126

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Osteomyelitis: Introduction

Osteomyelitis, an infection of bone that leads to tissue destruction and often to debility, can be caused by a wide variety of bacteria (including mycobacteria) and fungi and may be associated with viral infections. Its management must be individualized and depends on numerous factors, including the causative organism, the specific bone involved, vascular supply, nerve function, foreign bodies, recent injury, the physiologic status of the host, and associated comorbidities. The spectrum of the disease can range from extensive (e.g., tibial and vertebral osteomyelitis) to localized (e.g., bone invasion associated with a tooth abscess). Two major classification systems for osteomyelitis are used in making decisions about medical therapy and surgery. Lee and Waldvogel categorized cases as acute or chronic, hematogenous or contiguous, and with or without vascular compromise. The Cierny and Mader classification system for long-bone osteomyelitis encompasses the location and extent of the infection as well as a number of other factors.

Etiology (Table 126–1)

The foremost bacterial cause of osteomyelitis is Staphylococcus aureus. Gram-negative organisms such as Pseudomonas aeruginosa and Escherichia coli, coagulase-negative staphylococci, enterococci, and propionibacteria may also be involved. Mycobacterium tuberculosis is a common cause of osteomyelitis in countries with limited medical resources; other mycobacterial species that infect bone include M. marinum, M.chelonei, and M. fortuitum. Fungal etiologies include Candida, Coccidioides, Histoplasma, and Aspergillus species. Noninfectious pathogenic mechanisms that may cause disease mimicking osteomyelitis include avascular necrosis, rheumatoid diseases, neuropathy with chronic trauma, gout, and malignancies.

The precipitating event(s) for osteomyelitis vary greatly. The prosthetic joint implants and stabilization devices that are increasingly being used in orthopedic surgery are associated with complex infections. Trauma is also a common cause of infection, especially when a wound is involved and there is contamination of bone or surrounding tissue along with significant tissue damage or destruction. Even in the absence of an open wound or a compound fracture, damaged tissue and extravasated blood may slow the circulation, establishing a favorable medium for the growth of bacteria that may reach the area through low-level bacteremia from the peripheral venous circulation or from distal lymphatic channels. Bacteremia—whether due to endocarditis or due to seeding from other sites of infection (e.g., abscesses, boils, or vascular devices)—is also a frequent etiologic factor in osteomyelitis. Studies of S. aureus bacteremia indicate a rate of metastatic osteomyelitis approaching 28% if there is a prosthetic joint in place; S. aureus bacteremia can be complicated by the involvement of methicillin-resistant strains (MRSA), which are progressively replacing strains that are more susceptible to antibiotics. The overlapping circulations of the urinary tract and the spine may be a source of vertebral osteomyelitis due to urinary tract pathogens such as E. coli and Klebsiella. Additional predisposing factors include a poor arterial and venous supply, which may limit perfusion to bone to the point of an inadequate response and poor healing, even in patients with normal function. Host factors such as diabetes and its consequences contribute significantly to the development of osteomyelitis through impaired immunity with hyperglycemia, loss of sensation, vascular disease, and renal failure.

Epidemiology

In the United States, acute osteomyelitis affects 0.1–1.8% of the otherwise healthy adult population. After a foot puncture, 30–40% of adults with diabetes develop osteomyelitis. In this country, there has been a major change in the profile of certain bacterial pathogens, with the emergence of MRSA strains over the last decade. MRSA has become a source of great concern in hospitals, especially after surgery. The morbidity and economic consequences appear to be greater for MRSA osteomyelitis than for osteomyelitis caused by methicillin-sensitive S. aureus strains. However, it is not clear that these poorer outcomes for MRSA are due to new or more destructive virulence factors. Rather, they may simply be the result of a delay in effective antimicrobial treatment.

The types and etiologies of osteomyelitis vary by region and with time. The United States has seen a rise in infections related to the increasing use of orthopedic surgery for correction of deformities and implantation of screws, pins, rods, plates, and prosthetic joints. With the aging of populations and the epidemics of obesity and diabetes in some countries, the frequency of these predisposing factors continues to increase, requiring adaptations in treatment approaches. Any type of instrumentation may lead to infection in a small proportion of cases. Osteomyelitis attributable to orthopedic devices and surgical interventions is considerably less common in countries with limited medical resources, where tuberculosis may be the dominant infection and brucellosis is not unusual. In many of these areas, agricultural injuries, industrial accidents, and war wounds are much more common than in wealthy countries, and the pathogens causing infection reflect those injuries. Osteomyelitis is more common in situations where wounds cannot promptly be debrided and repaired, microbiology laboratories are not readily available, and effective antimicrobial agents are in short supply.

Pathogenesis

The most common predisposing factor for osteomyelitis is an area of bone or contiguous surrounding tissue that is abnormal in terms of viability, blood supply, sensation, or edema. The damaged tissue not only compromises healthy circulation to the area but may slow the flow of venous blood and lymph, thereby providing nutrients to bacteria and fueling ongoing damage. Host factors such as poor nutrition and immunosuppression may also be relevant. Diabetes in adults poses the most significant risk. Diabetic neuropathy adds to the progression of osteomyelitis as the patient may be unaware of infection as it spreads into the bone; the consequences include thousands of amputations each year. Additional sources of immunosuppression, such as chemotherapy and treatment with glucocorticoids or tumor necrosis factor (TNF) inhibitors, also inhibit normal defense mechanisms and thus predispose to more frequent and serious infections whose symptoms are diminished because of reduced inflammatory responses.

The bacteria involved in osteomyelitis perpetuate themselves by elaborating toxins that further damage tissues, including bone. S. aureus is particularly adept in this respect; it colonizes the nasal area in about one-third of healthy individuals and can produce a wide variety of cytokines, enzymes, and toxins that destroy tissue and affect neutrophil response. Some S. aureus bacteria survive uptake into the phagocytic vacuoles of macrophages and continue to cause disease and recrudescence by persistently eluding the usual defense mechanisms. This capacity for "hibernation" and persistence may allow S. aureus to remain dormant for decades before infection erupts at the sites of old injuries (e.g., shrapnel or other penetrating wounds).

Coagulase-negative staphylococci are generally not as virulent as S. aureus but have been found to persist by producing a biofilm that protects them from the host and apparently allows them to exist for many years on prosthetic joints, with minimal symptoms. The extent to which other organisms use biofilm to their advantage is unclear, but biofilm production probably plays a significant role in osteomyelitis, especially the chronic forms.

Multiple bacteria may be recovered from cultures, especially when there is an entry wound. Decisions about which ones to target in antibiotic therapy are often difficult. Common skin-dwelling and colonizing microbes usually do not need to be treated, and overtreatment in fact results in unnecessary toxicity and increases antimicrobial resistance among the organisms that survive. Anaerobic bacteria can often be recovered and may play a synergistic role with usual or unusual pathogens; specific therapy is sometimes beneficial in these situations.

The intrinsic factors of organisms that are responsible for persistence and bone destruction have not yet been identified. However, there is probably strain-to-strain variation in virulence factors produced by particular clones, with some strains consequently much more virulent than others. The prevention of biofilm production merits investigation in this regard.

Approach to the Patient: Osteomyelitis

The best approach to the care of a patient with significant osteomyelitis is to assemble a team of providers who can work together in considering the microbiology of the infection and make sound decisions about antibiotic therapy and surgery. The most effective program will include evaluation and management of antibiotics, microbiology, pharmacology, glucose levels, vascular disease, neuropathy, and renal function, with close follow-up by a knowledgeable physician who is interested in leading the team in coordinating care.

When osteomyelitis is suspected, a careful, methodical approach is needed (see "Clinical Manifestations and Diagnosis," below). Patients should be educated about the significance of an infection that involves bone, especially if risk factors cannot be eliminated. Blood tests, cultures, standard radiography, scans, biopsies, and surgery may all be necessary for a clear diagnosis and full delineation of the pathogen. Collection of this baseline information can be very important in both early and late decision-making.

Initial evaluations for osteomyelitis must be aggressive, as the infection can progress rapidly in the absence of antibiotic therapy effective against the wide variety of potential pathogens. Inadequacies in cultures, surgery, or temporizing measures may greatly exacerbate the damage caused by the infection. Hospitalization may be indicated for rapid multispecialty evaluation, imaging, and stabilization of complex infections such as with a diabetic foot. Outpatient therapy may not be adequate for the teamwork and interventions needed. Early admission and procedures may actually shorten the length of hospital stay.

The physician should inform the patient about the value of all the necessary evaluations, the implications of surgery, and the possibility of a prolonged course of IV antibiotic therapy, whether in the hospital or at home. A patient's fear of amputation can lead to inordinate delays in seeking treatment that allow the infection to progress. Moreover, it is not unusual for a patient to refuse surgery and amputation even though such treatments will clearly increase the likelihood of a functional lifestyle. Therefore, it is best to prepare patients early on if there may be negative outcomes such as amputation and perhaps to set criteria and timelines for success or failure of therapy and interventions.

Clinical Manifestations and Diagnosis

Diagnosis of acute osteomyelitis within the first few weeks of onset is important and is usually relatively easy. If the diagnosis is missed, however, the symptoms may become chronic, with slow progression or a dormant phase of several years.

A thorough history and physical examination are the mainstays of evaluation for osteomyelitis. A clear pattern of pain, swelling, and possibly drainage after surgery or injury should raise suspicion, but such indicators may not all be present, even in a patient with neuropathy, compromised circulation, chronic edema, organ failure, diabetes, or other predisposing factors. Direct questions about previous injuries, infections, surgeries, or hardware implantation—even decades earlier—can yield information critical in guiding empirical antibiotic therapy and surgery. A history of injury is particularly important, even if the skin was not broken and there were no clinical signs of bacteremia. It is not unusual for a soft tissue injury to serve as a nidus of secondary bone infection, presumably seeded by low-level bacteremia and often occurring without symptoms. Other sources of seeding may include boils, abscesses, cellulitis, or injection sites. A careful examination is essential in identifying additional predisposing factors and assessing the role of comorbidities such as neuropathy, arterial disease, venous insufficiency, and chronic trauma that can lead to severe accumulation of callus in insensate feet.

Careful consideration and assessment of disorders that may mimic or accompany osteomyelitis are essential. Arthritis, gout, ischemia, neuropathies, and recent surgery may be diagnosed when osteomyelitis is the real cause of symptoms on a cofactor. For example, chronic back pain may be attributed to degenerative arthritis, but there can be a substantial loss of neurologic function if the pain is actually due to diskitis with vertebral osteomyelitis.

Correctly diagnosing osteomyelitis early has crucial implications for later function, disability, treatment cost, and risk of a fatal outcome. A variety of tools must be used to definitively diagnose or conclusively rule out an infection. A standard x-ray is a good starting point that can reveal a variety of abnormalities (Fig. 126-1A) and may eliminate the need for further imaging studies. Bone loss, sequestra, periosteal elevation or swelling (which can develop early on), and shadows around foreign bodies are hallmarks of bone infection. However, these findings may also be found with other disorders, such as tumors, trauma, avascular necrosis, and gout. Standard two-dimensional images can be of limited value in assessing complex bones. The value of radiology may be limited by the time required for an infection to become apparent; actual dissolution or resorption of bone due to infection may not be apparent for several weeks or more.




Depending on the results of the initial x-ray, further investigations with invasive techniques may be appropriate. Collection of pus by needle aspiration through a clean area from a closed pocket not only documents bone infection but also permits recovery and evaluation of the pathogen(s). A culture of a wound swab may be of some value but is clearly less reliable in identifying the real culprit(s), which may be present in the bone but absent from its surface. Biopsy provides more accurate microbiologic information than needle aspiration and supplies tissue for pathology studies, which may be helpful. Some organisms that usually are not recovered (in a timely fashion or at all) by standard cultures may be rendered visible with special staining of tissue samples. Unfortunately, the size of the needle used for needle biopsy may not be appropriate for small bones of the hands or feet. Open surgical exploration, biopsy, and drainage, which can provide high-quality tissue samples for culture and pathology and offer a view of the infected bone and surrounding area, should also be considered. Necrotic tissue can be removed and circulation assessed with one procedure. Polymerase chain reaction and other sequencing technologies are increasingly being used to detect and identify specific organisms—and even to determine their susceptibilities—within hours instead of days or weeks. Information on specific strains of unusual organisms may be of value, especially in difficult cases.

Laboratory tests are useful in assessing osteomyelitis but usually do not yield specific information relevant to etiology or severity. Leukocytosis may be noted in acute infection but is less likely in chronic infection, which may also be associated with anemia. Determination of the erythrocyte sedimentation rate (ESR) is a simple, inexpensive aid to diagnosis; it serves as an indicator of response with S. aureus infections but is not as useful for gram-negative infections because the cytokines and inflammatory elements that result in elevations are different for gram-positive (S. aureus) than for gram-negative infections. C-reactive protein (CRP) measurement may be helpful, especially in the evaluation of children, but may not be as useful as an ESR determination in some cases. CRP changes occur earlier in response to bacterial infection. Both ESR and CRP determinations have significant limitations in multifactorial diseases, with elevated values reflecting conditions other than osteomyelitis. Additional laboratory tests for diseases associated with bone loss that may mimic or complicate osteomyelitis should include measurement of glucose levels and tests for renal failure, gout, vasculitis, and rheumatoid diseases.

Additional imaging studies may be of value if the diagnosis remains unclear. CT can delineate bone more clearly than standard radiography and offers three-dimensional displays that can be extremely useful in detecting abnormalities and devising a surgical approach. MRI (Fig. 126-1B–D) provides high-quality images of the soft tissue around the bone abnormality and may be essential in diagnosing an epidural abscess related to vertebral osteomyelitis. Technetium and leukocyte isotope scans offer insight into the activity of the disease process and the affected site(s). Although these additional screening tools may be helpful in evaluation and decision-making, they may not be cost-effective.

Treatment: Osteomyelitis

Therapy for osteomyelitis is challenging because of the variety of causative organisms, the usual comorbidities, the need for a prolonged course and IV administration, the common physical limitations of the patient, and high costs. An aggressive therapeutic approach is warranted given the dire consequences of failure of medical therapy, which can include loss of limbs. The sooner the infection is diagnosed and treated, the better the outcome and the less damage done during delays in intervention. Antibiotic therapy should be used aggressively to stop disease progression and should be designed to avoid the development of resistant organisms. Early surgical intervention (e.g., debridement) can confirm the infection, identify and characterize the etiologic agent(s), and remove dead or devitalized tissue that may be providing bacteria with nutrients and allowing them to spread. A variety of antibiotics are available for most of the likely pathogens (Table 126–2), although the most common pathogen—S. aureus—continues to evolve mechanisms to elude these drugs. MRSA strains represent an increasing problem in both the hospital and the community. Staphylococci and Enterobacteriaceae resistant to even more antibiotics than MRSA appear to be evolving.



