta-lactam antibiotic such as cefazolin (Ancef) may be considered in hospitalized patients with nonpurulent cellulitis, and the regimen can be modified to MRSA-active therapy if there is no clinical response. Linezolid, daptomycin, vancomycin, and telavancin have adequate streptococcal coverage in addition to MRSA coverage.

Clindamycin is approved by the FDA for treating serious infections due to S aureus. It has excellent tissue penetration, particularly in bone and abscesses.

Clindamycin resistance in staphylococci can be either constitutive or inducible, and clinicians must be watchful for signs of resistance.

Diarrhea is the most common adverse effect and occurs in up to 20% of patients. Clostridium difficile colitis may occur more frequently with clindamycin than with other oral agents, but it has also has been reported with fluoroquinolones and can be associated with any antibiotic therapy.³⁰

Trimethoprim-sulfamethoxazole is not FDA-approved for treating any staphylococcal infection. However, because 95% to 100% of community-acquired MRSA strains are susceptible to it in vitro, it has become an important option in the outpatient treatment of SSTIs. Caution is advised when using it in elderly patients, particularly those with chronic renal insufficiency, because of an increased risk of hyperkalemia.

Tetracyclines. Doxycycline is FDA-approved for treating SSTIs due to S aureus, although not specifically for MRSA. Minocycline may be an option even when strains are resistant to doxycycline, since it does not induce its own resistance as doxycycline does.

Tigecycline is a glycylcycline (a tetracycline derivative) and is FDA-approved in adults for complicated SSTIs and intra-abdominal infections. It has a large volume of distribution and achieves high concentrations in tissues and low concentrations in serum.

The FDA recently issued a warning to consider alternative agents in patients with serious infections because of higher rates of all-cause mortality noted in phase III and phase IV clinical trials. Due to this warning and the availability of multiple alternatives active against MRSA, tigecycline was not included in the Infectious Diseases Society of America guidelines.³¹

Linezolid is a synthetic oxazolidinone and is FDA-approved for treating SSTIs and nosocomial pneumonia caused by MRSA. It has 100% oral bioavailability, so parenteral therapy should only be given if there are problems with gastrointestinal absorption or if the patient is unable to take oral medications.

Long-term use of linezolid (> 2 weeks) is limited by hematologic toxicity, especially thrombocytopenia, which occurs more frequently than anemia and neutropenia. Lactic acidosis and peripheral and optic neuropathy are also limiting toxicities. Although myelosuppression is generally reversible, peripheral and optic neuropathy may not be.

Linezolid should not used in patients taking selective serotonin reuptake inhibitors if they cannot stop taking these antidepressant drugs during therapy, as the combination can lead to the serotonin syndrome.

Vancomycin is still the mainstay of parenteral therapy for MRSA infections. However, its efficacy has come into question, with concerns over its slow bactericidal activity and the emergence of resistant strains. The rate of treatment failure is high in those with infection caused by MRSA having minimum inhibitory concentrations of 1 μg/mL or greater. Vancomycin kills staphylococci more slowly than do beta-lactams in vitro and is clearly inferior to beta-lactams for methicillin-sensitive S aureus bacteremia.

Daptomycin is a lipopeptide antibiotic that is FDA-approved for adults with MRSA bacteremia, right-sided infective endocarditis, and complicated SSTI. Elevations in creatinine phosphokinase, which are rarely treatment-limiting, have occurred in patients receiving 6 mg/kg/day but not in those receiving 4 mg/kg/day. Patients should be observed for development of muscle pain or weakness and should have their creatine phosphokinase levels checked weekly, with more frequent monitoring in those with renal insufficiency or who are receiving concomitant statin therapy.

Telavancin is a parenteral lipoglycopeptide that is bactericidal against MRSA. It is FDA-approved for complicated SSTIs in adults. Creatinine levels should be monitored, and the dosage should be adjusted on the basis of creatinine clearance, because nephrotoxicity was more commonly reported among individuals treated with telavancin than among those treated with vancomycin.

Ceftaroline (Teflaro), a fifth-generation cephalosporin, was approved for SSTIs by the FDA in October 2010. It is active against MRSA and gram-negative pathogens.

Cost is a consideration

Cost is a consideration, as it may limit the availability of and access to treatment. In 2008, the expense for 10 days of treatment with generic vancomycin was $183, compared with $1,661 for daptomycin, $1,362 for tigecycline, and $1,560 for linezolid. For outpatient therapy, the contrast was even starker, as generic trimethoprim-sulfamethoxazole cost $9.40 and generic clindamycin cost $95.10.³²

 

INDICATIONS FOR HOSPITALIZATION

Patients who have evidence of tissue necrosis, fever, hypotension, severe pain, altered mental status, an immunocompromised state, or organ failure (respiratory, renal, or hepatic) must be hospitalized.

Although therapy for MRSA is the mainstay of empiric therapy, polymicrobial infections are not uncommon, and gram-negative and anaerobic coverage should be added as appropriate. One study revealed a longer length of stay for hospitalized patients who had inadequate initial empiric coverage.³³

Vigilance should be maintained for overlying cellulitis which can mask necrotizing fasciitis, septic joints, or osteomyelitis.

Perianal abscesses and infections, infected decubitus ulcers, and moderate to severe diabetic foot infections are often polymicrobial and warrant coverage for streptococci, MRSA, aerobic gram-negative bacilli, and anaerobes until culture results can guide therapy.

INDICATIONS FOR SURGICAL REFERRAL

Extensive perianal or multiple abscesses may require surgical drainage and debridement.

Surgical site infections should be referred for consideration of opening the incision for drainage.

Necrotizing infections warrant prompt aggressive surgical debridement. Strongly suggestive clinical signs include bullae, crepitus, gas on radiography, hypotension with systolic blood pressure less than 90 mm Hg, or skin necrosis. However, these are late findings, and fewer than 50% of these patients have one of these. Most cases of necrotizing fasciitis originally have an admitting diagnosis of cellulitis and cases of fasciitis are relatively rare, so the diagnosis is easy to miss.^15,16 Patients with an LRINEC score of six or more should have prompt surgical evaluation.^20,24,34,35

Skin and soft-tissue infections (SSTIs) are a common reason for presentation to outpatient practices, emergency rooms, and hospitals.^1–5 They account for more than 14 million outpatient visits in the United States each year,¹ and visits to the emergency room and admissions to the hospital for them are increasing.^2,3 Hospital admissions for SSTIs increased by 29% from 2000 to 2004.³

MORE MRSA NOW, BUT STREPTOCOCCI ARE STILL COMMON

The increase in hospital admissions for SSTIs has been attributed to a rising number of infections with methicillin-resistant Staphylococcus aureus (MRSA).^3–5

In addition, strains once seen mostly in the community and other strains that were associated with health care are now being seen more often in both settings. Clinical characteristics do not differ between community-acquired and health-care-associated MRSA, and therefore the distinction between the two is becoming less useful in guiding empiric therapy.^6,7

After steadily increasing for several years, the incidence of MRSA has recently stabilized. The US Centers for Disease Control and Prevention maintains a surveillance program and a Web site on MRSA.⁸

At the same time, infections with group A, B, C, or G streptococci continue to be common. The SENTRY Antimicrobial Surveillance Program for the United States and Canada collected data from medical centers in five Canadian provinces and 32 US states between 1998 and 2004. The data set represents mostly complicated infections (see below). Staphylococcus was the most commonly retrieved organism (Table 1).⁹ However, streptococci were likely underrepresented, since mild or superficial streptococcal cellulitis may not require hospital admission, and positive cultures can be difficult to obtain in streptococcal infection.

COMPLICATED OR UNCOMPLICATED

Complicated skin and skin structure infections is a relatively new term coined in a 1998 US Food and Drug Administration (FDA) guideline for industry on developing antimicrobial drugs.¹⁰ Subsequent trials of antibiotics and reviews of skin infections used the guideline and its definitions. However, the category of complicated skin infections contained widely disparate clinical entities ranging from deep decubitus ulcers to diabetic foot infections (Table 2).¹⁰

The intent of the 1998 guideline was to provide not a clinical framework but rather a guide for industry in designing trials that would include similar groups of infections and therefore be relevant when compared with each other. In 2008, the Anti-Infective Drugs Advisory Committee was convened,¹¹ and subsequently, in August 2010, the FDA released a revision of the guide.¹²

The revised guidelines specifically exclude many diagnoses, such as bite wounds, bone and joint infections, necrotizing fasciitis, diabetic foot infections, decubitus ulcers, catheter site infections, myonecrosis, and ecthyma gangrenosum. Notably, the word “bacterial” in the title excludes mycobacterial and fungal infections from consideration. The diagnoses that are included include cellulitis, erysipelas, major cutaneous abscess, and burn infections. These are further specified to include 75 cm² of redness, edema, or induration to standardize the extent of the infection—ie, the infection has to be at least this large or else it is not “complicated.”

The terms “complicated” and “uncomplicated” skin and skin structure infections persist and can be useful adjuncts in describing SSTIs.^13–16 However, more specific descriptions of SSTIs based on pathogenesis are more useful to the clinician and are usually the basis for guidelines, such as for preventing surgical site infections or for reducing amputations in diabetic foot infections.

This review will focus on the general categories of SSTI and will not address surgical site infections, pressure ulcers, diabetic foot infections, perirectal wounds, or adjuvant therapies in severe SSTIs, such as negative pressure wound care (vacuum-assisted closure devices) and hyperbaric chambers.

OTHER DISEASES CAN MIMIC SSTIs

SSTIs vary broadly in their location and severity.

Although the classic presentation of erythema, warmth, edema, and tenderness often signals infection, other diseases can mimic SSTIs. Common ones that should be included in the differential diagnosis include gout, thrombophlebitis, deep vein thrombosis, contact dermatitis, carcinoma erysipeloides, drug eruption, and a foreign body reaction.^17,18

CLUES FROM THE HISTORY

Specific exposures. A detailed history can point to possible organisms and appropriate therapy. Table 3 lists several risk factors or exposures that may be elicited in the history and the pathogens they suggest.¹⁴

Wounds. Skin infections are usually precipitated by a break in the skin from a cut, laceration, excoriation, fungal infection, insect or animal bite, or puncture wound.