The most common targets for empirical antibiotic therapy are staphylococci, which are carried asymptomatically in and around the nares by nearly one-third of healthy people. The common -lactam antibiotics provide excellent results against methicillin-sensitive S. aureus strains. Oxacillin and nafcillin are first-line agents but may elicit more adverse reactions than cephalosporins. Cefazolin is a reasonable alternative in the hospital, but ceftriaxone is preferred as an outpatient drug because it can be given (by the IV or IM route) only once a day.

MRSA strains have been controlled with vancomycin for many years, but this drug appears to be losing its effectiveness against these microbes. New antibiotics have been designed to fill this need, although their efficacy has not been documented. In an outpatient setting, vancomycin does not appear to be as effective against methicillin-susceptible staphylococcal osteomyelitis as oxacillin or ceftriaxone. Publications about the value of daptomycin for osteomyelitis are encouraging. Tigecycline is active against MRSA but is only bacteriostatic and does not yet have a well-established outcomes record. Telavancin may also be of value against vancomycin-resistant staphylococci but has not yet been adequately tested for bone infections.

Additional antimicrobial agents for use against staphylococcal infections include linezolid, which offers the advantage of both oral and IV formulations but is bacteriostatic and has not yet been well studied. Moreover, its use—although apparently less expensive than that of other parenteral drugs—is limited by its cost. Clindamycin can also be used as both an IV and an oral agent, although antimicrobial resistance is a growing problem. Rifampin, a potential adjunct to other antistaphylococcal agents, is highly active in vitro and can penetrate phagocytic vacuoles to reach staphylococci therein. Unfortunately, resistance develops rapidly if rifampin is used alone, and clinical outcomes are not always as good as anticipated. Other agents, such as aminoglycosides, folic acid inhibitors, and macrolides, may play a limited role; they generally are neither as effective nor as toxic as other available agents.

Fluoroquinolone antibiotics offer both IV and oral therapy options and are often included in the standard recommendation for treatment of many susceptible strains of Enterobacteriaceae and Pseudomonas species. Drugs of this class do, however, have some limitations in terms of emerging resistance (even during therapy) and may exert some adverse neuromuscular effects (e.g., tendon rupture and impaired healing) that may be particularly relevant to the prolonged courses of antibiotics usually needed to cure the infection. In general, fluoroquinolones should not be used to treat S. aureus infections because of these limitations and the availability of better-studied antibiotics.

The optimal route and duration of therapy for osteomyelitis remain controversial. The usual recommendations stem from a 1970 study in which cases of osteomyelitis were characterized and outcomes were evaluated in relation to the duration of IV therapy. Better outcomes appeared to be related to a course of 4 weeks in some types of infection. Even though the characteristics of the bacteria and the available antibiotics were quite different at that time, a 4- to 6-week course of IV therapy remains the standard and is the usual recommended minimum. This recommendation has been challenged in pediatric studies in light of increasing evidence that oral agents and shorter courses may be adequate. Because some of the active agents reach comparable levels when given by mouth, a switch from the recommended IV administration to oral therapy may be appropriate in some situations. The proper duration of antimicrobial therapy depends on a variety of factors, including the infecting organism, the bone involved, surgical procedures, and drug tolerance and safety. Prolonged courses may be justified by extensive disease, immunocompromise, poor clinical response, and vertebral osteomyelitis. Whether a bone infection has truly been cured becomes clear only over time; relapse is not uncommon and may occur years later, especially in patients with ongoing risk factors and comorbidities. The literature suggests that a 6-month follow-up period is adequate to determine the success of treatment. Patients should be followed for at least that long, even though antibiotics have been discontinued. The possibility of relapses and the potential for their prevention should not be overlooked.

Surgery is an important tool in the treatment of osteomyelitis, offering the benefits of direct observation, prompt removal of all devitalized tissue and bone, and drainage of the infection site. Nevertheless, it is not without risk, and loss of bone or other tissue may adversely affect function. In addition, because bone may regenerate to some degree when infection is eradicated, surgery is not always needed. Surgical approaches vary with the bone involved and the extent of disease. The Cierny-Mader classification system is helpful when three-dimensional imaging is done, and MRI may help determine the viability of bone or marrow. Residual dead spaces are a source of concern and may require tissue flaps and closure. Local antibiotics and impregnated cement or beads may be of value but not should not replace IV antibiotic therapy without further study. If surgery is performed and most or all of the infected bone is removed, a full 4- to 6-week course of IV therapy probably is not necessary. However, the precise duration that is required is not clear and most likely depends primarily on the other factors involved in individual cases. One week of IV therapy after surgery may be justified to ensure pathogen eradication and healing.

Outpatient parenteral antibiotic therapy (OPAT) is a valuable means of providing the long course of IV antibiotics that is considered the standard of care and has been proven efficacious over decades. Despite potential risks outside the hospital that patients and their providers must consider, OPAT is safe and effective when properly managed and administered. This approach is conducive to a better quality of life in a familiar setting, is considered safer because of the lack of exposure to hospital-related infections (which affect 1 patient in every 20 admitted), is much less expensive than treatment administered in the hospital, and generally facilitates recovery, often allowing the patient to return to work or resume other day-to-day activities during the treatment course.

Complications

The complications of osteomyelitis are numerous and are most commonly related to loss of full function of the bone or supporting tissues. Fractures are more likely with progressive disease. Local spread and dissemination of infection are also possible. Misdiagnosis is particularly likely when another disease is complicating the infection. In rare instances, chronic inflammation and infection may lead to malignant transformation into squamous cell carcinoma or sarcoma.

Prognosis

The outcomes of osteomyelitis vary tremendously depending on the bone involved, the predisposing factors, the underlying diseases, and the treatment provided. Standard guidelines cannot be applied uniformly; e.g., a case of mandible infection arising from a tooth abscess may be cured with an extraction alone, whereas a case of vertebral osteomyelitis may require a prolonged course of IV therapy as it cannot be approached surgically without neurologic sequelae. For large bones, the 4- to 6-week course of IV therapy still seems reasonable, although recent studies suggest that with some new antimicrobial agents a shorter course of IV therapy, possibly with an early switch to oral therapy, may be sufficient. Determining the outcome even of long-bone osteomyelitis is complicated by uncertainty as to the duration of follow-up needed. The actual outcome in terms of debility and limb salvage may be as dependent on underlying and complicating factors and care as it is on antibiotic therapy.

Prevention

Osteomyelitis can be prevented in some instances by better infection-control measures, especially before surgery. Both mupirocin and chlorhexidine are of proven value in preventing operative infections, which are an increasing cause of bone infections associated with implanted material. Prompt treatment of bacteremia and elimination of sources of infection (e.g., boils or folliculitis) before surgery and in other situations may prevent infections. Aggressive surgical management of injuries may also help avoid the constellation of factors that lead to bone infections.

Awareness of persistent sites of infection and reasonable attempts at eradication may promote prevention. Many persistent infections that do not initially impair function or cause pain are ignored by patients; an example is provided by the classic problem of diabetic foot infections, with ulcers that burrow into the soles of insensate feet and often reach bones. Likewise, sacral ulcers are often overlooked or ignored both by physicians and by patients with neurologic impairment. Attempts to eradicate or close entry wounds are critical and should be undertaken early on.

126

Osteomyelitis: Introduction

Osteomyelitis, an infection of bone that leads to tissue destruction and often to debility, can be caused by a wide variety of bacteria (including mycobacteria) and fungi and may be associated with viral infections. Its management must be individualized and depends on numerous factors, including the causative organism, the specific bone involved, vascular supply, nerve function, foreign bodies, recent injury, the physiologic status of the host, and associated comorbidities. The spectrum of the disease can range from extensive (e.g., tibial and vertebral osteomyelitis) to localized (e.g., bone invasion associated with a tooth abscess). Two major classification systems for osteomyelitis are used in making decisions about medical therapy and surgery. Lee and Waldvogel categorized cases as acute or chronic, hematogenous or contiguous, and with or without vascular compromise. The Cierny and Mader classification system for long-bone osteomyelitis encompasses the location and extent of the infection as well as a number of other factors.

Etiology (Table 126–1)

The foremost bacterial cause of osteomyelitis is Staphylococcus aureus. Gram-negative organisms such as Pseudomonas aeruginosa and Escherichia coli, coagulase-negative staphylococci, enterococci, and propionibacteria may also be involved. Mycobacterium tuberculosis is a common cause of osteomyelitis in countries with limited medical resources; other mycobacterial species that infect bone include M. marinum, M.chelonei, and M. fortuitum. Fungal etiologies include Candida, Coccidioides, Histoplasma, and Aspergillus species. Noninfectious pathogenic mechanisms that may cause disease mimicking osteomyelitis include avascular necrosis, rheumatoid diseases, neuropathy with chronic trauma, gout, and malignancies.

The precipitating event(s) for osteomyelitis vary greatly. The prosthetic joint implants and stabilization devices that are increasingly being used in orthopedic surgery are associated with complex infections. Trauma is also a common cause of infection, especially when a wound is involved and there is contamination of bone or surrounding tissue along with significant tissue damage or destruction. Even in the absence of an open wound or a compound fracture, damaged tissue and extravasated blood may slow the circulation, establishing a favorable medium for the growth of bacteria that may reach the area through low-level bacteremia from the peripheral venous circulation or from distal lymphatic channels. Bacteremia—whether due to endocarditis or due to seeding from other sites of infection (e.g., abscesses, boils, or vascular devices)—is also a frequent etiologic factor in osteomyelitis. Studies of S. aureus bacteremia indicate a rate of metastatic osteomyelitis approaching 28% if there is a prosthetic joint in place; S. aureus bacteremia can be complicated by the involvement of methicillin-resistant strains (MRSA), which are progressively replacing strains that are more susceptible to antibiotics. The overlapping circulations of the urinary tract and the spine may be a source of vertebral osteomyelitis due to urinary tract pathogens such as E. coli and Klebsiella. Additional predisposing factors include a poor arterial and venous supply, which may limit perfusion to bone to the point of an inadequate response and poor healing, even in patients with normal function. Host factors such as diabetes and its consequences contribute significantly to the development of osteomyelitis through impaired immunity with hyperglycemia, loss of sensation, vascular disease, and renal failure.

Epidemiology

In the United States, acute osteomyelitis affects 0.1–1.8% of the otherwise healthy adult population. After a foot puncture, 30–40% of adults with diabetes develop osteomyelitis. In this country, there has been a major change in the profile of certain bacterial pathogens, with the emergence of MRSA strains over the last decade. MRSA has become a source of great concern in hospitals, especially after surgery. The morbidity and economic consequences appear to be greater for MRSA osteomyelitis than for osteomyelitis caused by methicillin-sensitive S. aureus strains. However, it is not clear that these poorer outcomes for MRSA are due to new or more destructive virulence factors. Rather, they may simply be the result of a delay in effective antimicrobial treatment.

The types and etiologies of osteomyelitis vary by region and with time. The United States has seen a rise in infections related to the increasing use of orthopedic surgery for correction of deformities and implantation of screws, pins, rods, plates, and prosthetic joints. With the aging of populations and the epidemics of obesity and diabetes in some countries, the frequency of these predisposing factors continues to increase, requiring adaptations in treatment approaches. Any type of instrumentation may lead to infection in a small proportion of cases. Osteomyelitis attributable to orthopedic devices and surgical interventions is considerably less common in countries with limited medical resources, where tuberculosis may be the dominant infection and brucellosis is not unusual. In many of these areas, agricultural injuries, industrial accidents, and war wounds are much more common than in wealthy countries, and the pathogens causing infection reflect those injuries. Osteomyelitis is more common in situations where wounds cannot promptly be debrided and repaired, microbiology laboratories are not readily available, and effective antimicrobial agents are in short supply.

Pathogenesis

The most common predisposing factor for osteomyelitis is an area of bone or contiguous surrounding tissue that is abnormal in terms of viability, blood supply, sensation, or edema. The damaged tissue not only compromises healthy circulation to the area but may slow the flow of venous blood and lymph, thereby providing nutrients to bacteria and fueling ongoing damage. Host factors such as poor nutrition and immunosuppression may also be relevant. Diabetes in adults poses the most significant risk. Diabetic neuropathy adds to the progression of osteomyelitis as the patient may be unaware of infection as it spreads into the bone; the consequences include thousands of amputations each year. Additional sources of immunosuppression, such as chemotherapy and treatment with glucocorticoids or tumor necrosis factor (TNF) inhibitors, also inhibit normal defense mechanisms and thus predispose to more frequent and serious infections whose symptoms are diminished because of reduced inflammatory responses.

The bacteria involved in osteomyelitis perpetuate themselves by elaborating toxins that further damage tissues, including bone. S. aureus is particularly adept in this respect; it colonizes the nasal area in about one-third of healthy individuals and can produce a wide variety of cytokines, enzymes, and toxins that destroy tissue and affect neutrophil response. Some S. aureus bacteria survive uptake into the phagocytic vacuoles of macrophages and continue to cause disease and recrudescence by persistently eluding the usual defense mechanisms. This capacity for "hibernation" and persistence may allow S. aureus to remain dormant for decades before infection erupts at the sites of old injuries (e.g., shrapnel or other penetrating wounds).

Coagulase-negative staphylococci are generally not as virulent as S. aureus but have been found to persist by producing a biofilm that protects them from the host and apparently allows them to exist for many years on prosthetic joints, with minimal symptoms. The extent to which other organisms use biofilm to their advantage is unclear, but biofilm production probably plays a significant role in osteomyelitis, especially the chronic forms.

Multiple bacteria may be recovered from cultures, especially when there is an entry wound. Decisions about which ones to target in antibiotic therapy are often difficult. Common skin-dwelling and colonizing microbes usually do not need to be treated, and overtreatment in fact results in unnecessary toxicity and increases antimicrobial resistance among the organisms that survive. Anaerobic bacteria can often be recovered and may play a synergistic role with usual or unusual pathogens; specific therapy is sometimes beneficial in these situations.

The intrinsic factors of organisms that are responsible for persistence and bone destruction have not yet been identified. However, there is probably strain-to-strain variation in virulence factors produced by particular clones, with some strains consequently much more virulent than others. The prevention of biofilm production merits investigation in this regard.

Approach to the Patient: Osteomyelitis

The best approach to the care of a patient with significant osteomyelitis is to assemble a team of providers who can work together in considering the microbiology of the infection and make sound decisions about antibiotic therapy and surgery. The most effective program will include evaluation and management of antibiotics, microbiology, pharmacology, glucose levels, vascular disease, neuropathy, and renal function, with close follow-up by a knowledgeable physician who is interested in leading the team in coordinating care.

When osteomyelitis is suspected, a careful, methodical approach is needed (see "Clinical Manifestations and Diagnosis," below). Patients should be educated about the significance of an infection that involves bone, especially if risk factors cannot be eliminated. Blood tests, cultures, standard radiography, scans, biopsies, and surgery may all be necessary for a clear diagnosis and full delineation of the pathogen. Collection of this baseline information can be very important in both early and late decision-making.

Initial evaluations for osteomyelitis must be aggressive, as the infection can progress rapidly in the absence of antibiotic therapy effective against the wide variety of potential pathogens. Inadequacies in cultures, surgery, or temporizing measures may greatly exacerbate the damage caused by the infection. Hospitalization may be indicated for rapid multispecialty evaluation, imaging, and stabilization of complex infections such as with a diabetic foot. Outpatient therapy may not be adequate for the teamwork and interventions needed. Early admission and procedures may actually shorten the length of hospital stay.

The physician should inform the patient about the value of all the necessary evaluations, the implications of surgery, and the possibility of a prolonged course of IV antibiotic therapy, whether in the hospital or at home. A patient's fear of amputation can lead to inordinate delays in seeking treatment that allow the infection to progress. Moreover, it is not unusual for a patient to refuse surgery and amputation even though such treatments will clearly increase the likelihood of a functional lifestyle. Therefore, it is best to prepare patients early on if there may be negative outcomes such as amputation and perhaps to set criteria and timelines for success or failure of therapy and interventions.

Clinical Manifestations and Diagnosis

Diagnosis of acute osteomyelitis within the first few weeks of onset is important and is usually relatively easy. If the diagnosis is missed, however, the symptoms may become chronic, with slow progression or a dormant phase of several years.

A thorough history and physical examination are the mainstays of evaluation for osteomyelitis. A clear pattern of pain, swelling, and possibly drainage after surgery or injury should raise suspicion, but such indicators may not all be present, even in a patient with neuropathy, compromised circulation, chronic edema, organ failure, diabetes, or other predisposing factors. Direct questions about previous injuries, infections, surgeries, or hardware implantation—even decades earlier—can yield information critical in guiding empirical antibiotic therapy and surgery. A history of injury is particularly important, even if the skin was not broken and there were no clinical signs of bacteremia. It is not unusual for a soft tissue injury to serve as a nidus of secondary bone infection, presumably seeded by low-level bacteremia and often occurring without symptoms. Other sources of seeding may include boils, abscesses, cellulitis, or injection sites. A careful examination is essential in identifying additional predisposing factors and assessing the role of comorbidities such as neuropathy, arterial disease, venous insufficiency, and chronic trauma that can lead to severe accumulation of callus in insensate feet.

Careful consideration and assessment of disorders that may mimic or accompany osteomyelitis are essential. Arthritis, gout, ischemia, neuropathies, and recent surgery may be diagnosed when osteomyelitis is the real cause of symptoms on a cofactor. For example, chronic back pain may be attributed to degenerative arthritis, but there can be a substantial loss of neurologic function if the pain is actually due to diskitis with vertebral osteomyelitis.

Correctly diagnosing osteomyelitis early has crucial implications for later function, disability, treatment cost, and risk of a fatal outcome. A variety of tools must be used to definitively diagnose or conclusively rule out an infection. A standard x-ray is a good starting point that can reveal a variety of abnormalities (Fig. 126-1A) and may eliminate the need for further imaging studies. Bone loss, sequestra, periosteal elevation or swelling (which can develop early on), and shadows around foreign bodies are hallmarks of bone infection. However, these findings may also be found with other disorders, such as tumors, trauma, avascular necrosis, and gout. Standard two-dimensional images can be of limited value in assessing complex bones. The value of radiology may be limited by the time required for an infection to become apparent; actual dissolution or resorption of bone due to infection may not be apparent for several weeks or more.

Depending on the results of the initial x-ray, further investigations with invasive techniques may be appropriate. Collection of pus by needle aspiration through a clean area from a closed pocket not only documents bone infection but also permits recovery and evaluation of the pathogen(s). A culture of a wound swab may be of some value but is clearly less reliable in identifying the real culprit(s), which may be present in the bone but absent from its surface. Biopsy provides more accurate microbiologic information than needle aspiration and supplies tissue for pathology studies, which may be helpful. Some organisms that usually are not recovered (in a timely fashion or at all) by standard cultures may be rendered visible with special staining of tissue samples. Unfortunately, the size of the needle used for needle biopsy may not be appropriate for small bones of the hands or feet. Open surgical exploration, biopsy, and drainage, which can provide high-quality tissue samples for culture and pathology and offer a view of the infected bone and surrounding area, should also be considered. Necrotic tissue can be removed and circulation assessed with one procedure. Polymerase chain reaction and other sequencing technologies are increasingly being used to detect and identify specific organisms—and even to determine their susceptibilities—within hours instead of days or weeks. Information on specific strains of unusual organisms may be of value, especially in difficult cases.

Laboratory tests are useful in assessing osteomyelitis but usually do not yield specific information relevant to etiology or severity. Leukocytosis may be noted in acute infection but is less likely in chronic infection, which may also be associated with anemia. Determination of the erythrocyte sedimentation rate (ESR) is a simple, inexpensive aid to diagnosis; it serves as an indicator of response with S. aureus infections but is not as useful for gram-negative infections because the cytokines and inflammatory elements that result in elevations are different for gram-positive (S. aureus) than for gram-negative infections. C-reactive protein (CRP) measurement may be helpful, especially in the evaluation of children, but may not be as useful as an ESR determination in some cases. CRP changes occur earlier in response to bacterial infection. Both ESR and CRP determinations have significant limitations in multifactorial diseases, with elevated values reflecting conditions other than osteomyelitis. Additional laboratory tests for diseases associated with bone loss that may mimic or complicate osteomyelitis should include measurement of glucose levels and tests for renal failure, gout, vasculitis, and rheumatoid diseases.

Additional imaging studies may be of value if the diagnosis remains unclear. CT can delineate bone more clearly than standard radiography and offers three-dimensional displays that can be extremely useful in detecting abnormalities and devising a surgical approach. MRI (Fig. 126-1B–D) provides high-quality images of the soft tissue around the bone abnormality and may be essential in diagnosing an epidural abscess related to vertebral osteomyelitis. Technetium and leukocyte isotope scans offer insight into the activity of the disease process and the affected site(s). Although these additional screening tools may be helpful in evaluation and decision-making, they may not be cost-effective.

Treatment: Osteomyelitis

Therapy for osteomyelitis is challenging because of the variety of causative organisms, the usual comorbidities, the need for a prolonged course and IV administration, the common physical limitations of the patient, and high costs. An aggressive therapeutic approach is warranted given the dire consequences of failure of medical therapy, which can include loss of limbs. The sooner the infection is diagnosed and treated, the better the outcome and the less damage done during delays in intervention. Antibiotic therapy should be used aggressively to stop disease progression and should be designed to avoid the development of resistant organisms. Early surgical intervention (e.g., debridement) can confirm the infection, identify and characterize the etiologic agent(s), and remove dead or devitalized tissue that may be providing bacteria with nutrients and allowing them to spread. A variety of antibiotics are available for most of the likely pathogens (Table 126–2), although the most common pathogen—S. aureus—continues to evolve mechanisms to elude these drugs. MRSA strains represent an increasing problem in both the hospital and the community. Staphylococci and Enterobacteriaceae resistant to even more antibiotics than MRSA appear to be evolving.

The most common targets for empirical antibiotic therapy are staphylococci, which are carried asymptomatically in and around the nares by nearly one-third of healthy people. The common -lactam antibiotics provide excellent results against methicillin-sensitive S. aureus strains. Oxacillin and nafcillin are first-line agents but may elicit more adverse reactions than cephalosporins. Cefazolin is a reasonable alternative in the hospital, but ceftriaxone is preferred as an outpatient drug because it can be given (by the IV or IM route) only once a day.

MRSA strains have been controlled with vancomycin for many years, but this drug appears to be losing its effectiveness against these microbes. New antibiotics have been designed to fill this need, although their efficacy has not been documented. In an outpatient setting, vancomycin does not appear to be as effective against methicillin-susceptible staphylococcal osteomyelitis as oxacillin or ceftriaxone. Publications about the value of daptomycin for osteomyelitis are encouraging. Tigecycline is active against MRSA but is only bacteriostatic and does not yet have a well-established outcomes record. Telavancin may also be of value against vancomycin-resistant staphylococci but has not yet been adequately tested for bone infections.

Additional antimicrobial agents for use against staphylococcal infections include linezolid, which offers the advantage of both oral and IV formulations but is bacteriostatic and has not yet been well studied. Moreover, its use—although apparently less expensive than that of other parenteral drugs—is limited by its cost. Clindamycin can also be used as both an IV and an oral agent, although antimicrobial resistance is a growing problem. Rifampin, a potential adjunct to other antistaphylococcal agents, is highly active in vitro and can penetrate phagocytic vacuoles to reach staphylococci therein. Unfortunately, resistance develops rapidly if rifampin is used alone, and clinical outcomes are not always as good as anticipated. Other agents, such as aminoglycosides, folic acid inhibitors, and macrolides, may play a limited role; they generally are neither as effective nor as toxic as other available agents.

Fluoroquinolone antibiotics offer both IV and oral therapy options and are often included in the standard recommendation for treatment of many susceptible strains of Enterobacteriaceae and Pseudomonas species. Drugs of this class do, however, have some limitations in terms of emerging resistance (even during therapy) and may exert some adverse neuromuscular effects (e.g., tendon rupture and impaired healing) that may be particularly relevant to the prolonged courses of antibiotics usually needed to cure the infection. In general, fluoroquinolones should not be used to treat S. aureus infections because of these limitations and the availability of better-studied antibiotics.

The optimal route and duration of therapy for osteomyelitis remain controversial. The usual recommendations stem from a 1970 study in which cases of osteomyelitis were characterized and outcomes were evaluated in relation to the duration of IV therapy. Better outcomes appeared to be related to a course of 4 weeks in some types of infection. Even though the characteristics of the bacteria and the available antibiotics were quite different at that time, a 4- to 6-week course of IV therapy remains the standard and is the usual recommended minimum. This recommendation has been challenged in pediatric studies in light of increasing evidence that oral agents and shorter courses may be adequate. Because some of the active agents reach comparable levels when given by mouth, a switch from the recommended IV administration to oral therapy may be appropriate in some situations. The proper duration of antimicrobial therapy depends on a variety of factors, including the infecting organism, the bone involved, surgical procedures, and drug tolerance and safety. Prolonged courses may be justified by extensive disease, immunocompromise, poor clinical response, and vertebral osteomyelitis. Whether a bone infection has truly been cured becomes clear only over time; relapse is not uncommon and may occur years later, especially in patients with ongoing risk factors and comorbidities. The literature suggests that a 6-month follow-up period is adequate to determine the success of treatment. Patients should be followed for at least that long, even though antibiotics have been discontinued. The possibility of relapses and the potential for their prevention should not be overlooked.

Surgery is an important tool in the treatment of osteomyelitis, offering the benefits of direct observation, prompt removal of all devitalized tissue and bone, and drainage of the infection site. Nevertheless, it is not without risk, and loss of bone or other tissue may adversely affect function. In addition, because bone may regenerate to some degree when infection is eradicated, surgery is not always needed. Surgical approaches vary with the bone involved and the extent of disease. The Cierny-Mader classification system is helpful when three-dimensional imaging is done, and MRI may help determine the viability of bone or marrow. Residual dead spaces are a source of concern and may require tissue flaps and closure. Local antibiotics and impregnated cement or beads may be of value but not should not replace IV antibiotic therapy without further study. If surgery is performed and most or all of the infected bone is removed, a full 4- to 6-week course of IV therapy probably is not necessary. However, the precise duration that is required is not clear and most likely depends primarily on the other factors involved in individual cases. One week of IV therapy after surgery may be justified to ensure pathogen eradication and healing.

Outpatient parenteral antibiotic therapy (OPAT) is a valuable means of providing the long course of IV antibiotics that is considered the standard of care and has been proven efficacious over decades. Despite potential risks outside the hospital that patients and their providers must consider, OPAT is safe and effective when properly managed and administered. This approach is conducive to a better quality of life in a familiar setting, is considered safer because of the lack of exposure to hospital-related infections (which affect 1 patient in every 20 admitted), is much less expensive than treatment administered in the hospital, and generally facilitates recovery, often allowing the patient to return to work or resume other day-to-day activities during the treatment course.

Complications

The complications of osteomyelitis are numerous and are most commonly related to loss of full function of the bone or supporting tissues. Fractures are more likely with progressive disease. Local spread and dissemination of infection are also possible. Misdiagnosis is particularly likely when another disease is complicating the infection. In rare instances, chronic inflammation and infection may lead to malignant transformation into squamous cell carcinoma or sarcoma.

Prognosis

The outcomes of osteomyelitis vary tremendously depending on the bone involved, the predisposing factors, the underlying diseases, and the treatment provided. Standard guidelines cannot be applied uniformly; e.g., a case of mandible infection arising from a tooth abscess may be cured with an extraction alone, whereas a case of vertebral osteomyelitis may require a prolonged course of IV therapy as it cannot be approached surgically without neurologic sequelae. For large bones, the 4- to 6-week course of IV therapy still seems reasonable, although recent studies suggest that with some new antimicrobial agents a shorter course of IV therapy, possibly with an early switch to oral therapy, may be sufficient. Determining the outcome even of long-bone osteomyelitis is complicated by uncertainty as to the duration of follow-up needed. The actual outcome in terms of debility and limb salvage may be as dependent on underlying and complicating factors and care as it is on antibiotic therapy.

Prevention

Osteomyelitis can be prevented in some instances by better infection-control measures, especially before surgery. Both mupirocin and chlorhexidine are of proven value in preventing operative infections, which are an increasing cause of bone infections associated with implanted material. Prompt treatment of bacteremia and elimination of sources of infection (e.g., boils or folliculitis) before surgery and in other situations may prevent infections. Aggressive surgical management of injuries may also help avoid the constellation of factors that lead to bone infections.

Awareness of persistent sites of infection and reasonable attempts at eradication may promote prevention. Many persistent infections that do not initially impair function or cause pain are ignored by patients; an example is provided by the classic problem of diabetic foot infections, with ulcers that burrow into the soles of insensate feet and often reach bones. Likewise, sacral ulcers are often overlooked or ignored both by physicians and by patients with neurologic impairment. Attempts to eradicate or close entry wounds are critical and should be undertaken early on.

125

Infections of the Skin, Muscles, and Soft Tissues: Introduction

Anatomic Relationships: Clues to the Diagnosisof Soft Tissue Infections

Skin and soft tissue infections have been common human afflictions for centuries. However, between 2000 and 2004, hospital admissions for skin and soft tissue infections rose by 27%, a remarkable increase that was attributable largely to the emergence of the USA300 clone of methicillin-resistant Staphylococcus aureus (MRSA). This chapter provides an anatomic approach to understanding the types of soft tissue infections and the diverse microbes responsible.