Impaired response. Patients with diabetes, renal failure, cirrhosis, chronic glucocorticoid use, history of organ transplantation, chronic immunosuppressive therapy, HIV infection, or malnourishment have impaired host responses to infection and are at risk for both more severe infections and recurrent infections. Immunocompromised hosts may also have atypical infections with opportunistic organisms such as Pseudomonas, Proteus, Serratia, Enterobacter, Citrobacter, and anaerobes. Close follow-up of these patients is warranted to ascertain appropriate response to therapy.¹⁹

Surgery that includes lymph node dissection or saphenous vein resection for coronary artery bypass can lead to impaired lymphatic drainage and edema, and therefore predisposes patients to SSTIs.

 

PHYSICAL EXAMINATION

The physical examination should include descriptions of the extent and location of erythema, edema, warmth, and tenderness so that progression or resolution with treatment can be followed in detail.

Crepitus can be felt in gas-forming infections and raises the concern for necrotizing fasciitis and infection with anaerobic organisms such as Clostridium perfringens.

Necrosis can occur in brown recluse spider bites, venous snake bites, or group A streptococcal infections.

Fluctuance indicates fluid and a likely abscess that may need incision and drainage.

Purpura may be present in patients on anticoagulation therapy, but if it is accompanying an SSTI, it also raises the concern for the possibility of sepsis and disseminated intravascular coagulation, especially from streptococcal infections.

Bullae can be seen in impetigo caused by staphylococci or in infection with Vibrio vulnificus or Streptococcus pneumoniae.¹⁹

Systemic signs, in addition to fever, can include hypotension and tachycardia, which would prompt closer monitoring and possible hospitalization.

Lymphangitic spread also indicates severe infection.

Depth of infection. Figure 1 depicts the possible depths of involvement of SSTIs and the accompanying diagnoses. Superficial infections such as erysipelas, impetigo, folliculitis, furuncles, and carbuncles are located at the epidermal layer, while cellulitis reaches into the dermis. Deeper infections cross the subcutaneous tissue and become fasciitis or myonecrosis.¹⁵ However, the depth of infection is difficult to discern on examination; laboratory studies can help with this assessment.²⁰

LABORATORY STUDIES

Simple, localized SSTIs usually do not require laboratory evaluation. Jenkins et al²¹ recently demonstrated that by using an algorithm for the management of hospitalized patients with cellulitis or cutaneous abscess, they could decrease resource utilization, including laboratory testing, without adversely affecting clinical outcome.

If patients have underlying disease or more extensive infection, then baseline chemistry values, a complete blood cell count, and the C-reactive protein level should be acquired.¹⁹ Laboratory findings that suggest more severe disease include low sodium, low bicarbonate (or an anion gap), and high creatinine levels; new anemia; a high or very low white blood cell count; and a high C-reactive protein level. A high C-reactive protein level has been associated with longer hospitalization.²²

A score to estimate the risk of necrotizing fasciitis

Laboratory values should be used to calculate the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score (Table 4).^20,23 Points are allocated for high C-reactive protein, creatinine, glucose, and white blood cell count values and for low red blood cell counts and sodium levels. Patients with a score of five points or less are considered at low risk, while those with six or more points are considered to be at least at intermediate risk of necrotizing fasciitis.

This tool was developed retrospectively but has been validated prospectively. It has a high sensitivity and a positive predictive value of 92% in patients with a score of six points or more. Its specificity is also high, with a negative predictive value of 96%.^20,24

Necrotizing fasciitis has a mortality rate of 23.5%, but this may be reduced to 10% with early detection and prompt surgical intervention.¹⁵ Since necrotizing fasciitis is very difficult to diagnose, clinicians must maintain a high level of suspicion and use the LRINEC score to trigger early surgical evaluation. Surgical exploration is the only way to definitively diagnose necrotizing fasciitis.

Blood cultures in some cases

Blood cultures have a low yield and are usually not cost-effective, but they should be obtained in patients who have lymphedema, immune deficiency, fever, pain out of proportion to the findings on examination, tachycardia, or hypotension, as blood cultures are more likely to be positive in more serious infections and can help guide antimicrobial therapy. Blood cultures are also recommended in patients with infections involving specific anatomic sites, such as the mouth and eyes.¹⁹

Aspiration, swabs, incision and drainage

Fluid aspirated from abscesses and swabs of debrided ulcerated wounds should be sent for Gram stain and culture. Gram stain and culture have widely varying yields, from less than 5% to 40%, depending on the source and technique.¹⁹ Cultures were not routinely obtained before MRSA emerged, but knowing antimicrobial susceptibility is now important to guide antibiotic therapy. Unfortunately, in cellulitis, swabs and aspirates of the leading edge have a low yield of around 10%.²⁵ One prospective study of 25 hospitalized patients did report a higher yield of positive cultures in patients with fever or underlying disease,²⁶ so aspirates may be used in selected cases. In small studies, the yield of punch biopsies was slightly better than that of needle aspirates and was as high as 20% to 30%.²⁷

 

IMAGING STUDIES

Imaging can be helpful in determining the depth of involvement. Plain radiography can reveal gas or periosteal inflammation and is especially helpful in diabetic foot infections. Ultrasonography can detect abscesses.

Both magnetic resonance imaging (MRI) and computed tomography (CT) are useful to image fascial planes, although MRI is more sensitive. However, in cases of suspected necrotizing fasciitis, imaging should not delay surgical evaluation and debridement or be used as the definitive study. Therefore, the practicality of CT and MRI can be limited.^15,16

ANTIMICROBIAL TREATMENT FOR SSTIs IN OUTPATIENTS

An electronic poll conducted by the New England Journal of Medicine in 2008 revealed broad differences in how physicians treat SSTIs.²⁸ The Infectious Diseases Society of America released guidelines for treating MRSA in SSTIs in January 2011 (Table 5).²⁷

For minor skin infections such as impetigo and secondarily infected skin lesions such as eczema, ulcers, or lacerations, mupirocin 2% topical ointment (Bactroban) can be effective.²⁷

For a simple abscess or boil, incision and drainage is the primary treatment, and antibiotics are not needed.

For a complicated abscess or boil. Patients should be given oral or intravenous antibiotic therapy to cover MRSA and, depending on the severity, should be considered for hospitalization if the abscess is associated with severe disease, rapid progression in the presence of associated cellulitis, septic phlebitis, constitutional symptoms, comorbidity (including immunosuppression), or an abscess or boil in an area difficult to drain, such as the face, hands, or genitalia.²⁷

For purulent cellulitis in outpatients, empiric therapy for community-acquired MRSA is recommended, pending culture results. Empiric therapy for streptococcal infection is likely unnecessary. For empiric coverage of community-acquired MRSA in purulent cellulitis, oral antibiotic options include clindamycin (Cleocin), trimethoprim-sulfamethoxazole (Bactrim), doxycycline (Doryx), minocycline (Minocin), and linezolid (Zyvox).

For nonpurulent cellulitis in outpatients, empiric coverage for beta-hemolytic streptococci is warranted. Coverage for community-acquired MRSA should subsequently be added for patients who do not respond to beta-lactam therapy within 48 to 72 hours or who have chills, fever, a new abscess, increasing erythema, or uncontrolled pain.

Options for coverage of both beta-hemolytic streptococci and community-acquired MRSA for outpatient therapy include clindamycin on its own, trimethoprim-sulfamethoxazole or a tetracycline in combination with a beta-lactam, or linezolid on its own.

Increasing rates of resistance to clindamycin, tetracycline, and trimethoprim-sulfamethoxazole in community-acquired MRSA may limit empiric treatment. In areas where resistance is prevalent, culture with antimicrobial susceptibility testing may be required before starting one of these antibiotics.

The use of rifampin (Rifadin) as a single agent is not recommended because resistance is likely to develop. Also, rifampin is not useful as adjunctive therapy, as evidence does not support its efficacy.^19,27,29

ANTIMICROBIAL TREATMENT FOR SSTIs IN HOSPITALIZED PATIENTS

For hospitalized patients with a complicated or severe SSTI, empiric therapy for MRSA should be started pending culture results. FDA-approved options are vancomycin, linezolid, daptomycin (Cubicin), tigecycline (Tygacil), and telavancin (Vibativ). Data on clindamycin are very limited in this population. A beta-lactam antibiotic such as cefazolin (Ancef) may be considered in hospitalized patients with nonpurulent cellulitis, and the regimen can be modified to MRSA-active therapy if there is no clinical response. Linezolid, daptomycin, vancomycin, and telavancin have adequate streptococcal coverage in addition to MRSA coverage.

Clindamycin is approved by the FDA for treating serious infections due to S aureus. It has excellent tissue penetration, particularly in bone and abscesses.

Clindamycin resistance in staphylococci can be either constitutive or inducible, and clinicians must be watchful for signs of resistance.

Diarrhea is the most common adverse effect and occurs in up to 20% of patients. Clostridium difficile colitis may occur more frequently with clindamycin than with other oral agents, but it has also has been reported with fluoroquinolones and can be associated with any antibiotic therapy.³⁰

Trimethoprim-sulfamethoxazole is not FDA-approved for treating any staphylococcal infection. However, because 95% to 100% of community-acquired MRSA strains are susceptible to it in vitro, it has become an important option in the outpatient treatment of SSTIs. Caution is advised when using it in elderly patients, particularly those with chronic renal insufficiency, because of an increased risk of hyperkalemia.

Tetracyclines. Doxycycline is FDA-approved for treating SSTIs due to S aureus, although not specifically for MRSA. Minocycline may be an option even when strains are resistant to doxycycline, since it does not induce its own resistance as doxycycline does.

Tigecycline is a glycylcycline (a tetracycline derivative) and is FDA-approved in adults for complicated SSTIs and intra-abdominal infections. It has a large volume of distribution and achieves high concentrations in tissues and low concentrations in serum.

The FDA recently issued a warning to consider alternative agents in patients with serious infections because of higher rates of all-cause mortality noted in phase III and phase IV clinical trials. Due to this warning and the availability of multiple alternatives active against MRSA, tigecycline was not included in the Infectious Diseases Society of America guidelines.³¹

Linezolid is a synthetic oxazolidinone and is FDA-approved for treating SSTIs and nosocomial pneumonia caused by MRSA. It has 100% oral bioavailability, so parenteral therapy should only be given if there are problems with gastrointestinal absorption or if the patient is unable to take oral medications.

Long-term use of linezolid (> 2 weeks) is limited by hematologic toxicity, especially thrombocytopenia, which occurs more frequently than anemia and neutropenia. Lactic acidosis and peripheral and optic neuropathy are also limiting toxicities. Although myelosuppression is generally reversible, peripheral and optic neuropathy may not be.

Linezolid should not used in patients taking selective serotonin reuptake inhibitors if they cannot stop taking these antidepressant drugs during therapy, as the combination can lead to the serotonin syndrome.

Vancomycin is still the mainstay of parenteral therapy for MRSA infections. However, its efficacy has come into question, with concerns over its slow bactericidal activity and the emergence of resistant strains. The rate of treatment failure is high in those with infection caused by MRSA having minimum inhibitory concentrations of 1 μg/mL or greater. Vancomycin kills staphylococci more slowly than do beta-lactams in vitro and is clearly inferior to beta-lactams for methicillin-sensitive S aureus bacteremia.

Daptomycin is a lipopeptide antibiotic that is FDA-approved for adults with MRSA bacteremia, right-sided infective endocarditis, and complicated SSTI. Elevations in creatinine phosphokinase, which are rarely treatment-limiting, have occurred in patients receiving 6 mg/kg/day but not in those receiving 4 mg/kg/day. Patients should be observed for development of muscle pain or weakness and should have their creatine phosphokinase levels checked weekly, with more frequent monitoring in those with renal insufficiency or who are receiving concomitant statin therapy.

Telavancin is a parenteral lipoglycopeptide that is bactericidal against MRSA. It is FDA-approved for complicated SSTIs in adults. Creatinine levels should be monitored, and the dosage should be adjusted on the basis of creatinine clearance, because nephrotoxicity was more commonly reported among individuals treated with telavancin than among those treated with vancomycin.

Ceftaroline (Teflaro), a fifth-generation cephalosporin, was approved for SSTIs by the FDA in October 2010. It is active against MRSA and gram-negative pathogens.

Cost is a consideration

Cost is a consideration, as it may limit the availability of and access to treatment. In 2008, the expense for 10 days of treatment with generic vancomycin was $183, compared with $1,661 for daptomycin, $1,362 for tigecycline, and $1,560 for linezolid. For outpatient therapy, the contrast was even starker, as generic trimethoprim-sulfamethoxazole cost $9.40 and generic clindamycin cost $95.10.³²

 

INDICATIONS FOR HOSPITALIZATION

Patients who have evidence of tissue necrosis, fever, hypotension, severe pain, altered mental status, an immunocompromised state, or organ failure (respiratory, renal, or hepatic) must be hospitalized.

Although therapy for MRSA is the mainstay of empiric therapy, polymicrobial infections are not uncommon, and gram-negative and anaerobic coverage should be added as appropriate. One study revealed a longer length of stay for hospitalized patients who had inadequate initial empiric coverage.³³

Vigilance should be maintained for overlying cellulitis which can mask necrotizing fasciitis, septic joints, or osteomyelitis.

Perianal abscesses and infections, infected decubitus ulcers, and moderate to severe diabetic foot infections are often polymicrobial and warrant coverage for streptococci, MRSA, aerobic gram-negative bacilli, and anaerobes until culture results can guide therapy.

INDICATIONS FOR SURGICAL REFERRAL

Extensive perianal or multiple abscesses may require surgical drainage and debridement.

Surgical site infections should be referred for consideration of opening the incision for drainage.

Necrotizing infections warrant prompt aggressive surgical debridement. Strongly suggestive clinical signs include bullae, crepitus, gas on radiography, hypotension with systolic blood pressure less than 90 mm Hg, or skin necrosis. However, these are late findings, and fewer than 50% of these patients have one of these. Most cases of necrotizing fasciitis originally have an admitting diagnosis of cellulitis and cases of fasciitis are relatively rare, so the diagnosis is easy to miss.^15,16 Patients with an LRINEC score of six or more should have prompt surgical evaluation.^20,24,34,35

Skin and soft-tissue infections (SSTIs) are a common reason for presentation to outpatient practices, emergency rooms, and hospitals.^1–5 They account for more than 14 million outpatient visits in the United States each year,¹ and visits to the emergency room and admissions to the hospital for them are increasing.^2,3 Hospital admissions for SSTIs increased by 29% from 2000 to 2004.³

MORE MRSA NOW, BUT STREPTOCOCCI ARE STILL COMMON

The increase in hospital admissions for SSTIs has been attributed to a rising number of infections with methicillin-resistant Staphylococcus aureus (MRSA).^3–5

In addition, strains once seen mostly in the community and other strains that were associated with health care are now being seen more often in both settings. Clinical characteristics do not differ between community-acquired and health-care-associated MRSA, and therefore the distinction between the two is becoming less useful in guiding empiric therapy.^6,7

After steadily increasing for several years, the incidence of MRSA has recently stabilized. The US Centers for Disease Control and Prevention maintains a surveillance program and a Web site on MRSA.⁸

At the same time, infections with group A, B, C, or G streptococci continue to be common. The SENTRY Antimicrobial Surveillance Program for the United States and Canada collected data from medical centers in five Canadian provinces and 32 US states between 1998 and 2004. The data set represents mostly complicated infections (see below). Staphylococcus was the most commonly retrieved organism (Table 1).⁹ However, streptococci were likely underrepresented, since mild or superficial streptococcal cellulitis may not require hospital admission, and positive cultures can be difficult to obtain in streptococcal infection.

COMPLICATED OR UNCOMPLICATED

Complicated skin and skin structure infections is a relatively new term coined in a 1998 US Food and Drug Administration (FDA) guideline for industry on developing antimicrobial drugs.¹⁰ Subsequent trials of antibiotics and reviews of skin infections used the guideline and its definitions. However, the category of complicated skin infections contained widely disparate clinical entities ranging from deep decubitus ulcers to diabetic foot infections (Table 2).¹⁰

The intent of the 1998 guideline was to provide not a clinical framework but rather a guide for industry in designing trials that would include similar groups of infections and therefore be relevant when compared with each other. In 2008, the Anti-Infective Drugs Advisory Committee was convened,¹¹ and subsequently, in August 2010, the FDA released a revision of the guide.¹²

The revised guidelines specifically exclude many diagnoses, such as bite wounds, bone and joint infections, necrotizing fasciitis, diabetic foot infections, decubitus ulcers, catheter site infections, myonecrosis, and ecthyma gangrenosum. Notably, the word “bacterial” in the title excludes mycobacterial and fungal infections from consideration. The diagnoses that are included include cellulitis, erysipelas, major cutaneous abscess, and burn infections. These are further specified to include 75 cm² of redness, edema, or induration to standardize the extent of the infection—ie, the infection has to be at least this large or else it is not “complicated.”

The terms “complicated” and “uncomplicated” skin and skin structure infections persist and can be useful adjuncts in describing SSTIs.^13–16 However, more specific descriptions of SSTIs based on pathogenesis are more useful to the clinician and are usually the basis for guidelines, such as for preventing surgical site infections or for reducing amputations in diabetic foot infections.

This review will focus on the general categories of SSTI and will not address surgical site infections, pressure ulcers, diabetic foot infections, perirectal wounds, or adjuvant therapies in severe SSTIs, such as negative pressure wound care (vacuum-assisted closure devices) and hyperbaric chambers.

OTHER DISEASES CAN MIMIC SSTIs

SSTIs vary broadly in their location and severity.

Although the classic presentation of erythema, warmth, edema, and tenderness often signals infection, other diseases can mimic SSTIs. Common ones that should be included in the differential diagnosis include gout, thrombophlebitis, deep vein thrombosis, contact dermatitis, carcinoma erysipeloides, drug eruption, and a foreign body reaction.^17,18

CLUES FROM THE HISTORY

Specific exposures. A detailed history can point to possible organisms and appropriate therapy. Table 3 lists several risk factors or exposures that may be elicited in the history and the pathogens they suggest.¹⁴

Wounds. Skin infections are usually precipitated by a break in the skin from a cut, laceration, excoriation, fungal infection, insect or animal bite, or puncture wound.

Impaired response. Patients with diabetes, renal failure, cirrhosis, chronic glucocorticoid use, history of organ transplantation, chronic immunosuppressive therapy, HIV infection, or malnourishment have impaired host responses to infection and are at risk for both more severe infections and recurrent infections. Immunocompromised hosts may also have atypical infections with opportunistic organisms such as Pseudomonas, Proteus, Serratia, Enterobacter, Citrobacter, and anaerobes. Close follow-up of these patients is warranted to ascertain appropriate response to therapy.¹⁹

Surgery that includes lymph node dissection or saphenous vein resection for coronary artery bypass can lead to impaired lymphatic drainage and edema, and therefore predisposes patients to SSTIs.

 

PHYSICAL EXAMINATION

The physical examination should include descriptions of the extent and location of erythema, edema, warmth, and tenderness so that progression or resolution with treatment can be followed in detail.

Crepitus can be felt in gas-forming infections and raises the concern for necrotizing fasciitis and infection with anaerobic organisms such as Clostridium perfringens.

Necrosis can occur in brown recluse spider bites, venous snake bites, or group A streptococcal infections.

Fluctuance indicates fluid and a likely abscess that may need incision and drainage.

Purpura may be present in patients on anticoagulation therapy, but if it is accompanying an SSTI, it also raises the concern for the possibility of sepsis and disseminated intravascular coagulation, especially from streptococcal infections.

Bullae can be seen in impetigo caused by staphylococci or in infection with Vibrio vulnificus or Streptococcus pneumoniae.¹⁹

Systemic signs, in addition to fever, can include hypotension and tachycardia, which would prompt closer monitoring and possible hospitalization.

Lymphangitic spread also indicates severe infection.

Depth of infection. Figure 1 depicts the possible depths of involvement of SSTIs and the accompanying diagnoses. Superficial infections such as erysipelas, impetigo, folliculitis, furuncles, and carbuncles are located at the epidermal layer, while cellulitis reaches into the dermis. Deeper infections cross the subcutaneous tissue and become fasciitis or myonecrosis.¹⁵ However, the depth of infection is difficult to discern on examination; laboratory studies can help with this assessment.²⁰

LABORATORY STUDIES

Simple, localized SSTIs usually do not require laboratory evaluation. Jenkins et al²¹ recently demonstrated that by using an algorithm for the management of hospitalized patients with cellulitis or cutaneous abscess, they could decrease resource utilization, including laboratory testing, without adversely affecting clinical outcome.