Protection against infection of the epidermis depends on the mechanical barrier afforded by the stratum corneum, since the epidermis itself is devoid of blood vessels (Fig. 125-1). Disruption of this layer by burns or bites, abrasions, foreign bodies, primary dermatologic disorders (e.g., herpes simplex, varicella, ecthyma gangrenosum), surgery, or vascular or pressure ulcer allows penetration of bacteria to the deeper structures. Similarly, the hair follicle can serve as a portal either for components of the normal flora (e.g., Staphylococcus) or for extrinsic bacteria (e.g., Pseudomonas in hot-tub folliculitis). Intracellular infection of the squamous epithelium with vesicle formation may arise from cutaneous inoculation, as in infection with herpes simplex virus (HSV) type 1; from the dermal capillary plexus, as in varicella and infections due to other viruses associated with viremia; or from cutaneous nerve roots, as in herpes zoster. Bacteria infecting the epidermis, such as Streptococcus pyogenes, may be translocated laterally to deeper structures via lymphatics, an event that results in the rapid superficial spread of erysipelas. Later, engorgement or obstruction of lymphatics causes flaccid edema of the epidermis, another characteristic of erysipelas.

The rich plexus of capillaries beneath the dermal papillae provides nutrition to the stratum germinativum, and physiologic responses of this plexus produce important clinical signs and symptoms. For example, infective vasculitis of the plexus results in petechiae, Osler's nodes, Janeway lesions, and palpable purpura, which, if present, are important clues to the existence of endocarditis (Chap. 124). In addition, metastatic infection within this plexus can result in cutaneous manifestations of disseminated fungal infection (Chap. 203), gonococcal infection (Chap. 144), Salmonella infection (Chap. 153), Pseudomonas infection (i.e., ecthyma gangrenosum; Chap. 152), meningococcemia (Chap. 143), and staphylococcal infection (Chap. 135). The plexus also provides bacteria with access to the circulation, thereby facilitating local spread or bacteremia. The postcapillary venules of this plexus are a major site of polymorphonuclear leukocyte sequestration, diapedesis, and chemotaxis to the site of cutaneous infection.

Exaggeration of these physiologic mechanisms by excessive levels of cytokines or bacterial toxins causes leukostasis, venous occlusion, and pitting edema. Edema with purple bullae, ecchymosis, and cutaneous anesthesia suggests loss of vascular integrity and necessitates exploration of the deeper structures for evidence of necrotizing fasciitis or myonecrosis. An early diagnosis requires a high level of suspicion in instances of unexplained fever and of pain and tenderness in the soft tissue, even in the absence of acute cutaneous inflammation.

Infections Associated with Vesicles

(Table 125–1) Vesicle formation due to infection is caused by viral proliferation within the epidermis. In varicella and variola, viremia precedes the onset of a diffuse centripetal rash that progresses from macules to vesicles, then to pustules, and finally to scabs over the course of 1–2 weeks. Vesicles of varicella have a "dewdrop" appearance and develop in crops randomly about the trunk, extremities, and face over 3–4 days. Herpes zoster occurs in a single dermatome; the appearance of vesicles is preceded by pain for several days. Zoster may occur in persons of any age but is most common among immunosuppressed individuals and elderly patients, whereas most cases of varicella occur in young children. Vesicles due to HSV are found on or around the lips (HSV-1) or genitals (HSV-2) but may appear on the head and neck of young wrestlers (herpes gladiatorum) or on the digits of health care workers (herpetic whitlow). Recurrent herpes labialis (HSV-1) and herpes genitalis commonly follow primary infection. Coxsackievirus A16 characteristically causes vesicles on the hands, feet, and mouth of children. Orf is caused by a DNA virus related to smallpox virus and infects the fingers of individuals who work around goats and sheep.

Molluscum contagiosum virus induces flaccid vesicles on the skin of healthy and immunocompromised individuals. Although variola (smallpox) in nature was eradicated as of 1977, recent terrorist events have renewed interest in this devastating infection (Chap. 221). Viremia beginning after an incubation period of 12 days is followed by a diffuse maculopapular rash, with rapid evolution to vesicles, pustules, and then scabs. Secondary cases can occur among close contacts.

Rickettsialpox begins after mite-bite inoculation of Rickettsia akari into the skin. A papule with a central vesicle evolves to form a 1- to 2.5-cm painless crusted black eschar with an erythematous halo and proximal adenopathy. While more common in the northeastern United States and the Ukraine in 1940–1950, rickettsialpox has recently been described in Ohio, Arizona, and Utah. Blistering dactylitis is a painful, vesicular, localized S. aureus or group A streptococcal infection of the pulps of the distal digits of the hands.

Infections Associated with Bullae

(Table 125–1) Staphylococcal scalded-skin syndrome (SSSS) in neonates is caused by a toxin (exfoliatin) from phage group IIS. aureus. SSSS must be distinguished from toxic epidermal necrolysis (TEN), which occurs primarily in adults, is drug-induced, and is associated with a higher mortality rate. Punch biopsy with frozen section is useful in making this distinction since the cleavage plane is the stratum corneum in SSSS and the stratum germinativum in TEN (Fig. 125-1). Intravenous -globulin is a promising treatment for TEN. Necrotizing fasciitis and gas gangrene also induce bulla formation (see "Necrotizing Fasciitis," below). Halophilic vibrio infection can be as aggressive and fulminant as necrotizing fasciitis; a helpful clue in its diagnosis is a history of exposure to waters of the Gulf of Mexico or the Atlantic seaboard or (in a patient with cirrhosis) the ingestion of raw seafood. The etiologic organism (Vibrio vulnificus) is highly susceptible to tetracycline.

Infections Associated with Crusted Lesions

(Table 125–1) Impetigo contagiosa is caused by S. pyogenes, and bullous impetigo is due to S. aureus. Both skin lesions may have an early bullous stage but then appear as thick crusts with a golden-brown color. Epidemics of impetigo caused by MRSA have been reported. Streptococcal lesions are most common among children 2–5 years of age, and epidemics may occur in settings of poor hygiene, particularly among children in lower socioeconomic settings in tropical climates. It is important to recognize impetigo contagiosa because of its relationship to poststreptococcal glomerulonephritis.

Rheumatic fever is not a complication of skin infection caused byS. pyogenes. Superficial dermatophyte infection (ringworm) can occur on any skin surface, and skin scrapings with KOH staining are diagnostic. Primary infections with dimorphic fungi such as Blastomyces dermatitidis and Sporothrix schenckii can initially present as crusted skin lesions resembling ringworm. Disseminated infection with Coccidioides immitis can also involve the skin, and biopsy and culture should be performed on crusted lesions in patients from endemic areas. Crusted nodular lesions caused by Mycobacterium chelonei have been described in HIV-seropositive patients. Treatment with clarithromycin looks promising.

Folliculitis

(Table 125–1) Hair follicles serve as portals for a number of bacteria, although S. aureus is the most common cause of localized folliculitis. Sebaceous glands empty into hair follicles and ducts and, if these portals are blocked, form sebaceous cysts that may resemble staphylococcal abscesses or may become secondarily infected. Infection of sweat glands (hidradenitis suppurativa) can also mimic infection of hair follicles, particularly in the axillae. Chronic folliculitis is uncommon except in acnevulgaris, where constituents of the normal flora (e.g., Propionibacterium acnes) may play a role.

Diffuse folliculitis occurs in two settings. Hot-tub folliculitis is caused by Pseudomonas aeruginosa in waters that are insufficiently chlorinated and maintained at temperatures of 37–40°C. Infection is usually self-limited, although bacteremia and shock have been reported. Swimmer's itch occurs when a skin surface is exposed to water infested with freshwater avian schistosomes. Warm water temperatures and alkaline pH are suitable for mollusks that serve as intermediate hosts between birds and humans. Free-swimming schistosomal cercariae readily penetrate human hair follicles or pores but quickly die and elicit a brisk allergic reaction, causing intense itching and erythema.

Papular and Nodular Lesions

(Table 125–1) Raised lesions of the skin occur in many different forms. Mycobacterium marinum infections of the skin may present as cellulitis or as raised erythematous nodules. Erythematous papules are early manifestations of cat-scratch disease (with lesions developing at the primary site of inoculation of Bartonella henselae) and bacillary angiomatosis (also caused by B. henselae). Raised serpiginous or linear eruptions are characteristic of cutaneous larva migrans, which is caused by burrowing larvae of dog or cat hookworms (Ancylostoma braziliense) and which humans acquire through contact with soil that has been contaminated with dog or cat feces. Similar burrowing raised lesions are present in dracunculiasis caused by migration of the adult female nematode Dracunculus medinensis. Nodules caused by Onchocerca volvulus measure 1–10 cm in diameter and occur mostly in persons bitten by Simulium flies in Africa. The nodules contain the adult worm encased in fibrous tissue. Migration of microfilariae into the eyes may result in blindness. Verruga peruana is caused by Bartonella bacilliformis, which is transmitted to humans by the sandfly Phlebotomus. This condition can take the form of single gigantic lesions (several centimeters in diameter) or multiple small lesions (several millimeters in diameter). Numerous subcutaneous nodules may also be present in cysticercosis caused by larvae of Taenia solium. Multiple erythematous papules develop in schistosomiasis; each represents a cercarial invasion site. Skin nodules as well as thickened subcutaneous tissue are prominent features of lepromatous leprosy. Large nodules or gummas are features of tertiary syphilis, whereas flat papulosquamous lesions are characteristic of secondary syphilis. Human papillomavirus may cause singular warts (verruca vulgaris) or multiple warts in the anogenital area (condylomata acuminata). The latter are major problems in HIV-infected individuals.

Ulcers with or Without Eschars

(Table 125–1) Cutaneousanthrax begins as a pruritic papule, which develops within days into an ulcer with surrounding vesicles and edema and then into an enlarging ulcer with a black eschar. Cutaneous anthrax may cause chronic nonhealing ulcers with an overlying dirty-gray membrane, although lesions may also mimic psoriasis, eczema, or impetigo. Ulceroglandular tularemia may have associated ulcerated skin lesions with painful regional adenopathy. Although buboes are the major cutaneous manifestation of plague, ulcers with eschars, papules, or pustules are also present in 25% of cases.

Mycobacterium ulcerans typically causes chronic skin ulcers on the extremities of individuals living in the tropics. Mycobacterium leprae may be associated with cutaneous ulcerations in patients with lepromatous leprosy related to Lucio's phenomenon, in which immune-mediated destruction of tissue bearing high concentrations of M. leprae bacilli occurs, usually several months after initiation of effective therapy. Mycobacterium tuberculosis may also cause ulcerations, papules, or erythematous macular lesions of the skin in both normal and immunocompromised patients.

Decubitus ulcers are due to tissue hypoxemia secondary to pressure-induced vascular insufficiency and may become secondarily infected with components of the skin and gastrointestinal flora, including anaerobes. Ulcerative lesions on the anterior shins may be due to pyoderma gangrenosum, which must be distinguished from similar lesions of infectious etiology by histologic evaluation of biopsy sites. Ulcerated lesions on the genitals may be either painful (chancroid) or painless (primary syphilis).

Erysipelas

(Table 125–1) Erysipelas is due to S. pyogenes and is characterized by an abrupt onset of fiery-red swelling of the face or extremities. The distinctive features of erysipelas are well-defined indurated margins, particularly along the nasolabial fold; rapid progression; and intense pain. Flaccid bullae may develop during the second or third day of illness, but extension to deeper soft tissues is rare. Treatment with penicillin is effective; swelling may progress despite appropriate treatment, although fever, pain, and the intense red color diminish. Desquamation of the involved skin occurs 5–10 days into the illness. Infants and elderly adults are most commonly afflicted, and the severity of systemic toxicity varies.

Cellulitis

(Table 125–1) Cellulitis is an acute inflammatory condition of the skin that is characterized by localized pain, erythema, swelling, and heat. It may be caused by indigenous flora colonizing the skin and appendages (e.g., S. aureus and S. pyogenes) or by a wide variety of exogenous bacteria. Because the exogenous bacteria involved in cellulitis occupy unique niches in nature, a thorough history (including epidemiologic data) provides important clues to etiology. When there is drainage, an open wound, or an obvious portal of entry, Gram's stain and culture provide a definitive diagnosis. In the absence of these findings, the bacterial etiology of cellulitis is difficult to establish, and in some cases staphylococcal and streptococcal cellulitis may have similar features. Even with needle aspiration of the leading edge or a punch biopsy of the cellulitis tissue itself, cultures are positive in only 20% of cases. This observation suggests that relatively low numbers of bacteria may cause cellulitis and that the expanding area of erythema within the skin may be a direct effect of extracellular toxins or of the soluble mediators of inflammation elicited by the host.

Bacteria may gain access to the epidermis through cracks in the skin, abrasions, cuts, burns, insect bites, surgical incisions, and IV catheters. Cellulitis caused by S. aureus spreads from a central localized infection, such as an abscess, folliculitis, or an infected foreign body (e.g., a splinter, a prosthetic device, or an IV catheter). MRSA is rapidly replacing methicillin-sensitive S. aureus (MSSA) as a cause of cellulitis in both inpatient and outpatient settings. Cellulitis caused by MSSA or MRSA is usually associated with a focal infection, such as a furuncle, a carbuncle, a surgical wound, or an abscess. In contrast, cellulitis due to S. pyogenes is a more rapidly spreading, diffuse process that is frequently associated with lymphangitis and fever. Recurrent streptococcal cellulitis of the lower extremities may be caused by organisms of group A, C, or G in association with chronic venous stasis or with saphenous venectomy for coronary artery bypass surgery. Streptococci also cause recurrent cellulitis among patients with chronic lymphedema resulting from elephantiasis, lymph node dissection, or Milroy's disease. Recurrent staphylococcal cutaneous infections are more common among individuals who have eosinophilia and elevated serum levels of IgE (Job's syndrome) and among nasal carriers of staphylococci. Cellulitis caused by Streptococcus agalactiae (group B Streptococcus) occurs primarily in elderly patients and those with diabetes mellitus or peripheral vascular disease. Haemophilus influenzae typically causes periorbital cellulitis in children in association with sinusitis, otitis media, or epiglottitis. It is unclear whether this form of cellulitis will (like meningitis) become less common as a result of the impressive efficacy of the H. influenzae type b vaccine.