If patients have underlying disease or more extensive infection, then baseline chemistry values, a complete blood cell count, and the C-reactive protein level should be acquired.¹⁹ Laboratory findings that suggest more severe disease include low sodium, low bicarbonate (or an anion gap), and high creatinine levels; new anemia; a high or very low white blood cell count; and a high C-reactive protein level. A high C-reactive protein level has been associated with longer hospitalization.²²

A score to estimate the risk of necrotizing fasciitis

Laboratory values should be used to calculate the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score (Table 4).^20,23 Points are allocated for high C-reactive protein, creatinine, glucose, and white blood cell count values and for low red blood cell counts and sodium levels. Patients with a score of five points or less are considered at low risk, while those with six or more points are considered to be at least at intermediate risk of necrotizing fasciitis.

This tool was developed retrospectively but has been validated prospectively. It has a high sensitivity and a positive predictive value of 92% in patients with a score of six points or more. Its specificity is also high, with a negative predictive value of 96%.^20,24

Necrotizing fasciitis has a mortality rate of 23.5%, but this may be reduced to 10% with early detection and prompt surgical intervention.¹⁵ Since necrotizing fasciitis is very difficult to diagnose, clinicians must maintain a high level of suspicion and use the LRINEC score to trigger early surgical evaluation. Surgical exploration is the only way to definitively diagnose necrotizing fasciitis.

Blood cultures in some cases

Blood cultures have a low yield and are usually not cost-effective, but they should be obtained in patients who have lymphedema, immune deficiency, fever, pain out of proportion to the findings on examination, tachycardia, or hypotension, as blood cultures are more likely to be positive in more serious infections and can help guide antimicrobial therapy. Blood cultures are also recommended in patients with infections involving specific anatomic sites, such as the mouth and eyes.¹⁹

Aspiration, swabs, incision and drainage

Fluid aspirated from abscesses and swabs of debrided ulcerated wounds should be sent for Gram stain and culture. Gram stain and culture have widely varying yields, from less than 5% to 40%, depending on the source and technique.¹⁹ Cultures were not routinely obtained before MRSA emerged, but knowing antimicrobial susceptibility is now important to guide antibiotic therapy. Unfortunately, in cellulitis, swabs and aspirates of the leading edge have a low yield of around 10%.²⁵ One prospective study of 25 hospitalized patients did report a higher yield of positive cultures in patients with fever or underlying disease,²⁶ so aspirates may be used in selected cases. In small studies, the yield of punch biopsies was slightly better than that of needle aspirates and was as high as 20% to 30%.²⁷

 

IMAGING STUDIES

Imaging can be helpful in determining the depth of involvement. Plain radiography can reveal gas or periosteal inflammation and is especially helpful in diabetic foot infections. Ultrasonography can detect abscesses.

Both magnetic resonance imaging (MRI) and computed tomography (CT) are useful to image fascial planes, although MRI is more sensitive. However, in cases of suspected necrotizing fasciitis, imaging should not delay surgical evaluation and debridement or be used as the definitive study. Therefore, the practicality of CT and MRI can be limited.^15,16

ANTIMICROBIAL TREATMENT FOR SSTIs IN OUTPATIENTS

An electronic poll conducted by the New England Journal of Medicine in 2008 revealed broad differences in how physicians treat SSTIs.²⁸ The Infectious Diseases Society of America released guidelines for treating MRSA in SSTIs in January 2011 (Table 5).²⁷

For minor skin infections such as impetigo and secondarily infected skin lesions such as eczema, ulcers, or lacerations, mupirocin 2% topical ointment (Bactroban) can be effective.²⁷

For a simple abscess or boil, incision and drainage is the primary treatment, and antibiotics are not needed.

For a complicated abscess or boil. Patients should be given oral or intravenous antibiotic therapy to cover MRSA and, depending on the severity, should be considered for hospitalization if the abscess is associated with severe disease, rapid progression in the presence of associated cellulitis, septic phlebitis, constitutional symptoms, comorbidity (including immunosuppression), or an abscess or boil in an area difficult to drain, such as the face, hands, or genitalia.²⁷

For purulent cellulitis in outpatients, empiric therapy for community-acquired MRSA is recommended, pending culture results. Empiric therapy for streptococcal infection is likely unnecessary. For empiric coverage of community-acquired MRSA in purulent cellulitis, oral antibiotic options include clindamycin (Cleocin), trimethoprim-sulfamethoxazole (Bactrim), doxycycline (Doryx), minocycline (Minocin), and linezolid (Zyvox).

For nonpurulent cellulitis in outpatients, empiric coverage for beta-hemolytic streptococci is warranted. Coverage for community-acquired MRSA should subsequently be added for patients who do not respond to beta-lactam therapy within 48 to 72 hours or who have chills, fever, a new abscess, increasing erythema, or uncontrolled pain.

Options for coverage of both beta-hemolytic streptococci and community-acquired MRSA for outpatient therapy include clindamycin on its own, trimethoprim-sulfamethoxazole or a tetracycline in combination with a beta-lactam, or linezolid on its own.

Increasing rates of resistance to clindamycin, tetracycline, and trimethoprim-sulfamethoxazole in community-acquired MRSA may limit empiric treatment. In areas where resistance is prevalent, culture with antimicrobial susceptibility testing may be required before starting one of these antibiotics.

The use of rifampin (Rifadin) as a single agent is not recommended because resistance is likely to develop. Also, rifampin is not useful as adjunctive therapy, as evidence does not support its efficacy.^19,27,29

ANTIMICROBIAL TREATMENT FOR SSTIs IN HOSPITALIZED PATIENTS

For hospitalized patients with a complicated or severe SSTI, empiric therapy for MRSA should be started pending culture results. FDA-approved options are vancomycin, linezolid, daptomycin (Cubicin), tigecycline (Tygacil), and telavancin (Vibativ). Data on clindamycin are very limited in this population. A beta-lactam antibiotic such as cefazolin (Ancef) may be considered in hospitalized patients with nonpurulent cellulitis, and the regimen can be modified to MRSA-active therapy if there is no clinical response. Linezolid, daptomycin, vancomycin, and telavancin have adequate streptococcal coverage in addition to MRSA coverage.

Clindamycin is approved by the FDA for treating serious infections due to S aureus. It has excellent tissue penetration, particularly in bone and abscesses.

Clindamycin resistance in staphylococci can be either constitutive or inducible, and clinicians must be watchful for signs of resistance.

Diarrhea is the most common adverse effect and occurs in up to 20% of patients. Clostridium difficile colitis may occur more frequently with clindamycin than with other oral agents, but it has also has been reported with fluoroquinolones and can be associated with any antibiotic therapy.³⁰

Trimethoprim-sulfamethoxazole is not FDA-approved for treating any staphylococcal infection. However, because 95% to 100% of community-acquired MRSA strains are susceptible to it in vitro, it has become an important option in the outpatient treatment of SSTIs. Caution is advised when using it in elderly patients, particularly those with chronic renal insufficiency, because of an increased risk of hyperkalemia.

Tetracyclines. Doxycycline is FDA-approved for treating SSTIs due to S aureus, although not specifically for MRSA. Minocycline may be an option even when strains are resistant to doxycycline, since it does not induce its own resistance as doxycycline does.

Tigecycline is a glycylcycline (a tetracycline derivative) and is FDA-approved in adults for complicated SSTIs and intra-abdominal infections. It has a large volume of distribution and achieves high concentrations in tissues and low concentrations in serum.

The FDA recently issued a warning to consider alternative agents in patients with serious infections because of higher rates of all-cause mortality noted in phase III and phase IV clinical trials. Due to this warning and the availability of multiple alternatives active against MRSA, tigecycline was not included in the Infectious Diseases Society of America guidelines.³¹

Linezolid is a synthetic oxazolidinone and is FDA-approved for treating SSTIs and nosocomial pneumonia caused by MRSA. It has 100% oral bioavailability, so parenteral therapy should only be given if there are problems with gastrointestinal absorption or if the patient is unable to take oral medications.

Long-term use of linezolid (> 2 weeks) is limited by hematologic toxicity, especially thrombocytopenia, which occurs more frequently than anemia and neutropenia. Lactic acidosis and peripheral and optic neuropathy are also limiting toxicities. Although myelosuppression is generally reversible, peripheral and optic neuropathy may not be.

Linezolid should not used in patients taking selective serotonin reuptake inhibitors if they cannot stop taking these antidepressant drugs during therapy, as the combination can lead to the serotonin syndrome.

Vancomycin is still the mainstay of parenteral therapy for MRSA infections. However, its efficacy has come into question, with concerns over its slow bactericidal activity and the emergence of resistant strains. The rate of treatment failure is high in those with infection caused by MRSA having minimum inhibitory concentrations of 1 μg/mL or greater. Vancomycin kills staphylococci more slowly than do beta-lactams in vitro and is clearly inferior to beta-lactams for methicillin-sensitive S aureus bacteremia.

Daptomycin is a lipopeptide antibiotic that is FDA-approved for adults with MRSA bacteremia, right-sided infective endocarditis, and complicated SSTI. Elevations in creatinine phosphokinase, which are rarely treatment-limiting, have occurred in patients receiving 6 mg/kg/day but not in those receiving 4 mg/kg/day. Patients should be observed for development of muscle pain or weakness and should have their creatine phosphokinase levels checked weekly, with more frequent monitoring in those with renal insufficiency or who are receiving concomitant statin therapy.

Telavancin is a parenteral lipoglycopeptide that is bactericidal against MRSA. It is FDA-approved for complicated SSTIs in adults. Creatinine levels should be monitored, and the dosage should be adjusted on the basis of creatinine clearance, because nephrotoxicity was more commonly reported among individuals treated with telavancin than among those treated with vancomycin.

Ceftaroline (Teflaro), a fifth-generation cephalosporin, was approved for SSTIs by the FDA in October 2010. It is active against MRSA and gram-negative pathogens.