Many other bacteria also cause cellulitis. It is fortunate that these organisms occur in such characteristic settings that a good history provides useful clues to the diagnosis. Cellulitis associated with cat bites and, to a lesser degree, with dog bites is commonly caused by Pasteurella multocida, although in the latter case Staphylococcus intermedius and Capnocytophaga canimorsus (formerly DF-2) must also be considered. Sites of cellulitis and abscesses associated with dog bites and human bites also contain a variety of anaerobic organisms, including Fusobacterium, Bacteroides, aerobic and anaerobic streptococci, and Eikenella corrodens. Pasteurella is notoriously resistant to dicloxacillin and nafcillin but is sensitive to all other -lactam antimicrobial agents as well as to quinolones, tetracycline, and erythromycin. Ampicillin/clavulanate, ampicillin/sulbactam, and cefoxitin are good choices for the treatment of animal or human bite infections. Aeromonas hydrophila causes aggressive cellulitis in tissues surrounding lacerations sustained in freshwater (lakes, rivers, and streams). This organism remains sensitive to aminoglycosides, fluoroquinolones, chloramphenicol, trimethoprim- sulfamethoxazole, and third-generation cephalosporins; it is resistant to ampicillin, however.

P. aeruginosa causes three types of soft tissue infection: ecthyma gangrenosum in neutropenic patients, hot-tub folliculitis, and cellulitis following penetrating injury. Most commonly, P. aeruginosa is introduced into the deep tissues when a person steps on a nail. Treatment includes surgical inspection and drainage, particularly if the injury also involves bone or joint capsule. Choices for empirical treatment while antimicrobial susceptibility data are awaited include an aminoglycoside, a third-generation cephalosporin (ceftazidime, cefoperazone, or cefotaxime), a semisynthetic penicillin (ticarcillin, mezlocillin, or piperacillin), or a fluoroquinolone (although drugs of the last class are not indicated for the treatment of children <13 years old).

Gram-negative bacillary cellulitis, including that due to P. aeruginosa, is most common among hospitalized, immunocompromised hosts. Cultures and sensitivity tests are critically important in this setting because of multidrug resistance (Chap. 152).

The gram-positive aerobic rod Erysipelothrix rhusiopathiae is most often associated with fish and domestic swine and causes cellulitis primarily in bone renderers and fishmongers. E. rhusiopathiae remains susceptible to most -lactam antibiotics (including penicillin), erythromycin, clindamycin, tetracycline, and cephalosporins but is resistant to sulfonamides, chloramphenicol, and vancomycin. Its resistance to vancomycin, which is unusual among gram-positive bacteria, is of potential clinical significance since this agent is sometimes used in empirical therapy for skin infection. Fish food containing the water flea Daphnia is sometimes contaminated with M. marinum, which can cause cellulitis or granulomas on skin surfaces exposed to the water in aquariums or injured in swimming pools. Rifampin plus ethambutol has been an effective therapeutic combination in some cases, although no comprehensive studies have been undertaken. In addition, some strains of M. marinum are susceptible to tetracycline or to trimethoprim-sulfamethoxazole.

Necrotizing Fasciitis

(Table 125–1) Necrotizing fasciitis, formerly called streptococcal gangrene, may be associated with group A Streptococcus or mixed aerobic-anaerobic bacteria or may occur as part of gas gangrene caused by Clostridium perfringens. Strains of MRSA that produce the Panton-Valentine leukocidin (PVL) toxin have been reported to cause necrotizing fasciitis. Early diagnosis may be difficult when pain or unexplained fever is the only presenting manifestation. Swelling then develops and is followed by brawny edema and tenderness. With progression, dark-red induration of the epidermis appears, along with bullae filled with blue or purple fluid. Later the skin becomes friable and takes on a bluish, maroon, or black color. By this stage, thrombosis of blood vessels in the dermal papillae (Fig. 125-1) is extensive. Extension of infection to the level of the deep fascia causes this tissue to take on a brownish-gray appearance. Rapid spread occurs along fascial planes, through venous channels and lymphatics. Patients in the later stages are toxic and frequently manifest shock and multiorgan failure.

Necrotizing fasciitis caused by mixed aerobic-anaerobic bacteria begins with a breach in the integrity of a mucous membrane barrier, such as the mucosa of the gastrointestinal or genitourinary tract. The portal can be a malignancy, a diverticulum, a hemorrhoid, an anal fissure, or a urethral tear. Other predisposing factors include peripheral vascular disease, diabetes mellitus, surgery, and penetrating injury to the abdomen. Leakage into the perineal area results in a syndrome called Fournier's gangrene, characterized by massive swelling of the scrotum and penis with extension into the perineum or the abdominal wall and legs.

Necrotizing fasciitis caused by S. pyogenes has increased in frequency and severity since 1985. There are two distinct clinical presentations: those with no portal of entry and those with a defined portal of entry. Infections in the first category often begin deep at the site of a nonpenetrating minor trauma, such as a bruise or a muscle strain. Seeding of the site via transient bacteremia is likely, although most patients deny antecedent streptococcal infection. The affected patients present with only severe pain and fever. Late in the course, the classic signs of necrotizing fasciitis, such as purple (violaceous) bullae, skin sloughing, and progressive toxicity, develop. In infections of the second type, S. pyogenes may reach the deep fascia from a site of cutaneous infection or penetrating trauma. These patients have early signs of superficial skin infection with progression to necrotizing fasciitis. In either case, toxicity is severe, and renal impairment may precede the development of shock. In 20–40% of cases, myositis occurs concomitantly, and, as in gas gangrene (see below), serum creatine phosphokinase levels may be markedly elevated. Necrotizing fasciitis due to mixed aerobic-anaerobic bacteria may be associated with gas in deep tissue, but gas usually is not present when the cause is S. pyogenes or MRSA. Prompt surgical exploration down to the deep fascia and muscle is essential. Necrotic tissue must be surgically removed, and Gram's staining and culture of excised tissue are useful in establishing whether group A streptococci, mixed aerobic-anaerobic bacteria, MRSA, or Clostridium species are present (see "Treatment," below).

Myositis and Myonecrosis

(Table 125–1) Muscle involvement can occur with viral infection (e.g., influenza, dengue, or coxsackievirus B infection) or parasitic invasion (e.g., trichinellosis, cysticercosis, or toxoplasmosis). Although myalgia can occur in most of these infections, severe muscle pain is the hallmark of pleurodynia (coxsackievirus B), trichinellosis, and bacterial infection. Acute rhabdomyolysis predictably occurs with clostridial and streptococcal myositis but may also be associated with influenza virus, echovirus, coxsackievirus, Epstein-Barr virus, and Legionella infections.

Pyomyositis is usually due to S. aureus, is common in tropical areas, and generally has no known portal of entry. Cases of pyomyositis caused by MRSA producing the PVL toxin have been described among children in the United States. Muscle infection begins at the exact site of blunt trauma or muscle strain. Infection remains localized, and shock does not develop unless organisms produce toxic shock syndrome toxin 1 or certain enterotoxins and the patient lacks antibodies to the toxin produced by the infecting organisms. In contrast, S. pyogenes may induce primary myositis (referred to as streptococcal necrotizing myositis) in association with severe systemic toxicity. Myonecrosis occurs concomitantly with necrotizing fasciitis in ~50% of cases. Both are part of the streptococcal toxic shock syndrome.

Gas gangrene usually follows severe penetrating injuries that result in interruption of the blood supply and introduction of soil into wounds. Such cases of traumatic gangrene are usually caused by the clostridial species C. perfringens, C. septicum, and C. histolyticum. Rarely, latent or recurrent gangrene can occur years after penetrating trauma; dormant spores that reside at the site of previous injury are most likely responsible. Spontaneous nontraumatic gangrene among patients with neutropenia, gastrointestinal malignancy, diverticulosis, or recent radiation therapy to the abdomen is caused by several clostridial species, of which C. septicum is the most commonly involved. The tolerance of this anaerobe to oxygen probably explains why it can initiate infection spontaneously in normal tissue anywhere in the body.

Gas gangrene of the uterus, especially that due to C. sordellii, historically occurred as a consequence of illegal or self-induced abortion and nowadays also follows spontaneous abortion, vaginal delivery, and cesarean section. C. sordellii has also been implicated in medically induced abortion. Postpartum C. sordellii infections in young, previously healthy women present as a unique clinical picture: little or no fever, lack of a purulent discharge, refractory hypotension, extensive peripheral edema and effusions, hemoconcentration, and a markedly elevated white blood cell count. The infection is almost uniformly fatal, with death ensuing rapidly.

Synergistic nonclostridial anaerobic myonecrosis, also known as necrotizing cutaneousmyositis and synergistic necrotizing cellulitis, is a variant of necrotizing fasciitis caused by mixed aerobic and anaerobic bacteria with the exclusion of clostridial organisms (see "Necrotizing Fasciitis," above).

Diagnosis

This chapter has emphasized the physical appearance and location of lesions within the soft tissues as important diagnostic clues. The temporal progression of the lesions as well as the patient's travel history, animal exposure or bite history, age, underlying disease status, and lifestyle are also crucial considerations in narrowing the differential diagnosis. However, even the astute clinician may find it challenging to diagnose all infections of the soft tissues by history and inspection alone. Soft tissue radiography, computed tomography (Fig. 125-2), and magnetic resonance imaging may be useful in determining the depth of infection and should be performed when the patient has rapidly progressing lesions or evidence of a systemic inflammatory response syndrome. These tests are particularly valuable for defining a localized abscess or detecting gas in tissue. Unfortunately, they may reveal only soft tissue swelling and thus are not specific for fulminant infections such as necrotizing fasciitis or myonecrosis caused by group A Streptococcus (Fig. 125-2), where gas is not found in lesions.

Aspiration of the leading edge or punch biopsy with frozen section may be helpful if the results of imaging tests are positive, but false-negative results occur in ∑80% of cases. There is some evidence that aspiration alone may be superior to injection and aspiration with normal saline. Frozen sections are especially useful in distinguishing SSSS from TEN and are quite valuable in cases of necrotizing fasciitis. Open surgical inspection, with debridement as indicated, is clearly the best way to determine the extent and severity of infection and to obtain material for Gram's staining and culture. Such an aggressive approach is important and may be lifesaving if undertaken early in the course of fulminant infections where there is evidence of systemic toxicity.

Treatment: Infections of the Skin, Muscles, and Soft Tissues

A full description of the treatment of all the clinical entities described herein is beyond the scope of this chapter. As a guide to the clinician in selecting appropriate treatment, the antimicrobial agents useful in the most common and the most fulminant cutaneous infections are listed in Table 125–2.

Furuncles, carbuncles, and abscesses caused by MRSA and MSSA are common, and their treatment depends upon the size of the lesion. Furuncles <2.5 cm in diameter are usually treated with moist heat. Those that are larger (4.5 cm of erythema and induration) require surgical drainage, and the occurrence of these larger lesions in association with fever, chills, or leukocytosis requires both drainage and antibiotic treatment. A study in children demonstrated that surgical drainage of abscesses (mean diameter, 3.8 cm) was as effective when used alone as when combined with trimethoprim-sulfamethoxazole treatment. However, the rate of recurrence of new lesions was lower in the group undergoing both drainage and antibiotic treatment.

Early and aggressive surgical exploration is essential in cases of suspected necrotizing fasciitis, myositis, or gangrene in order to (1) visualize the deep structures, (2) remove necrotic tissue, (3) reduce compartment pressure, and (4) obtain suitable material for Gram's staining and for aerobic and anaerobic cultures. Appropriate empirical antibiotic treatment for mixed aerobic-anaerobic infections could consist of ampicillin/sulbactam, cefoxitin, or the following combination: (1) clindamycin (600–900 mg intravenously every 8 h) or metronidazole (500 mg every 6 h) plus (2) ampicillin or ampicillin/sulbactam (1.5-3 g intravenously every 6 h) plus (3) gentamicin (1–1.5 mg/kg every 8 h). Group A streptococcal and clostridial infection of the fascia and/or muscle carries a mortality rate of 20–50% with penicillin treatment. In experimental models of streptococcal and clostridial necrotizing fasciitis/myositis, clindamycin has exhibited markedly superior efficacy, but no comparative clinical trials have been performed. A retrospective study of children with invasive group A streptococcal infection demonstrated higher survival rates with clindamycin treatment than with -lactam antibiotic therapy. Hyperbaric oxygen treatment may also be useful in gas gangrene due to clostridial species. Antibiotic treatment should be continued until all signs of systemic toxicity have resolved, all devitalized tissue has been removed, and granulation tissue has developed (Chaps. 136, 142, and 164).

In summary, infections of the skin and soft tissues are diverse in presentation and severity and offer a great challenge to the clinician. This chapter provides an approach to diagnosis and understanding of the pathophysiologic mechanisms involved in these infections. More in-depth information is found in chapters on specific infections.

124

Infective Endocarditis: Introduction

The prototypic lesion of infective endocarditis, the vegetation(Fig. 124-1), is a mass of platelets, fibrin, microcolonies of microorganisms, and scant inflammatory cells. Infection most commonly involves heart valves (either native or prosthetic) but may also occur on the low-pressure side of a ventricular septal defect, on the mural endocardium where it is damaged by aberrant jets of blood or foreign bodies, or on intracardiac devices themselves. The analogous process involving arteriovenous shunts, arterioarterial shunts (patent ductus arteriosus), or a coarctation of the aorta is called infective endarteritis.

Figure 124-1




Vegetations (arrows) due to viridans streptococcal endocarditis involving the mitral valve.




Endocarditis may be classified according to the temporal evolution of disease, the site of infection, the cause of infection, or a predisposing risk factor such as injection drug use. While each classification criterion provides therapeutic and prognostic insight, none is sufficient alone. Acute endocarditis is a hectically febrile illness that rapidly damages cardiac structures, hematogenously seeds extracardiac sites, and, if untreated, progresses to death within weeks. Subacute endocarditis follows an indolent course; causes structural cardiac damage only slowly, if at all; rarely metastasizes; and is gradually progressive unless complicated by a major embolic event or ruptured mycotic aneurysm.

In developed countries, the incidence of endocarditis ranges from 2.6 to 7 cases per 100,000 population per year and has remained relatively stable during recent decades. While congenital heart diseases remain a constant predisposition, predisposing conditions in developed countries have shifted from chronic rheumatic heart disease (which remains a common predisposition in developing countries) to illicit IV drug use, degenerative valve disease, and intracardiac devices. The incidence of endocarditis is notably increased among the elderly. In developed countries, 30–35% of cases of native valve endocarditis (NVE) are associated with health care, and 16–30% of all cases of endocarditis involve prosthetic valves. The risk of prosthesis infection is greatest during the first 6–12 months after valve replacement; gradually declines to a low, stable rate thereafter; and is similar for mechanical and bioprosthetic devices.

Etiology

Although many species of bacteria and fungi cause sporadic episodes of endocarditis, a few bacterial species cause the majority of cases (Tables 124–1). Because of their different portals of entry, the pathogens involved vary somewhat with the clinical types of endocarditis. The oral cavity, skin, and upper respiratory tract are the respective primary portals for the viridans streptococci, staphylococci, and HACEK organisms (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella; Haemophilus aphrophilus and Actinobacillus actinomycetemcomitans have been reclassified into the genus Aggregatibacter). Streptococcus gallolyticus (formerly S. bovis) originates from the gastrointestinal tract, where it is associated with polyps and colonic tumors, and enterococci enter the bloodstream from the genitourinary tract. Health care–associated NVE, commonly caused by Staphylococcus aureus, coagulase-negative staphylococci (CoNS), and enterococci, has a nosocomial onset (55%) or a community onset (45%) in patients who have had extensive contact with the health care system over the preceding 90 days. Endocarditis complicates 6–25% of episodes of catheter-associated S. aureus bacteremia; the higher rates are detected by careful transesophageal echocardiography (TEE) screening (see "Echocardiography," below).