Cost is a consideration

Cost is a consideration, as it may limit the availability of and access to treatment. In 2008, the expense for 10 days of treatment with generic vancomycin was $183, compared with $1,661 for daptomycin, $1,362 for tigecycline, and $1,560 for linezolid. For outpatient therapy, the contrast was even starker, as generic trimethoprim-sulfamethoxazole cost $9.40 and generic clindamycin cost $95.10.³²

 

INDICATIONS FOR HOSPITALIZATION

Patients who have evidence of tissue necrosis, fever, hypotension, severe pain, altered mental status, an immunocompromised state, or organ failure (respiratory, renal, or hepatic) must be hospitalized.

Although therapy for MRSA is the mainstay of empiric therapy, polymicrobial infections are not uncommon, and gram-negative and anaerobic coverage should be added as appropriate. One study revealed a longer length of stay for hospitalized patients who had inadequate initial empiric coverage.³³

Vigilance should be maintained for overlying cellulitis which can mask necrotizing fasciitis, septic joints, or osteomyelitis.

Perianal abscesses and infections, infected decubitus ulcers, and moderate to severe diabetic foot infections are often polymicrobial and warrant coverage for streptococci, MRSA, aerobic gram-negative bacilli, and anaerobes until culture results can guide therapy.

INDICATIONS FOR SURGICAL REFERRAL

Extensive perianal or multiple abscesses may require surgical drainage and debridement.

Surgical site infections should be referred for consideration of opening the incision for drainage.

Necrotizing infections warrant prompt aggressive surgical debridement. Strongly suggestive clinical signs include bullae, crepitus, gas on radiography, hypotension with systolic blood pressure less than 90 mm Hg, or skin necrosis. However, these are late findings, and fewer than 50% of these patients have one of these. Most cases of necrotizing fasciitis originally have an admitting diagnosis of cellulitis and cases of fasciitis are relatively rare, so the diagnosis is easy to miss.^15,16 Patients with an LRINEC score of six or more should have prompt surgical evaluation.^20,24,34,35

In the article “Measles: Not just a childhood rash” (Sabella C. Measles: Not just a childhood rash. Cleve Clin J Med 2010; 77:207–213), Figure 1 contained an error. The red line in the graph represents cases reported for ages 5 to 19, and the green line represents cases reported for ages under 5 years. The corrected figure appears below. This error has been corrected in the online version.

 

In the article “Measles: Not just a childhood rash” (Sabella C. Measles: Not just a childhood rash. Cleve Clin J Med 2010; 77:207–213), Figure 1 contained an error. The red line in the graph represents cases reported for ages 5 to 19, and the green line represents cases reported for ages under 5 years. The corrected figure appears below. This error has been corrected in the online version.

 

In the article “Measles: Not just a childhood rash” (Sabella C. Measles: Not just a childhood rash. Cleve Clin J Med 2010; 77:207–213), Figure 1 contained an error. The red line in the graph represents cases reported for ages 5 to 19, and the green line represents cases reported for ages under 5 years. The corrected figure appears below. This error has been corrected in the online version.

 

Although the exact cause of knee OA is unclear, its incidence increases with age and it is particularly prevalent among women and those who are obese and have occupations requiring heavy lifting and frequent kneeling or squatting.^3-6 Lifelong sport-specific activity^7,8 and joint injury⁹ also seem to increase the risk for knee OA. Knee malalignment also may predispose people to knee OA,¹⁰ and the presence of early degenerative changes predicts progression of the disease.¹¹ The disability and pain associated with knee OA correlate with a loss of quadriceps femoris muscle strength and limited joint range of motion.^12-14

Medications and surgery carry substantial risks. Pharmacologic interventions for knee OA include nonsteroidal anti-inflammatory drugs, acetaminophen, and cyclooxygenase-2-selective inhibitors.^15-17 While each of these drugs reduces pain and improves function, potential side effects include gastrointestinal, cardiovascular, renal, and hepatic complications.^16,18-21

Effective surgical options—most appropriate for advanced OA—include high-tibial osteotomy and total knee arthroplasty (TKA). There is good evidence that arthroscopic surgery is not an effective intervention for knee OA, yielding results for pain and function equivalent to those seen with knee capsule injections of saline, tidal irrigation, and placebo surgery.^22-25 TKA reduces pain, improves function, and decreases arthritis-related costs in older individuals with advanced knee OA.^26,27 However, this procedure is not without risk.²⁸ Total knee replacement in patients younger than 55 years is associated with increased mortality.²⁹ Reported adverse outcomes of TKA include death, deep vein thrombosis, pulmonary embolus, deep wound infections,^30,31 arterial lacerations, amputations,³² postoperative ileus,³³ fractures, joint stiffness, and ligamentous instability.³⁴ Viscosupplementation reduces pain and improves function, most evident at 5 to 13 weeks posttreatment, with few reported serious complications and moderate rates of local complications.³⁵

Physical therapy is beneficial for mild to moderate OA and confers very low risk. Both physical therapy and exercise programs for OA have demonstrated benefit in a variety of settings.^36-42 As shown in 2 independently conducted randomized controlled trials (RCTs) (one placebo controlled and one with an alternate treatment comparison), manual physical therapy applied during a small number of clinical sessions and supplemented by home exercise yields large reductions in pain and stiffness and improvements in functional ability persisting to 1 year as measured on the WOMAC Osteoarthritis Index,^1,2 a validated self-report outcome instrument for OA of the hip and knee.⁴³ In these studies, 60% of subjects receiving manual physical therapy and exercise achieved more than 50% improvement in WOMAC scores (pain, stiffness, and function) postintervention. Additionally, 83% achieved more than the minimal clinically important difference (MCID) of 12% improvement.^1,2 Physical therapy and exercise combined also decreased the need for TKA and long-term medication use.^1,2

For an intervention that benefits most patients, there is clearly an interest in determining predictors of treatment failure⁴⁴ to expedite referral for alternative care. When the time or resources required to attend physical therapy appointments would create financial or personal hardships, more appropriate interventions may be home-based physical therapy exercise programs or medications and injections. Equally important, patients for whom knee OA rehabilitation is predicted to fail can be reprioritized for physical therapy aimed at coexisting conditions or injuries such as a functionally limiting impingement syndrome of the shoulder or chronic degenerative back or hip conditions.

 

Methods

Using a retrospective combined-cohort study design, we reviewed baseline patient examinations from 2 RCTs^1,2 to identify variables that indicate which individuals with knee OA are unlikely to benefit from manual physical therapy and exercise, and to thereby develop a preliminary CPR. We extracted data from the research folders of all study participants. The institutional review board of Brooke Army Medical Center determined that the study was exempt from review. From April to December 2008, we prepared an extensive database of examination findings and performed analyses to determine the variables that predict likely treatment nonsuccess with manual physical therapy and exercise. Improvement of <12% in the total WOMAC score after 4 weeks of treatment defined nonsuccess.⁴⁵

Data sets from the previously published trials contained 22 variables measured at baseline that were potential predictors of nonsuccess. We combined these variables with an additional 145 variables manually retrieved from standardized examination forms used for each subject, for a total of 167 potential predictors. We combined only data from treatment groups receiving manual therapy and exercise.

We limited the extent of some examination procedures in the earlier studies, due to the high level of symptoms experienced by some subjects at rest and during the initial examination. For example, if there was severe pain with active knee flexion, we did not perform passive manual overpressure to flexion; nor did we record a finding. Thus, the total number of data points for each subject varied somewhat.

Data analysis

We compared success and nonsuccess groups with 2-tailed unpaired t-tests for continuous variables, and chi-square tests for categorical variables. We additionally performed logistic regression analysis on potential predictors that yielded P values <.10, using a forward conditional stepwise procedure with probability levels set to .05 for entry and .10 for removal from the model. Predictors retained by the final logistic regression model comprised the CPR.

We coded each patient in the data set as positive or negative for each predictor in the CPR. To determine a cut score, we dichotomized the single retained continuous predictor variable using receiver-operator characteristic (ROC) curve analysis and the Youden index.⁴⁶ For each CPR level (ie, increasing number of predictors positive), we constructed a 2 × 2 contingency table with numbers of patients with true-positive test results, false-positive test results, true-negative test results, and false-negative test results. We characterized prognostic performance of the CPR by calculating sensitivity, specificity, and positive likelihood ratios for each level of positive predictors. To determine overall prognostic accuracy, we added true positives and true negatives and divided by the total number of patients in the cross tabulation.

For each CPR level, we derived posttest probabilities of nonsuccess from generalized pretest probability (incidence of treatment nonsuccess in the sample) and the positive likelihood ratios.⁴⁷ Finally, to determine how consistently the CPR performed with subjects in the original studies,^1,2 we generated separate cross-tabulations and prognostic accuracy statistics from each RCT.

Results

Baseline patient attributes are summarized in TABLE 1. Of the 101 subjects in the combined data set, 17 (16.8%) met the definition of nonsuccess. Among 47 continuous-scale variables available, 11 predictors significantly discriminated between those in the treatment success and nonsuccess groups. Among 120 categorical-scale variables, 15 predictors significantly discriminated between groups. We identified 6 potential predictors for entry into the final logistic regression analysis: height, assistive device type, prone knee bend degrees, baseline WOMAC visual analog scale (VAS) for difficulty descending stairs, anterior cruciate ligament (ACL) laxity, and pain with passive patellofemoral glide.

TABLE 1
Baseline descriptive summaries of patients (n=101)

Sex, n (%)   Men   Women	37 (36.6) 64 (63.4)
Age, y   Mean±SD   Range	62.5±10.4 39-85
Height, m   Mean±SD   Range	1.66±0.1041 1.42-1.91
Side(s) involved, n (%)   Unilateral   Bilateral	63 (62.4) 38 (37.6)
Weight, kg   Mean±SD   Range	84.5±17.8 48.6-132.7
Duration of symptoms, mo   Mean±SD   Range	76.1±87.9 1-480
WOMAC (VAS) total baseline, mm   Mean±SD   Range	1059.8±447.1 193-2289
6-minute walk test baseline, m   Mean±SD   Range	425.6±114.8 118.2-683.3
Physical activity relative to peers (self-report), n (%)   Much more active   Somewhat more active   About the same   Somewhat less active	26 (26) 33 (33) 20 (20) 21 (21)
Radiographic severity score, n (%)   0   1   2   3   4	6 (6.1) 25 (25.5) 33 (33.7) 25 (25.5) 9 (9.2)
*Baseline data were available for all 101 subjects except for duration of symptoms (n=98); physical activity (n=100); and radiographic severity (n=98). VAS, visual analog scale; WOMAC, Western Ontario MacMaster.