Tables 124–1 Organisms Causing Major Clinical Forms of Endocarditis


Organism
Percentage of Cases
Native Valve Endocarditis Prosthetic Valve Endocarditis at Indicated Time of Onset (Months) after Valve Surgery Endocarditis in Injection Drug Users
Community-Acquired (n =1718) Health Care–Associated (n =788) <2 (n = 144) 2–12 (n = 31) >12 (n = 194) Right-Sided (n = 346) Left-Sided (n = 204) Total (n = 675)a
Streptococcib 40 9 1 9 31 5 15 12
Pneumococci 2 — — — — — — —
Enterococci 9 13 8 12 11 2 24 9
Staphylococcus aureus 28 53c 22 12 18 77 23 57
Coagulase-negative staphylococci 5 12 33 32 11 — — —
Fastidious gram-negative coccobacilli (HACEK group)d 3 — — — 6 — — —
Gram-negative bacilli 1 2 13 3 6 5 13 7
Candida spp. <1 2 8 12 1 — 12 4
Polymicrobial/miscellaneous 3 4 3 6 5 8 10 7
Diphtheroids — <1 6 — 3 — — 0.1
Culture-negative 9 5 5 6 8 3 3 3


a The total number of cases is larger than the sum of right- and left-sided cases because the location of infection was not specified in some cases.
b Includes viridans streptococci; Streptococcus gallolyticus; other non–group A, groupable streptococci; and Abiotrophia spp. (nutritionally variant, pyridoxal-requiring streptococci).
c Methicillin resistance is common among these S. aureus strains.
d Includes Haemophilus spp., Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella spp., and Kingella spp.
Note: Data are compiled from multiple studies.



Prosthetic valve endocarditis (PVE) arising within 2 months of valve surgery is generally nosocomial, the result of intraoperative contamination of the prosthesis or a bacteremic postoperative complication. This nosocomial origin is reflected in the primary microbial causes: S. aureus, CoNS, facultative gram-negative bacilli, diphtheroids, and fungi. The portals of entry and organisms causing cases beginning >12 months after surgery are similar to those in community-acquired NVE. PVE due to CoNS that presents 2–12 months after surgery often represents delayed-onset nosocomial infection. Regardless of the time of onset after surgery, at least 68–85% of CoNS strains that cause PVE are resistant to methicillin.

Transvenous pacemaker– or implanted defibrillator–associated endocarditis is usually nosocomial. The majority of episodes occur within weeks of implantation or generator change and are caused by S. aureus or CoNS, both of which are commonly resistant to methicillin.

Endocarditis occurring among injection drug users, especially that involving the tricuspid valve, is commonly caused by S. aureus, many strains of which are resistant to methicillin. Left-sided valve infections in addicts have a more varied etiology. In addition to the usual causes of endocarditis, these cases are caused by Pseudomonas aeruginosa and Candida species and sporadically by unusual organisms such as Bacillus, Lactobacillus, and Corynebacterium species. Polymicrobial endocarditis occurs among injection drug users. HIV infection in drug users does not significantly influence the causes of endocarditis.

From 5% to 15% of patients with endocarditis have negative blood cultures; in one-third to one-half of these cases, cultures are negative because of prior antibiotic exposure. The remainder of these patients are infected by fastidious organisms, such as nutritionally variant organisms (now designated Granulicatella and Abiotrophia species), HACEK organisms, Coxiella burnetii, and Bartonella species. Some fastidious organisms occur in characteristic geographic settings (e.g., C. burnetii and Bartonella species in Europe, Brucella species in the Middle East). Tropheryma whipplei causes an indolent, culture-negative, afebrile form of endocarditis.

Pathogenesis

The endothelium, unless damaged, is resistant to infection by most bacteria and to thrombus formation. Endothelial injury (e.g., at the site of impact of high-velocity blood jets or on the low-pressure side of a cardiac structural lesion) allows either direct infection by virulent organisms or the development of an uninfected platelet-fibrin thrombus—a condition called nonbacterial thrombotic endocarditis (NBTE). The thrombus subsequently serves as a site of bacterial attachment during transient bacteremia. The cardiac conditions most commonly resulting in NBTE are mitral regurgitation, aortic stenosis, aortic regurgitation, ventricular septal defects, and complex congenital heart disease. NBTE also arises as a result of a hypercoagulable state; this phenomenon gives rise to the clinical entity of marantic endocarditis (uninfected vegetations seen in patients with malignancy and chronic diseases) and to bland vegetations complicating systemic lupus erythematosus and the antiphospholipid antibody syndrome.

Organisms that cause endocarditis generally enter the bloodstream from mucosal surfaces, the skin, or sites of focal infection. Except for more virulent bacteria (e.g., S. aureus) that can adhere directly to intact endothelium or exposed subendothelial tissue, microorganisms in the blood adhere at sites of NBTE. If resistant to the bactericidal activity of serum and the microbicidal peptides released locally by platelets, the organisms proliferate and induce platelet deposition and a procoagulant state at the site by eliciting tissue factor from the endothelium or, in the case of S. aureus, from monocytes as well. Fibrin deposition combines with platelet aggregation and microorganism proliferation to generate an infected vegetation. The organisms that commonly cause endocarditis have surface adhesin molecules, collectively called microbial surface components recognizing adhesin matrix molecules (MSCRAMMs), that mediate adherence to NBTE sites or injured endothelium. Fibronectin-binding proteins present on many gram-positive bacteria, clumping factor (a fibrinogen- and fibrin-binding surface protein) on S. aureus, and glucans or FimA (a member of the family of oral mucosal adhesins) on streptococci facilitate adherence. Fibronectin-binding proteins are required for S. aureus invasion of intact endothelium; thus these surface proteins may facilitate infection of previously normal valves. In the absence of host defenses, organisms enmeshed in the growing platelet-fibrin vegetation proliferate to form dense microcolonies. Organisms deep in vegetations are metabolically inactive (nongrowing) and relatively resistant to killing by antimicrobial agents. Proliferating surface organisms are shed into the bloodstream continuously.

The pathophysiologic consequences and clinical manifestations of endocarditis—other than constitutional symptoms, which probably result from cytokine production—arise from damage to intracardiac structures; embolization of vegetation fragments, leading to infection or infarction of remote tissues; hematogenous infection of sites during bacteremia; and tissue injury due to the deposition of circulating immune complexes or immune responses to deposited bacterial antigens.

Clinical Manifestations

The clinical syndrome of infective endocarditis is highly variable and spans a continuum between acute and subacute presentations. NVE (whether acquired in the community or in association with health care), PVE, and endocarditis due to injection drug use share clinical and laboratory manifestations (Tables 124–2). The causative microorganism is primarily responsible for the temporal course of endocarditis. -Hemolytic streptococci, S. aureus, and pneumococci typically result in an acute course, although S. aureus occasionally causes subacute disease. Endocarditis caused by Staphylococcus lugdunensis (a coagulase-negative species) or by enterococci may present acutely. Subacute endocarditis is typically caused by viridans streptococci, enterococci, CoNS, and the HACEK group. Endocarditis caused by Bartonella species, T. whipplei, or C. burnetii is exceptionally indolent.

Tables 124–2 Clinical and Laboratory Features of Infective Endocarditis

Feature Frequency, %
Fever 80–90
Chills and sweats 40–75
Anorexia, weight loss, malaise 25–50
Myalgias, arthralgias 15–30
Back pain 7–15
Heart murmur 80–85
New/worsened regurgitant murmur 20–50
Arterial emboli 20–50
Splenomegaly 15–50
Clubbing 10–20
Neurologic manifestations 20–40
Peripheral manifestations (Osler's nodes, subungual hemorrhages, Janeway lesions, Roth's spots) 2–15
Petechiae 10–40
Laboratory manifestations
Anemia 70–90
Leukocytosis 20–30
Microscopic hematuria 30–50
Elevated erythrocyte sedimentation rate 60–90
Elevated C-reactive protein level >90
Rheumatoid factor 50
Circulating immune complexes 65–100
Decreased serum complement 5–40





The clinical features of endocarditis are nonspecific. However, these symptoms in a febrile patient with valvular abnormalities or a behavior pattern that predisposes to endocarditis (e.g., injection drug use) suggest the diagnosis, as do bacteremia with organisms that frequently cause endocarditis, otherwise-unexplained arterial emboli, and progressive cardiac valvular incompetence. In patients with subacute presentations, fever is typically low-grade and rarely exceeds 39.4°C (103°F); in contrast, temperatures of 39.4°–40°C (103°–104°F) are often noted in acute endocarditis. Fever may be blunted or absent in patients who are elderly or severely debilitated or who have marked cardiac or renal failure.

Cardiac Manifestations

Although heart murmurs are usually indicative of the predisposing cardiac pathology rather than of endocarditis, valvular damage and ruptured chordae may result in new regurgitant murmurs. In acute endocarditis involving a normal valve, murmurs may be absent initially but ultimately are detected in 85% of cases. Congestive heart failure (CHF) develops in 30–40% of patients; it is usually a consequence of valvular dysfunction but occasionally is due to endocarditis-associated myocarditis or an intracardiac fistula. Heart failure due to aortic valve dysfunction progresses more rapidly than does that due to mitral valve dysfunction. Extension of infection beyond valve leaflets into adjacent annular or myocardial tissue results in perivalvular abscesses, which in turn may cause intracardiac fistulae with new murmurs. Abscesses may burrow from the aortic valve annulus through the epicardium, causing pericarditis, or into the upper ventricular septum, where they may interrupt the conduction system, leading to varying degrees of heart block. Perivalvular abscesses arising from the mitral valve rarely interrupt conduction pathways near the atrioventricular node or in the proximal bundle of His. Emboli to a coronary artery occur in 2% of patients and may result in myocardial infarction.

Noncardiac Manifestations

The classic nonsuppurative peripheral manifestations of subacuteendocarditis are related to the duration of infection and, with early diagnosis and treatment, have become infrequent. In contrast, septic embolization mimicking some of these lesions (subungual hemorrhage, Osler's nodes) is common in patients with acute S. aureus endocarditis (Fig. 124-2). Musculoskeletal pain usually remits promptly with treatment but must be distinguished from focal metastatic infections (e.g., spondylodiscitis), which may complicate 10–15% of cases. Hematogenously seeded focal infection is most often clinically evident in the skin, spleen, kidneys, skeletal system, and meninges. Arterial emboli are clinically apparent in up to 50% of patients. Endocarditis caused by S. aureus, vegetations >10 mm in diameter (as measured by echocardiography), and infection involving the mitral valve are independently associated with an increased risk of embolization. Emboli occurring late during or after effective therapy do not in themselves constitute evidence of failed antimicrobial treatment. Cerebrovascular emboli presenting as strokes or occasionally as encephalopathy complicate 15–35% of cases of endocarditis. One-half of these events precede the diagnosis of endocarditis. The frequency of stroke is 8 per 1000 patient-days during the week prior to diagnosis; the figure falls to 4.8 and 1.7 per 1000 patient-days during the first and second weeks of effective antimicrobial therapy, respectively. This decline exceeds that which can be attributed to change in vegetation size. Only 3% of strokes occur after 1 week of effective therapy. Other neurologic complications include aseptic or purulent meningitis, intracranial hemorrhage due to hemorrhagic infarcts or ruptured mycotic aneurysms, and seizures. (Mycotic aneurysms are focal dilations of arteries occurring at points in the artery wall that have been weakened by infection in the vasa vasorum or where septic emboli have lodged.) Microabscesses in brain and meninges occur commonly in S. aureus endocarditis; surgically drainable intracerebral abscesses are infrequent.

Figure 124-2




Septic emboli with hemorrhage and infarction due to acute Staphylococcus aureus endocarditis. (Used with permission of L. Baden.)



Immune complex deposition on the glomerular basement membrane causes diffuse hypocomplementemic glomerulonephritis and renal dysfunction, which typically improve with effective antimicrobial therapy. Embolic renal infarcts cause flank pain and hematuria but rarely cause renal dysfunction.

Manifestations of Specific Predisposing Conditions

Almost 50% of endocarditis cases associated with injection drug use are limited to the tricuspid valve and present with fever but with faint or no murmur. In 75% of cases, septic emboli cause cough, pleuritic chest pain, nodular pulmonary infiltrates, or occasionally pyopneumothorax. Infection of the aortic or mitral valves on the left side of the heart presents with the typical clinical features of endocarditis.

Health care–associated endocarditis has typical manifestations if it is not associated with a retained intracardiac device or masked by the symptoms of concurrent comorbid illness. Transvenous pacemaker– or implanted defibrillator–associated endocarditis may be associated with obvious or cryptic generator pocket infection and results in fever, minimal murmur, and pulmonary symptoms due to septic emboli.

Late-onset PVE presents with typical clinical features. In cases arising within 60 days of valve surgery (early onset), typical symptoms may be obscured by comorbidity associated with recent surgery. In both early-onset and more delayed presentations, paravalvular infection is common and often results in partial valve dehiscence, regurgitant murmurs, CHF, or disruption of the conduction system.

Diagnosis

The Duke Criteria

The diagnosis of infective endocarditis is established with certainty only when vegetations are examined histologically and microbiologically. Nevertheless, a highly sensitive and specific diagnostic schema—known as the Duke criteria—has been developed on the basis of clinical, laboratory, and echocardiographic findings (Tables 124–3). Documentation of two major criteria, of one major criterion and three minor criteria, or of five minor criteria allows a clinical diagnosis of definite endocarditis. The diagnosis of endocarditis is rejected if an alternative diagnosis is established, if symptoms resolve and do not recur with ≤4 days of antibiotic therapy, or if surgery or autopsy after ≤4 days of antimicrobial therapy yields no histologic evidence of endocarditis. Illnesses not classified as definite endocarditis or rejected as such are considered cases of possible infective endocarditis when either one major criterion and one minor criterion or three minor criteria are fulfilled. Requiring the identification of clinical features of endocarditis for classification as possible infective endocarditis increases the specificity of the schema without significantly reducing its sensitivity.

Tables 124–3 The Duke Criteria for the Clinical Diagnosis of Infective Endocarditisa

Major Criteria
1. Positive blood culture

Typical microorganism for infective endocarditis from two separate blood cultures

Viridans streptococci, Streptococcus gallolyticus, HACEK group, Staphylococcus aureus, or

Community-acquired enterococci in the absence of a primary focus, or

Persistently positive blood culture, defined as recovery of a microorganism consistent with infective endocarditis from:

Blood cultures drawn >12 h apart; or

All of 3 or a majority of 4 separate blood cultures, with first and last drawn at least 1 h apart

Single positive blood culture for Coxiella burnetii or phase I IgG antibody titer of >1:800

2. Evidence of endocardial involvement

Positive echocardiogramb

Oscillating intracardiac mass on valve or supporting structures or in the path of regurgitant jets or in implanted material, in the absence of an alternative anatomic explanation, or

Abscess, or

New partial dehiscence of prosthetic valve, or

New valvular regurgitation (increase or change in preexisting murmur not sufficient)

Minor Criteria
1. Predisposition: predisposing heart condition or injection drug use
2. Fever 38.0°C (100.4°F)
3. Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, Janeway lesions
4. Immunologic phenomena: glomerulonephritis, Osler's nodes, Roth's spots, rheumatoid factor
5. Microbiologic evidence: positive blood culture but not meeting major criterion as noted previouslyc or serologic evidence of active infection with organism consistent with infective endocarditis



aDefinite endocarditis is defined by documentation of two major criteria, of one major criterion and three minor criteria, or of five minor criteria. See text for further details.

b Transesophageal echocardiography is recommended for assessing possible prosthetic valve endocarditis or complicated endocarditis.

cExcluding single positive cultures for coagulase-negative staphylococci and diphtheroids, which are common culture contaminants, and organisms that do not cause endocarditis frequently, such as gram-negative bacilli.

Note: HACEK, Haemophilus spp., Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella spp.

Source: Adapted from Li et al, with permission from the University of Chicago Press.




The roles of bacteremia and echocardiographic findings in the diagnosis of endocarditis are emphasized in the Duke criteria. The requirement for multiple positive blood cultures over time is consistent with the continuous low-density bacteremia characteristic of endocarditis. Among patients with untreated endocarditis who ultimately have a positive blood culture, 95% of all blood cultures are positive. The diagnostic criteria attach significance to the species of organism isolated from blood cultures. To fulfill a major criterion, the isolation of an organism that causes both endocarditis and bacteremia in the absence of endocarditis (e.g., S. aureus, enterococci) must take place repeatedly (i.e., persistent bacteremia) and in the absence of a primary focus of infection. Organisms that rarely cause endocarditis but commonly contaminate blood cultures (e.g., diphtheroids, CoNS) must be isolated repeatedly if their isolation is to serve as a major criterion.

Blood Cultures

Isolation of the causative microorganism from blood cultures is critical for diagnosis, determination of antimicrobial susceptibility, and planning of treatment. In the absence of prior antibiotic therapy, three 2-bottle blood culture sets, separated from one another by at least 1 h, should be obtained from different venipuncture sites over 24 h. If the cultures remain negative after 48–72 h, two or three additional blood culture sets should be obtained, and the laboratory should be consulted for advice regarding optimal culture techniques. Pending culture results, empirical antimicrobial therapy should be withheld initially from hemodynamically stable patients with suspected subacuteendocarditis, especially those who have received antibiotics within the preceding 2 weeks; thus, if necessary, additional blood culture sets can be obtained without the confounding effect of empirical treatment. Patients with acute endocarditis or with deteriorating hemodynamics who may require urgent surgery should be treated empirically immediately after three sets of blood cultures are obtained over several hours.

Non-Blood-Culture Tests

Serologic tests can be used to implicate causally some organisms that are difficult to recover by blood culture: Brucella, Bartonella, Legionella, Chlamydophila psittaci, and C. burnetii. Pathogens can also be identified in vegetations by culture, microscopicexamination with special stains (i.e., the periodic acid–Schiff stain for T. whipplei), or direct fluorescence antibody techniques and by the use of polymerase chain reaction (PCR) to recover unique microbial DNA or 16S rRNA that, when sequenced, allows identification of organisms.

Echocardiography

Echocardiography allows anatomic confirmation of infective endocarditis, sizing of vegetations, detection of intracardiac complications, and assessment of cardiac function (Fig. 124-3). Transthoracic echocardiography (TTE) is noninvasive and exceptionally specific; however, it cannot image vegetations <2 mm in diameter, and in 20% of patients it is technically inadequate because of emphysema or body habitus. TTE detects vegetations in only 65% of patients with definite clinical endocarditis. Moreover, TTE is not adequate for evaluating prosthetic valves or detecting intracardiac complications. TEE is safe and detects vegetations in >90% of patients with definite endocarditis; nevertheless, initial studies may be false-negative in 6–18% of endocarditis patients. When endocarditis is likely, a negative TEE result does not exclude the diagnosis but rather warrants repetition of the study in 7–10 days. TEE is the optimal method for the diagnosis of PVE or the detection of myocardial abscess, valve perforation, or intracardiac fistulae.

Figure 124-3





Imaging of a mitral valve infected with Staphylococcus aureus by low-esophageal four-chamber-view transesophageal echocardiography (TEE). A. Two-dimensional echocardiogram showing a large vegetation with an adjacent echolucent abscess cavity. B. Color-flow Doppler image showing severe mitral regurgitation through both the abscess-fistula and the central valve orifice. A, abscess; A-F, abscess-fistula; L, valve leaflets; LA, left atrium; LV, left ventricle; MR, mitral central valve regurgitation; RV, right ventricle; veg, vegetation. (With permission of Andrew Burger, MD)




Experts favor echocardiographic evaluation of all patients with a clinical diagnosis of endocarditis; however, the test should not be used to screen patients with a low probability of endocarditis (e.g., patients with unexplained fever). An American Heart Association approach to the use of echocardiography for evaluation of patients with suspected endocarditis is illustrated in Fig. 124-4.

Figure 124-4




The diagnostic use of transesophageal and transtracheal echocardiography (TEE and TTE, respectively).High initial patient risk for endocarditis as listed in Tables 124–8 or evidence of intracardiac complications (new regurgitant murmur, new electrocardiographic conduction changes, or congestive heart failure).* High-risk echocardiographic features include large vegetations, valve insufficiency, paravalvular infection, or ventricular dysfunction. Rx indicates initiation of antibiotic therapy. [Reproduced with permission from Diagnosis and Management of Infective Endocarditis and Its Complications (Circulation 1998; 98:2936-2948. © 1998 American Heart Association.)]



Other Studies

Many laboratory studies that are not diagnostic—i.e., complete blood count, creatinine determination, liver function tests, chest radiography, and electrocardiography—are nevertheless important in the management of patients with endocarditis. The erythrocyte sedimentation rate, C-reactive protein level, and circulating immune complex titer are commonly increased in endocarditis (Tables 124–2). Cardiac catheterization is useful primarily to assess coronary artery patency in older individuals who are to undergo surgery for endocarditis.

Treatment: Infective Endocarditis

Antimicrobial Therapy

It is difficult to eradicate bacteria from the vegetation because local host defenses are deficient and because the largely nongrowing, metabolically inactive bacteria are less easily killed by antibiotics. To cure endocarditis, all bacteria in the vegetation must be killed; therefore, therapy must be bactericidal and prolonged. Antibiotics are generally given parenterally to achieve serum concentrations that, through passive diffusion, lead to effective concentrations in the depths of the vegetation. To select effective therapy requires knowledge of the susceptibility of the causative microorganisms. The decision to initiate treatment empirically must balance the need to establish a microbiologic diagnosis against the potential progression of disease or the need for urgent surgery (see "Blood Cultures," above). Simultaneous infection at other sites (such as meningitis), allergies, end-organ dysfunction, interactions with concomitant medications, and risks of adverse events must be considered in the selection of therapy.

Although given for several weeks longer, the regimens recommended for the treatment of endocarditis involving prosthetic valves (except for staphylococcal infections) are similar to those used to treat NVE (Tables 124–4). Recommended doses and durations of therapy should be adhered to unless alterations are required by end-organ dysfunction or adverse events.

Tables 124–4 Antibiotic Treatment for Infective Endocarditis Caused by Common Organismsa

Organism Drug (Dose, Duration) Comments
Streptococci
Penicillin-susceptbleb streptococci, S. gallolyticus Penicillin G (2–3 mU IV q4h for 4 weeks)

Ceftriaxone (2 g/d IV as a single dose for 4 weeks)

Vancomycinc (15 mg/kg IV q12h for 4 weeks)

Penicillin G (2–3 mU IV q4h) or ceftriaxone (2 g IV qd) for 2 weeks plus

Gentamicind (3 mg/kg qd IV or IM, as a single dosee or divided into equal doses q8h for 2 weeks)
—

Can use ceftriaxone in patients with nonimmediate penicillin allergy

Use vancomycin in patients with severe or immediate -lactam allergy

Avoid 2-week regimen when risk of aminoglycoside toxicity is increased and in prosthetic valve or complicated endocarditis

Relatively penicillin-resistantf streptococci Penicillin G (4 mU IV q4h) or ceftriaxone (2 g IV qd) for 4 weeks plus

Gentamicind (3 mg/kg qd IV or IM, as a single dosee or divided into equal doses q8h for 2 weeks)

Vancomycinc as noted above for 4 weeks
Penicillin alone at this dose for 6 weeks or with gentamicin during initial 2 weeks preferred for prosthetic valve endocarditis caused by streptococci with penicillin MICs of 0.1 g/mL

—

Moderately penicillin-resistantg streptococci, nutritionally variant organisms, or Gemella morbillorum Penicillin G (4–5 mU IV q4h) or ceftriaxone (2 g IV qd) for 6 weeks plus

Gentamicind (3 mg/kg qd IV or IM as a single dosee or divided into equal doses q8h for 6 weeks)

Vancomycinc as noted above for 4 weeks
Preferred for prosthetic valve endocarditis caused by streptococci with penicillin MICs of >0.1 g/mL







—

Enterococcih
Penicillin G (4–5 mU IV q4h) plus

Gentamicind (1 mg/kg IV q8h), both for 4–6 weeks

Ampicillin (2 g IV q4h) plus Gentamicind (1 mg/kg IV q8h), both for 4–6 weeks

Vancomycinc (15 mg/kg IV q12h) plus

Gentamicind (1 mg/kg IV q8h), both for 4–6 weeks
Can use streptomycin (7.5 mg/kg q12h) in lieu of gentamicin if there is not high-level resistance to streptomycin

—





Use vancomycin plus gentamicin for penicillin-allergic patients, or desensitize to penicillin

Staphylococci
Methicillin-susceptible, infecting native valves (no foreign devices) Nafcillin or oxacillin (2 g IV q4h for 4–6 weeks)

Cefazolin (2 g IV q8h for 4–6 weeks)

Vancomycinc (15 mg/kg IV q12h for 4–6 weeks)
Can use penicillin (4 mU q4h) if isolate is penicillin-susceptible (does not produce -lactamase)

Can use cefazolin regimen for patients with nonimmediate penicillin allergy

Use vancomycin for patients with immediate (urticarial) or severe penicillin allergy

Methicillin-resistant, infecting native valves (no foreign devices) Vancomycinc (15 mg/kg IV q8–12h for 4–6 weeks) No role for routine use of rifampin
Methicillin-susceptible, infecting prosthetic valves Nafcillin or oxacillin (2 g IV q4h for 6–8 weeks) plus

Gentamicind (1 mg/kg IM or IV q8h for 2 weeks) plus Rifampini (300 mg PO q8h for 6–8 weeks)
Use gentamicin during initial 2 weeks; determine susceptibility to gentamicin before initiating rifampin (see text); if patient is highly allergic to penicillin, use regimen for methicillin-resistant staphylococci; if -lactam allergy is of the minor, nonimmediate type, can substitute cefazolin for oxacillin/nafcillin
Methicillin-resistant, infecting prosthetic valves Vancomycinc (15 mg/kg IV q12h for 6–8 weeks) plus

Gentamicind (1 mg/kg IM or IV q8h for 2 weeks) plus Rifampini (300 mg PO q8h for 6–8 weeks)
Use gentamicin during initial 2 weeks; determine gentamicin susceptibility before initiating rifampin (see text)
HACEK Organisms
Ceftriaxone (2 g/d IV as a single dose for 4 weeks)

Ampicillin/sulbactam (3 g IV q6h for 4 weeks)
Can use another third-generation cephalosporin at comparable dosage

—




a Doses are for adults with normal renal function. Doses of gentamicin, streptomycin, and vancomycin must be adjusted for reduced renal function. Ideal body weight is used to calculate doses of gentamicin and streptomycin per kilogram (men = 50 kg + 2.3 kg per inch over 5 feet; women = 45.5 kg + 2.3 kg per inch over 5 feet).

b MIC, 0.1 g/mL.

c Vancomycin dose is based on actual body weight. Adjust for trough level of 10–15 g/mL for streptococcal and enterococcal infections and 15–20 g/mL for staphylococcal infections.

d Aminoglycosides should not be administered as single daily doses for enterococcal endocarditis and should be introduced as part of the initial treatment. Target peak and trough serum concentrations of divided-dose gentamicin 1 h after a 20- to 30-min infusion or IM injection are 3.5 g/mL and 1 g/mL, respectively; target peak and trough serum concentrations of streptomycin (timing as with gentamicin) are 20–35 g/mL and <10 g/mL, respectively.

e Netilmicin (4 mg/kg qd, as a single dose) can be used in lieu of gentamicin.

f MIC, >0.1 g/mL and <0.5 g/mL.

g MIC, 0.5 g/mL and <8 g/mL.

h Antimicrobial susceptibility must be evaluated; see text.

i Rifampin increases warfarin and dicumarol requirements for anticoagulation.



Organism-Specific Therapies

Streptococci

Optimal therapy for streptococcal endocarditis is based on the minimal inhibitory concentration (MIC) of penicillin for the causative isolate (Tables 124–4). The 2-week penicillin/gentamicin or ceftriaxone/gentamicin regimens should not be used to treat complicated NVE or PVE. The regimen recommended for relatively penicillin-resistant streptococci is advocated for treatment of group B, C, or G streptococcal endocarditis. Nutritionally variant organisms (Granulicatella or Abiotrophia species) and Gemella morbillorum are treated with the regimen for moderately penicillin-resistant streptococci, as is PVE caused by these organisms or by streptococci with a penicillin MIC of >0.1 g/mL (Tables 124–4).