The final regression model retained 3 predictors comprising the CPR: height, ACL laxity, and pain with passive patellofemoral glides. We dichotomized height with a cut point of 1.71 m (5’7”), which corresponded with a deflection point at the upper left extent of the ROC curve (area under the curve=0.72; 95% CI, 0.57-0.87; P=.001). We thus deemed a patient 1.71 m or taller as positive for nonsuccess. We considered a patient with laxity of the ACL as positive for nonsuccess if a test result on the Lachman test (or the anterior drawer test) was positive (any grade other than 0). We regarded passive patellofemoral glide as positive for nonsuccess if a patient reported pain with any direction of passive gliding motion imposed by the therapist. The final regression model was a good fit to the data: Hosmer & Lemeshow test χ² = 2.90 (P=.940); Nagelkerke R²=0.680.

 

TABLE 2 presents prognostic accuracy profiles for each predictor in the CPR; TABLE 3 summarizes the accuracy for each level of the multivariate CPR. Values in TABLE 3 reflect complete sets of data for the 3 predictors found for 50 patients. Of those 50 patients, 6 (12%) were in the nonsuccess group.

TABLE 2
Prognostic accuracy statistics for individual predictors

Predictor	Sensitivity (95% CI)	Specificity (95% CI)	Positive likelihood ratio (95% CI)	Posttest probability of nonsuccess*
Height ≥1.71 m	0.65 (0.41-0.83)	0.77 (0.67-0.85)	2.86 (1.69-4.86)	37%
ACL laxity	0.27 (0.10-0.57)	0.93 (0.83-0.97)	3.68 (0.96-14.19)	43%
Pain with passive patellofemoral glide in any direction	0.71 (0.35-0.92)	0.61 (0.47-0.74)	1.84 (1.03-3.31)	27%
ACL, anterior cruciate ligament; CI, confidence interval. *Assumes pretest probability of nonsuccess=17% (incidence in this sample).

With any 2 of the 3 tests positive, the CPR yielded a sensitivity of 83% (95% CI, 44%-97%), specificity of 98% (95% CI, 88%-100%), and positive likelihood ratio of 36.7 (95% CI, 5.1-263.0). Only 2 patients out of 50 were misclassified (one false positive and one false negative) at this level of the CPR, yielding an overall prognostic accuracy of 96% (95% CI, 87%-99%). Application of the positive likelihood ratio for a patient with any 2 positive tests yielded a posttest probability of 88% for nonsuccess with this treatment.

TABLE 3
Prognostic accuracy statistics for 3-level clinical prediction rule

CPR level	Sensitivity (95% CI)	Specificity (95% CI)	Positive likelihood ratio (95% CI)	Posttest probability of nonsuccess*
All 3 tests positive	0.21 (0.05-0.58)	0.99 (0.90-1.00)	19.29 (0.87-428.09)	80%
At least 2 tests positive	0.83 (0.44-0.97)	0.98 (0.88-1.00)	36.67 (5.11-263.01)	88%
At least 1 test positive	0.92 (0.56-0.99)	0.48 (0.34-0.62)	1.78 (1.26-2.52)	27%
CI, confidence interval; CPR, clinical prediction rule. *Assumes pretest probability of nonsuccess=17% (incidence in this sample).

In the sensitivity analysis, the CPR performed similarly well for patients in each of the 2 original studies when applied separately to the groups of patients. Among the 30 patients from the first trial² who had data for all 3 predictors in the CPR, only one was misclassified (a false positive), yielding a prognostic accuracy of 97% (95% CI, 83%-99%). Among the 20 patients from the second trial¹ who had data for all 3 predictors, only one was misclassified (a false negative), yielding a prognostic accuracy of 95% (95% CI, 76%-99%).

DISCUSSION

Family physicians and physical therapists should be able to discuss with confidence how any given patient with knee OA will likely respond to treatment options. Our study is a preliminary step toward defining the population of patients with knee OA who are unlikely to benefit from manual physical therapy and exercise. We found such patients to be those with height >1.71 m, ACL laxity, and pain with passive glides of the patellofemoral joint.

A limitation of our study is the retrospective nature of gathering data. However, retrospective CPR derivation studies have made valuable contributions to many areas of medical practice.^48-53 Additionally, if there had been uniformly available data across all patients, there may have been other, perhaps more powerful, predictors for treatment nonsuccess.

 

Patient height >1.71 m is the least intuitive of the predictors for nonsuccess, but that underscores the value of data-driven prediction rules. Variables regarded as unimportant in a typical clinical assessment may show clinical usefulness if validated in independent studies. It may be that in taller patients with knee OA, biomechanical forces are such that a positive response to conservative therapy is less likely—particularly in the presence of ligamentous laxity or patellofemoral dysfunction.

For most patients with knee OA, the combined intervention of manual physical therapy and exercise is clinically beneficial, relatively inexpensive, and has no known adverse effects.⁵⁴ However, unique circumstances may increase the importance of determining the likelihood that a patient will benefit. A validated CPR will facilitate timely decisions for those relatively few patients requiring alternative interventions. Although the rule is preliminary and needs to be validated, these results provide current best evidence to define patients with knee OA who are unlikely to respond to manual physical therapy and exercise.

Although the exact cause of knee OA is unclear, its incidence increases with age and it is particularly prevalent among women and those who are obese and have occupations requiring heavy lifting and frequent kneeling or squatting.^3-6 Lifelong sport-specific activity^7,8 and joint injury⁹ also seem to increase the risk for knee OA. Knee malalignment also may predispose people to knee OA,¹⁰ and the presence of early degenerative changes predicts progression of the disease.¹¹ The disability and pain associated with knee OA correlate with a loss of quadriceps femoris muscle strength and limited joint range of motion.^12-14

Medications and surgery carry substantial risks. Pharmacologic interventions for knee OA include nonsteroidal anti-inflammatory drugs, acetaminophen, and cyclooxygenase-2-selective inhibitors.^15-17 While each of these drugs reduces pain and improves function, potential side effects include gastrointestinal, cardiovascular, renal, and hepatic complications.^16,18-21

Effective surgical options—most appropriate for advanced OA—include high-tibial osteotomy and total knee arthroplasty (TKA). There is good evidence that arthroscopic surgery is not an effective intervention for knee OA, yielding results for pain and function equivalent to those seen with knee capsule injections of saline, tidal irrigation, and placebo surgery.^22-25 TKA reduces pain, improves function, and decreases arthritis-related costs in older individuals with advanced knee OA.^26,27 However, this procedure is not without risk.²⁸ Total knee replacement in patients younger than 55 years is associated with increased mortality.²⁹ Reported adverse outcomes of TKA include death, deep vein thrombosis, pulmonary embolus, deep wound infections,^30,31 arterial lacerations, amputations,³² postoperative ileus,³³ fractures, joint stiffness, and ligamentous instability.³⁴ Viscosupplementation reduces pain and improves function, most evident at 5 to 13 weeks posttreatment, with few reported serious complications and moderate rates of local complications.³⁵

Physical therapy is beneficial for mild to moderate OA and confers very low risk. Both physical therapy and exercise programs for OA have demonstrated benefit in a variety of settings.^36-42 As shown in 2 independently conducted randomized controlled trials (RCTs) (one placebo controlled and one with an alternate treatment comparison), manual physical therapy applied during a small number of clinical sessions and supplemented by home exercise yields large reductions in pain and stiffness and improvements in functional ability persisting to 1 year as measured on the WOMAC Osteoarthritis Index,^1,2 a validated self-report outcome instrument for OA of the hip and knee.⁴³ In these studies, 60% of subjects receiving manual physical therapy and exercise achieved more than 50% improvement in WOMAC scores (pain, stiffness, and function) postintervention. Additionally, 83% achieved more than the minimal clinically important difference (MCID) of 12% improvement.^1,2 Physical therapy and exercise combined also decreased the need for TKA and long-term medication use.^1,2

For an intervention that benefits most patients, there is clearly an interest in determining predictors of treatment failure⁴⁴ to expedite referral for alternative care. When the time or resources required to attend physical therapy appointments would create financial or personal hardships, more appropriate interventions may be home-based physical therapy exercise programs or medications and injections. Equally important, patients for whom knee OA rehabilitation is predicted to fail can be reprioritized for physical therapy aimed at coexisting conditions or injuries such as a functionally limiting impingement syndrome of the shoulder or chronic degenerative back or hip conditions.

 

Methods

Using a retrospective combined-cohort study design, we reviewed baseline patient examinations from 2 RCTs^1,2 to identify variables that indicate which individuals with knee OA are unlikely to benefit from manual physical therapy and exercise, and to thereby develop a preliminary CPR. We extracted data from the research folders of all study participants. The institutional review board of Brooke Army Medical Center determined that the study was exempt from review. From April to December 2008, we prepared an extensive database of examination findings and performed analyses to determine the variables that predict likely treatment nonsuccess with manual physical therapy and exercise. Improvement of <12% in the total WOMAC score after 4 weeks of treatment defined nonsuccess.⁴⁵

Data sets from the previously published trials contained 22 variables measured at baseline that were potential predictors of nonsuccess. We combined these variables with an additional 145 variables manually retrieved from standardized examination forms used for each subject, for a total of 167 potential predictors. We combined only data from treatment groups receiving manual therapy and exercise.

We limited the extent of some examination procedures in the earlier studies, due to the high level of symptoms experienced by some subjects at rest and during the initial examination. For example, if there was severe pain with active knee flexion, we did not perform passive manual overpressure to flexion; nor did we record a finding. Thus, the total number of data points for each subject varied somewhat.

Data analysis

We compared success and nonsuccess groups with 2-tailed unpaired t-tests for continuous variables, and chi-square tests for categorical variables. We additionally performed logistic regression analysis on potential predictors that yielded P values <.10, using a forward conditional stepwise procedure with probability levels set to .05 for entry and .10 for removal from the model. Predictors retained by the final logistic regression model comprised the CPR.

We coded each patient in the data set as positive or negative for each predictor in the CPR. To determine a cut score, we dichotomized the single retained continuous predictor variable using receiver-operator characteristic (ROC) curve analysis and the Youden index.⁴⁶ For each CPR level (ie, increasing number of predictors positive), we constructed a 2 × 2 contingency table with numbers of patients with true-positive test results, false-positive test results, true-negative test results, and false-negative test results. We characterized prognostic performance of the CPR by calculating sensitivity, specificity, and positive likelihood ratios for each level of positive predictors. To determine overall prognostic accuracy, we added true positives and true negatives and divided by the total number of patients in the cross tabulation.

For each CPR level, we derived posttest probabilities of nonsuccess from generalized pretest probability (incidence of treatment nonsuccess in the sample) and the positive likelihood ratios.⁴⁷ Finally, to determine how consistently the CPR performed with subjects in the original studies,^1,2 we generated separate cross-tabulations and prognostic accuracy statistics from each RCT.

Results

Baseline patient attributes are summarized in TABLE 1. Of the 101 subjects in the combined data set, 17 (16.8%) met the definition of nonsuccess. Among 47 continuous-scale variables available, 11 predictors significantly discriminated between those in the treatment success and nonsuccess groups. Among 120 categorical-scale variables, 15 predictors significantly discriminated between groups. We identified 6 potential predictors for entry into the final logistic regression analysis: height, assistive device type, prone knee bend degrees, baseline WOMAC visual analog scale (VAS) for difficulty descending stairs, anterior cruciate ligament (ACL) laxity, and pain with passive patellofemoral glide.

TABLE 1
Baseline descriptive summaries of patients (n=101)

Sex, n (%)   Men   Women	37 (36.6) 64 (63.4)
Age, y   Mean±SD   Range	62.5±10.4 39-85
Height, m   Mean±SD   Range	1.66±0.1041 1.42-1.91
Side(s) involved, n (%)   Unilateral   Bilateral	63 (62.4) 38 (37.6)
Weight, kg   Mean±SD   Range	84.5±17.8 48.6-132.7
Duration of symptoms, mo   Mean±SD   Range	76.1±87.9 1-480
WOMAC (VAS) total baseline, mm   Mean±SD   Range	1059.8±447.1 193-2289
6-minute walk test baseline, m   Mean±SD   Range	425.6±114.8 118.2-683.3
Physical activity relative to peers (self-report), n (%)   Much more active   Somewhat more active   About the same   Somewhat less active	26 (26) 33 (33) 20 (20) 21 (21)
Radiographic severity score, n (%)   0   1   2   3   4	6 (6.1) 25 (25.5) 33 (33.7) 25 (25.5) 9 (9.2)
*Baseline data were available for all 101 subjects except for duration of symptoms (n=98); physical activity (n=100); and radiographic severity (n=98). VAS, visual analog scale; WOMAC, Western Ontario MacMaster.

The final regression model retained 3 predictors comprising the CPR: height, ACL laxity, and pain with passive patellofemoral glides. We dichotomized height with a cut point of 1.71 m (5’7”), which corresponded with a deflection point at the upper left extent of the ROC curve (area under the curve=0.72; 95% CI, 0.57-0.87; P=.001). We thus deemed a patient 1.71 m or taller as positive for nonsuccess. We considered a patient with laxity of the ACL as positive for nonsuccess if a test result on the Lachman test (or the anterior drawer test) was positive (any grade other than 0). We regarded passive patellofemoral glide as positive for nonsuccess if a patient reported pain with any direction of passive gliding motion imposed by the therapist. The final regression model was a good fit to the data: Hosmer & Lemeshow test χ² = 2.90 (P=.940); Nagelkerke R²=0.680.

 

TABLE 2 presents prognostic accuracy profiles for each predictor in the CPR; TABLE 3 summarizes the accuracy for each level of the multivariate CPR. Values in TABLE 3 reflect complete sets of data for the 3 predictors found for 50 patients. Of those 50 patients, 6 (12%) were in the nonsuccess group.

TABLE 2
Prognostic accuracy statistics for individual predictors

Predictor	Sensitivity (95% CI)	Specificity (95% CI)	Positive likelihood ratio (95% CI)	Posttest probability of nonsuccess*
Height ≥1.71 m	0.65 (0.41-0.83)	0.77 (0.67-0.85)	2.86 (1.69-4.86)	37%
ACL laxity	0.27 (0.10-0.57)	0.93 (0.83-0.97)	3.68 (0.96-14.19)	43%
Pain with passive patellofemoral glide in any direction	0.71 (0.35-0.92)	0.61 (0.47-0.74)	1.84 (1.03-3.31)	27%
ACL, anterior cruciate ligament; CI, confidence interval. *Assumes pretest probability of nonsuccess=17% (incidence in this sample).

With any 2 of the 3 tests positive, the CPR yielded a sensitivity of 83% (95% CI, 44%-97%), specificity of 98% (95% CI, 88%-100%), and positive likelihood ratio of 36.7 (95% CI, 5.1-263.0). Only 2 patients out of 50 were misclassified (one false positive and one false negative) at this level of the CPR, yielding an overall prognostic accuracy of 96% (95% CI, 87%-99%). Application of the positive likelihood ratio for a patient with any 2 positive tests yielded a posttest probability of 88% for nonsuccess with this treatment.

TABLE 3
Prognostic accuracy statistics for 3-level clinical prediction rule

CPR level	Sensitivity (95% CI)	Specificity (95% CI)	Positive likelihood ratio (95% CI)	Posttest probability of nonsuccess*
All 3 tests positive	0.21 (0.05-0.58)	0.99 (0.90-1.00)	19.29 (0.87-428.09)	80%
At least 2 tests positive	0.83 (0.44-0.97)	0.98 (0.88-1.00)	36.67 (5.11-263.01)	88%
At least 1 test positive	0.92 (0.56-0.99)	0.48 (0.34-0.62)	1.78 (1.26-2.52)	27%
CI, confidence interval; CPR, clinical prediction rule. *Assumes pretest probability of nonsuccess=17% (incidence in this sample).

In the sensitivity analysis, the CPR performed similarly well for patients in each of the 2 original studies when applied separately to the groups of patients. Among the 30 patients from the first trial² who had data for all 3 predictors in the CPR, only one was misclassified (a false positive), yielding a prognostic accuracy of 97% (95% CI, 83%-99%). Among the 20 patients from the second trial¹ who had data for all 3 predictors, only one was misclassified (a false negative), yielding a prognostic accuracy of 95% (95% CI, 76%-99%).

DISCUSSION

Family physicians and physical therapists should be able to discuss with confidence how any given patient with knee OA will likely respond to treatment options. Our study is a preliminary step toward defining the population of patients with knee OA who are unlikely to benefit from manual physical therapy and exercise. We found such patients to be those with height >1.71 m, ACL laxity, and pain with passive glides of the patellofemoral joint.

A limitation of our study is the retrospective nature of gathering data. However, retrospective CPR derivation studies have made valuable contributions to many areas of medical practice.^48-53 Additionally, if there had been uniformly available data across all patients, there may have been other, perhaps more powerful, predictors for treatment nonsuccess.

 

Patient height >1.71 m is the least intuitive of the predictors for nonsuccess, but that underscores the value of data-driven prediction rules. Variables regarded as unimportant in a typical clinical assessment may show clinical usefulness if validated in independent studies. It may be that in taller patients with knee OA, biomechanical forces are such that a positive response to conservative therapy is less likely—particularly in the presence of ligamentous laxity or patellofemoral dysfunction.

For most patients with knee OA, the combined intervention of manual physical therapy and exercise is clinically beneficial, relatively inexpensive, and has no known adverse effects.⁵⁴ However, unique circumstances may increase the importance of determining the likelihood that a patient will benefit. A validated CPR will facilitate timely decisions for those relatively few patients requiring alternative interventions. Although the rule is preliminary and needs to be validated, these results provide current best evidence to define patients with knee OA who are unlikely to respond to manual physical therapy and exercise.

Although the exact cause of knee OA is unclear, its incidence increases with age and it is particularly prevalent among women and those who are obese and have occupations requiring heavy lifting and frequent kneeling or squatting.^3-6 Lifelong sport-specific activity^7,8 and joint injury⁹ also seem to increase the risk for knee OA. Knee malalignment also may predispose people to knee OA,¹⁰ and the presence of early degenerative changes predicts progression of the disease.¹¹ The disability and pain associated with knee OA correlate with a loss of quadriceps femoris muscle strength and limited joint range of motion.^12-14

Medications and surgery carry substantial risks. Pharmacologic interventions for knee OA include nonsteroidal anti-inflammatory drugs, acetaminophen, and cyclooxygenase-2-selective inhibitors.^15-17 While each of these drugs reduces pain and improves function, potential side effects include gastrointestinal, cardiovascular, renal, and hepatic complications.^16,18-21

Effective surgical options—most appropriate for advanced OA—include high-tibial osteotomy and total knee arthroplasty (TKA). There is good evidence that arthroscopic surgery is not an effective intervention for knee OA, yielding results for pain and function equivalent to those seen with knee capsule injections of saline, tidal irrigation, and placebo surgery.^22-25 TKA reduces pain, improves function, and decreases arthritis-related costs in older individuals with advanced knee OA.^26,27 However, this procedure is not without risk.²⁸ Total knee replacement in patients younger than 55 years is associated with increased mortality.²⁹ Reported adverse outcomes of TKA include death, deep vein thrombosis, pulmonary embolus, deep wound infections,^30,31 arterial lacerations, amputations,³² postoperative ileus,³³ fractures, joint stiffness, and ligamentous instability.³⁴ Viscosupplementation reduces pain and improves function, most evident at 5 to 13 weeks posttreatment, with few reported serious complications and moderate rates of local complications.³⁵

Physical therapy is beneficial for mild to moderate OA and confers very low risk. Both physical therapy and exercise programs for OA have demonstrated benefit in a variety of settings.^36-42 As shown in 2 independently conducted randomized controlled trials (RCTs) (one placebo controlled and one with an alternate treatment comparison), manual physical therapy applied during a small number of clinical sessions and supplemented by home exercise yields large reductions in pain and stiffness and improvements in functional ability persisting to 1 year as measured on the WOMAC Osteoarthritis Index,^1,2 a validated self-report outcome instrument for OA of the hip and knee.⁴³ In these studies, 60% of subjects receiving manual physical therapy and exercise achieved more than 50% improvement in WOMAC scores (pain, stiffness, and function) postintervention. Additionally, 83% achieved more than the minimal clinically important difference (MCID) of 12% improvement.^1,2 Physical therapy and exercise combined also decreased the need for TKA and long-term medication use.^1,2

For an intervention that benefits most patients, there is clearly an interest in determining predictors of treatment failure⁴⁴ to expedite referral for alternative care. When the time or resources required to attend physical therapy appointments would create financial or personal hardships, more appropriate interventions may be home-based physical therapy exercise programs or medications and injections. Equally important, patients for whom knee OA rehabilitation is predicted to fail can be reprioritized for physical therapy aimed at coexisting conditions or injuries such as a functionally limiting impingement syndrome of the shoulder or chronic degenerative back or hip conditions.

 

Methods

Using a retrospective combined-cohort study design, we reviewed baseline patient examinations from 2 RCTs^1,2 to identify variables that indicate which individuals with knee OA are unlikely to benefit from manual physical therapy and exercise, and to thereby develop a preliminary CPR. We extracted data from the research folders of all study participants. The institutional review board of Brooke Army Medical Center determined that the study was exempt from review. From April to December 2008, we prepared an extensive database of examination findings and performed analyses to determine the variables that predict likely treatment nonsuccess with manual physical therapy and exercise. Improvement of <12% in the total WOMAC score after 4 weeks of treatment defined nonsuccess.⁴⁵

Data sets from the previously published trials contained 22 variables measured at baseline that were potential predictors of nonsuccess. We combined these variables with an additional 145 variables manually retrieved from standardized examination forms used for each subject, for a total of 167 potential predictors. We combined only data from treatment groups receiving manual therapy and exercise.

We limited the extent of some examination procedures in the earlier studies, due to the high level of symptoms experienced by some subjects at rest and during the initial examination. For example, if there was severe pain with active knee flexion, we did not perform passive manual overpressure to flexion; nor did we record a finding. Thus, the total number of data points for each subject varied somewhat.

Data analysis

We compared success and nonsuccess groups with 2-tailed unpaired t-tests for continuous variables, and chi-square tests for categorical variables. We additionally performed logistic regression analysis on potential predictors that yielded P values <.10, using a forward conditional stepwise procedure with probability levels set to .05 for entry and .10 for removal from the model. Predictors retained by the final logistic regression model comprised the CPR.

We coded each patient in the data set as positive or negative for each predictor in the CPR. To determine a cut score, we dichotomized the single retained continuous predictor variable using receiver-operator characteristic (ROC) curve analysis and the Youden index.⁴⁶ For each CPR level (ie, increasing number of predictors positive), we constructed a 2 × 2 contingency table with numbers of patients with true-positive test results, false-positive test results, true-negative test results, and false-negative test results. We characterized prognostic performance of the CPR by calculating sensitivity, specificity, and positive likelihood ratios for each level of positive predictors. To determine overall prognostic accuracy, we added true positives and true negatives and divided by the total number of patients in the cross tabulation.

For each CPR level, we derived posttest probabilities of nonsuccess from generalized pretest probability (incidence of treatment nonsuccess in the sample) and the positive likelihood ratios.⁴⁷ Finally, to determine how consistently the CPR performed with subjects in the original studies,^1,2 we generated separate cross-tabulations and prognostic accuracy statistics from each RCT.

Results

Baseline patient attributes are summarized in TABLE 1. Of the 101 subjects in the combined data set, 17 (16.8%) met the definition of nonsuccess. Among 47 continuous-scale variables available, 11 predictors significantly discriminated between those in the treatment success and nonsuccess groups. Among 120 categorical-scale variables, 15 predictors significantly discriminated between groups. We identified 6 potential predictors for entry into the final logistic regression analysis: height, assistive device type, prone knee bend degrees, baseline WOMAC visual analog scale (VAS) for difficulty descending stairs, anterior cruciate ligament (ACL) laxity, and pain with passive patellofemoral glide.

TABLE 1
Baseline descriptive summaries of patients (n=101)

Sex, n (%)   Men   Women	37 (36.6) 64 (63.4)
Age, y   Mean±SD   Range	62.5±10.4 39-85
Height, m   Mean±SD   Range	1.66±0.1041 1.42-1.91
Side(s) involved, n (%)   Unilateral   Bilateral	63 (62.4) 38 (37.6)
Weight, kg   Mean±SD   Range	84.5±17.8 48.6-132.7
Duration of symptoms, mo   Mean±SD   Range	76.1±87.9 1-480
WOMAC (VAS) total baseline, mm   Mean±SD   Range	1059.8±447.1 193-2289
6-minute walk test baseline, m   Mean±SD   Range	425.6±114.8 118.2-683.3
Physical activity relative to peers (self-report), n (%)   Much more active   Somewhat more active   About the same   Somewhat less active	26 (26) 33 (33) 20 (20) 21 (21)
Radiographic severity score, n (%)   0   1   2   3   4	6 (6.1) 25 (25.5) 33 (33.7) 25 (25.5) 9 (9.2)
*Baseline data were available for all 101 subjects except for duration of symptoms (n=98); physical activity (n=100); and radiographic severity (n=98). VAS, visual analog scale; WOMAC, Western Ontario MacMaster.

The final regression model retained 3 predictors comprising the CPR: height, ACL laxity, and pain with passive patellofemoral glides. We dichotomized height with a cut point of 1.71 m (5’7”), which corresponded with a deflection point at the upper left extent of the ROC curve (area under the curve=0.72; 95% CI, 0.57-0.87; P=.001). We thus deemed a patient 1.71 m or taller as positive for nonsuccess. We considered a patient with laxity of the ACL as positive for nonsuccess if a test result on the Lachman test (or the anterior drawer test) was positive (any grade other than 0). We regarded passive patellofemoral glide as positive for nonsuccess if a patient reported pain with any direction of passive gliding motion imposed by the therapist. The final regression model was a good fit to the data: Hosmer & Lemeshow test χ² = 2.90 (P=.940); Nagelkerke R²=0.680.

 

TABLE 2 presents prognostic accuracy profiles for each predictor in the CPR; TABLE 3 summarizes the accuracy for each level of the multivariate CPR. Values in TABLE 3 reflect complete sets of data for the 3 predictors found for 50 patients. Of those 50 patients, 6 (12%) were in the nonsuccess group.

TABLE 2
Prognostic accuracy statistics for individual predictors

Predictor	Sensitivity (95% CI)	Specificity (95% CI)	Positive likelihood ratio (95% CI)	Posttest probability of nonsuccess*
Height ≥1.71 m	0.65 (0.41-0.83)	0.77 (0.67-0.85)	2.86 (1.69-4.86)	37%
ACL laxity	0.27 (0.10-0.57)	0.93 (0.83-0.97)	3.68 (0.96-14.19)	43%
Pain with passive patellofemoral glide in any direction	0.71 (0.35-0.92)	0.61 (0.47-0.74)	1.84 (1.03-3.31)	27%
ACL, anterior cruciate ligament; CI, confidence interval. *Assumes pretest probability of nonsuccess=17% (incidence in this sample).

With any 2 of the 3 tests positive, the CPR yielded a sensitivity of 83% (95% CI, 44%-97%), specificity of 98% (95% CI, 88%-100%), and positive likelihood ratio of 36.7 (95% CI, 5.1-263.0). Only 2 patients out of 50 were misclassified (one false positive and one false negative) at this level of the CPR, yielding an overall prognostic accuracy of 96% (95% CI, 87%-99%). Application of the positive likelihood ratio for a patient with any 2 positive tests yielded a posttest probability of 88% for nonsuccess with this treatment.

TABLE 3
Prognostic accuracy statistics for 3-level clinical prediction rule

CPR level	Sensitivity (95% CI)	Specificity (95% CI)	Positive likelihood ratio (95% CI)	Posttest probability of nonsuccess*
All 3 tests positive	0.21 (0.05-0.58)	0.99 (0.90-1.00)	19.29 (0.87-428.09)	80%
At least 2 tests positive	0.83 (0.44-0.97)	0.98 (0.88-1.00)	36.67 (5.11-263.01)	88%
At least 1 test positive	0.92 (0.56-0.99)	0.48 (0.34-0.62)	1.78 (1.26-2.52)	27%
CI, confidence interval; CPR, clinical prediction rule. *Assumes pretest probability of nonsuccess=17% (incidence in this sample).

In the sensitivity analysis, the CPR performed similarly well for patients in each of the 2 original studies when applied separately to the groups of patients. Among the 30 patients from the first trial² who had data for all 3 predictors in the CPR, only one was misclassified (a false positive), yielding a prognostic accuracy of 97% (95% CI, 83%-99%). Among the 20 patients from the second trial¹ who had data for all 3 predictors, only one was misclassified (a false negative), yielding a prognostic accuracy of 95% (95% CI, 76%-99%).

DISCUSSION

Family physicians and physical therapists should be able to discuss with confidence how any given patient with knee OA will likely respond to treatment options. Our study is a preliminary step toward defining the population of patients with knee OA who are unlikely to benefit from manual physical therapy and exercise. We found such patients to be those with height >1.71 m, ACL laxity, and pain with passive glides of the patellofemoral joint.

A limitation of our study is the retrospective nature of gathering data. However, retrospective CPR derivation studies have made valuable contributions to many areas of medical practice.^48-53 Additionally, if there had been uniformly available data across all patients, there may have been other, perhaps more powerful, predictors for treatment nonsuccess.

 

Patient height >1.71 m is the least intuitive of the predictors for nonsuccess, but that underscores the value of data-driven prediction rules. Variables regarded as unimportant in a typical clinical assessment may show clinical usefulness if validated in independent studies. It may be that in taller patients with knee OA, biomechanical forces are such that a positive response to conservative therapy is less likely—particularly in the presence of ligamentous laxity or patellofemoral dysfunction.

For most patients with knee OA, the combined intervention of manual physical therapy and exercise is clinically beneficial, relatively inexpensive, and has no known adverse effects.⁵⁴ However, unique circumstances may increase the importance of determining the likelihood that a patient will benefit. A validated CPR will facilitate timely decisions for those relatively few patients requiring alternative interventions. Although the rule is preliminary and needs to be validated, these results provide current best evidence to define patients with knee OA who are unlikely to respond to manual physical therapy and exercise.