Enterococci

Enterococci are resistant to oxacillin, nafcillin, and the cephalosporins and are only inhibited—not killed—by penicillin, ampicillin, teicoplanin (not available in the United States), and vancomycin. To kill enterococci requires the synergistic interaction of a cell wall–active antibiotic (penicillin, ampicillin, vancomycin, or teicoplanin) that is effective at achievable serum concentrations and an aminoglycoside (gentamicin or streptomycin) to which the isolate does not exhibit high-level resistance. An isolate's resistance to cell wall–active agents or its ability to replicate in the presence of gentamicin at 500 g/mL or streptomycin at 1000–2000 g/mL—a phenomenon called high-level aminoglycoside resistance—indicates that the ineffective antimicrobial agent cannot participate in the interaction to produce killing. High-level resistance to gentamicin predicts that tobramycin, netilmicin, amikacin, and kanamycin also will be ineffective. In fact, even when enterococci are not highly resistant to gentamicin, it is difficult to predict the ability of these other aminoglycosides to participate in synergistic killing; consequently, they should not in general be used to treat enterococcal endocarditis. High concentrations of ampicillin plus ceftriaxone or cefotaxime, by expanded binding of penicillin-binding proteins, kill E. faecalis in vitro and in animal models of endocarditis.

Enterococci causing endocarditis must be tested for high-level resistance to streptomycin and gentamicin, -lactamase production, and susceptibility to penicillin and ampicillin (MIC, <8 g/mL) and to vancomycin (MIC, ≤4 g/mL). If the isolate produces -lactamase, ampicillin/sulbactam or vancomycin can be used as the cell wall–active component; if the penicillin/ampicillin MIC is 8 g/mL, vancomycin can be considered; and if the vancomycin MIC is 8 g/mL, penicillin or ampicillin can be considered. In the absence of high-level resistance, gentamicin or streptomycin should be used as the aminoglycoside (Tables 124–4). If there is high-level resistance to both these drugs, no aminoglycoside should be given; instead, an 8- to 12-week course of a single cell wall–active agent—or, for E. faecalis, high doses of ampicillin combined with ceftriaxone or cefotaxime—is suggested. If this alternative therapy fails or the isolate is resistant to all of the commonly used agents, surgical treatment is advised. The role of newer agents potentially active against multidrug-resistant enterococci [quinupristin/dalfopristin (E. faecium only), linezolid, and daptomycin] in the treatment of endocarditis has not been established. Although the dose of gentamicin used to achieve bactericidal synergy in treating enterococcal endocarditis is smaller than that used in standard therapy, nephrotoxicity is not uncommon during treatment for 4–6 weeks. Regimens in which the aminoglycoside component is discontinued at2–3 weeks because of toxicity have been curative. Thus, discontinuation of the aminoglycoside is recommended when nephrotoxicity develops in patients who have responded satisfactorily to therapy. Alternatively, the ampicillin-ceftriaxone regimen can be used to treat E. faecalis endocarditis if nephrotoxicity develops or is exceptionally threatening.

Staphylococci

The regimens used to treat staphylococcal endocarditis (Tables 124–4) are based not on coagulase production but rather on the presence or absence of a prosthetic valve or foreign device, the native valve(s) involved, and the susceptibility of the isolate to penicillin, methicillin, and vancomycin. All staphylococci are considered penicillin-resistant until shown not to produce penicillinase. Similarly, methicillin resistance has become so prevalent among staphylococci that therapy should be initiated with a regimen for methicillin-resistant organisms and subsequently revised if the strain proves to be susceptible to methicillin. The addition of 3–5 days of gentamicin (if the isolate is susceptible) to a -lactam antibiotic to enhance therapy for native mitral or aortic valve endocarditis has been optional. While the addition of gentamicin minimally hastens eradication of bacteremia, it does not improve survival rates, and even abbreviated gentamicin therapy may be associated with nephrotoxicity and thus is not recommended. Gentamicin generally is not added to the vancomycin regimen in this setting.

For treatment of endocarditis caused by methicillin-resistant S. aureus (MRSA), vancomycin dosing to achieve trough concentrations of 15–20 g/mL is recommended, with the recognition that this regimen may be associated with nephrotoxicity. Although resistance to vancomycin among staphylococci is rare, reduced vancomycin susceptibility among MRSA strains is increasingly encountered. Isolates with a vancomycin MIC of 4–16 g/mL have intermediate susceptibility and are referred to as vancomycin-intermediate S. aureus (VISA). Isolates with an MIC of 2 g/mL may harbor subpopulations with higher MICs. These isolates, called hetero-resistant VISA (hVISA), are not detectable by routine susceptibility testing. Because of the pharmacokinetics/pharmacodynamics of vancomycin, killing of MRSA with a vancomycin MIC of 2 g/mL is unpredictable even with aggressive vancomycin dosing. Although not approved by the U.S. Food and Drug Administration, daptomycin [6 mg/kg (or, as some experts prefer, 8–10 mg/kg) IV once daily] has been recommended as an alternative to vancomycin, particularly for endocarditis caused by VISA, hVISA, and isolates with a vancomycin MIC of2 g/mL. These isolates should be tested to document daptomycin susceptibility. Treatment of endocarditis in which bacteremia persists despite this therapy is beyond the scope of this chapter and requires consultation with an infectious disease specialist. The efficacy of linezolid for left-sided MRSA endocarditis has not been established.

Methicillin-susceptible S. aureus endocarditis that is uncomplicated and limited to the tricuspid or pulmonic valve—a condition occurring almost exclusively in injection drug users—can often be treated with a 2-week course that combines oxacillin or nafcillin (but not vancomycin) with gentamicin. Patients with prolonged fever (5 days) during therapy or multiple septic pulmonary emboli should receive standard therapy. Right-sided endocarditis caused by MRSA is treated for 4 weeks with a standard vancomycin regimen or with daptomycin (6 mg/kg as a single daily dose).

Staphylococcal PVE is treated for 6–8 weeks with a multidrug regimen. Rifampin is an essential component because it kills staphylococci that are adherent to foreign material in a biofilm. Two other agents (selected on the basis of susceptibility testing) are combined with rifampin to prevent in vivo emergence of resistance. Because many staphylococci (particularly MRSA and S. epidermidis) are resistant to gentamicin, susceptibility to gentamicin or an alternative agent should be established before rifampin treatment is begun. If the isolate is resistant to gentamicin, then another aminoglycoside, a fluoroquinolone (chosen on the basis of susceptibility), or another active agent should be substituted for gentamicin.

Other Organisms

In the absence of meningitis, endocarditis caused by S. pneumoniae with a penicillin MIC of ≤1 g/mL can be treated with IV penicillin (4 million units every 4 h), ceftriaxone (2 g/d as a single dose), or cefotaxime (at a comparable dosage). Infection caused by pneumococcal strains with a penicillin MIC of 2 g/mL should be treated with vancomycin. Until the strain's susceptibility to penicillin is established, therapy should consist of vancomycin plus ceftriaxone, especially if concurrent meningitis is suspected. P. aeruginosa endocarditis is treated with an antipseudomonal penicillin (ticarcillin or piperacillin) and high doses of tobramycin (8 mg/kg per day in three divided doses). Endocarditis caused by Enterobacteriaceae is treated with a potent -lactam antibiotic plus an aminoglycoside. Corynebacterial endocarditis is treated with penicillin plus an aminoglycoside (if the organism is susceptible to the aminoglycoside) or with vancomycin, which is highly bactericidal for most strains. Therapy for Candida endocarditis consists of amphotericin B plus flucytosine and early surgery; long-term (if not indefinite) suppression with an oral azole is advised. Caspofungin treatment of Candida endocarditis has been effective in sporadic cases; nevertheless, the role of echinocandins in this setting has not been established.

Empirical Therapy

In the design and execution of therapy without culture data (i.e., before culture results are known or when cultures are negative), clinical clues (e.g., site of infection, patient's predispositions) as well as epidemiologic clues to etiology must be considered. Thus, empirical therapy for acute endocarditis in an injection drug user should cover MRSA and gram-negative bacilli. Treatment with vancomycin plus gentamicin, initiated immediately after blood is obtained for cultures, covers these as well as many other potential causes. Similarly, treatment of health care–associated endocarditis must cover MRSA. In the treatment of culture-negative episodes, marantic endocarditis must be excluded and fastidious organisms sought by serologic testing. In the absence of prior antibiotic therapy, it is unlikely that S. aureus, CoNS, or enterococcal infection will present with negative blood cultures; thus, in this situation, recommended empirical therapy targets not these organisms but rather nutritionally variant organisms, the HACEK group, and Bartonella species. Pending the availability of diagnostic data, blood culture–negative subacute NVE is treated either with ampicillin-sulbactam (12 g every 24 h) or with ceftriaxone plus gentamicin; doxycycline (100 mg twice daily) is added for Bartonella coverage. Vancomycin, gentamicin, cefepime, and rifampin should be used if prosthetic valves in place for 1 year are involved. Empirical therapy for infected prosthetic valves in place for ≤1 year is similar to that for culture-negative PVE. If negative cultures have been confounded by prior antibiotic administration, broader empirical therapy may be indicated, with particular attention to pathogens likely to be inhibited by the specific prior therapy.

Outpatient Antimicrobial Therapy

Fully compliant patients who have sterile blood cultures, no fever, and no clinical or echocardiographic findings that suggest an impending complication may complete therapy as outpatients. Careful follow-up and a stable home setting are necessary, as are predictable IV access and use of antimicrobial agents that are stable in solution.

Monitoring Antimicrobial Therapy

The serum bactericidal titer—the highest dilution of the patient's serum during therapy that kills 99.9% of the standard inoculum of the infecting organism—is no longer recommended for assessment of standard regimens. However, in the treatment of endocarditis caused by unusual organisms, this measurement may provide a patient-specific assessment of in vivo antibiotic effect. Serum concentrations of aminoglycosides and vancomycin should be monitored.

Antibiotic toxicities, including allergic reactions, occur in 25–40% of patients and commonly arise during the third week of therapy. Blood tests to detect renal, hepatic, and hematologic toxicity should be performed periodically.

Blood cultures should be repeated daily until sterile, rechecked if there is recrudescent fever, and performed again 4–6 weeks after therapy to document cure. Blood cultures become sterile within 2 days after the start of appropriate therapy when infection is caused by viridans streptococci, enterococci, or HACEK organisms. In S. aureus endocarditis, -lactam therapy results in sterile cultures in 3–5 days, whereas with MRSA endocarditis positive cultures may persist for 7–9 days with vancomycin treatment. MRSA bacteremia persisting despite an adequate dosage of vancomycin may indicate infection due to a strain with reduced vancomycin susceptibility and therefore may point to a need for alternative therapy. When fever persists for 7 days despite appropriate antibiotic therapy, patients should be evaluated for paravalvular abscess, extracardiac abscesses (spleen, kidney), or complications (embolic events). Recrudescent fever raises the question of these complications but also of drug reactions or complications of hospitalization. Vegetations become smaller with effective therapy; however, 3 months after cure, 50% are unchanged and 25% are slightly larger.

Surgical Treatment

Intracardiac and central nervous system complications of endocarditis are important causes of morbidity and death. In some cases, effective treatment for these complications requires surgery. The indications for cardiac surgical treatment of endocarditis (Tables 124–5) have been derived from observational studies and expert opinion. The strength of individual indications vary; thus, the risks and benefits as well as the timing of surgery must be individualized (Tables 124–6). From 25% to 40% of patients with left-sided endocarditis undergo cardiac surgery during active infection, with slightly higher surgery rates with PVE than with NVE. Clinical events resulting from intracardiac complications, which are most reliably detected by TEE, justify most surgery. In the absence of randomized trials to evaluate a survival benefit for surgical intervention, the effect of surgery has been assessed in studies comparing populations of medically and surgically treated patients matched for the necessity of surgery (indication), with adjustments for predictors of death (comorbidity) and time of the surgical intervention. Although study results vary, surgery for currently advised indications appears to convey a significant survival benefit (27–55%) that becomes apparent only with follow-up for 6 months after the intervention. During the initial weeks after surgery, mortality risk is actually increased (disease- plus surgery-related mortality). With less demanding surgical indications, this combined mortality risk may erode potential long-term benefits. Benefit is greatest for NVE complicated by heart failure or myocardial abscess and is less clear for PVE; this difference may reflect sample size in the relevant studies.

Tables 124–5 Indications for Cardiac Surgical Intervention in Patients with Endocarditis

Surgery required for optimal outcome

Moderate to severe congestive heart failure due to valve dysfunction

Partially dehisced unstable prosthetic valve

Persistent bacteremia despite optimal antimicrobial therapy

Lack of effective microbicidal therapy (e.g., fungal or Brucella endocarditis)

S. aureus prosthetic valve endocarditis with an intracardiac complication

Relapse of prosthetic valve endocarditis after optimal antimicrobial therapy

Surgery to be strongly considered for improved outcomea

Perivalvular extension of infection

Poorly responsive S. aureus endocarditis involving the aortic or mitral valve

Large (>10-mm diameter) hypermobile vegetations with increased risk of embolism

Persistent unexplained fever (10 days) in culture-negative native valve endocarditis

Poorly responsive or relapsed endocarditis due to highly antibiotic-resistant enterococci or gram-negative bacilli




a Surgery must be carefully considered; findings are often combined with other indications to prompt surgery.


Tables 124–6 Timing of Cardiac Surgical Intervention in Patients with Endocarditis


Indication for Surgical Intervention
Timing
Strong Supporting Evidence
Conflicting Evidence, but Majority of Opinions Favor Surgery
Emergent (same day)

Acute aortic regurgitation plus preclosure of mitral valve
Sinus of Valsalva abscess ruptured into right heart
Rupture into pericardial sac

Urgent (within 1–2 days)

Valve obstruction by vegetation
Unstable (dehisced) prosthesis
Acute aortic or mitral regurgitation with heart failure (New York Heart Association class III or IV)
Septal perforation
Perivalvular extension of infection with/without new electrocardiographic conduction system changes
Lack of effective antibiotic therapy

Major embolus plus persisting large vegetation (>10 mm in diameter)
Elective (earlier usually preferred)

Progressive paravalvular prosthetic regurgitation
Valve dysfunction plus persisting infection after 7–10 days of antimicrobial therapy
Fungal (mold) endocarditis

Staphylococcal PVE
Early PVE (2 months after valve surgery)
Fungal endocarditis (Candida spp.)
Antibiotic-resistant organisms
Note: PVE, prosthetic valve endocarditis.
Source: Adapted from L Olaison, G Pettersson: Infect Dis Clin North Am 16:453, 2002.




Congestive Heart Failure

Moderate to severe refractory CHF caused by new or worsening valve dysfunction is the major indication for cardiac surgical treatment of endocarditis. At 6 months of follow-up, patients with left-sided endocarditis and moderate to severe heart failure due to valve dysfunction who are treated only medically have a 50% mortality rate; the figure is 15% among matched patients who undergo surgery. The survival benefit with surgery is seen in both NVE and PVE. Surgery can relieve functional stenosis due to large vegetations or restore competence to damaged regurgitant valves by repair or replacement.

Perivalvular Infection

This complication, which is most common with aortic valve infection, occurs in 10–15% of native valve and 45–60% of prosthetic valve infections. It is suggested by persistent unexplained fever during appropriate therapy, new electrocardiographic conduction disturbances, and pericarditis. TEE with color Doppler is the test of choice to detect perivalvular abscesses (sensitivity, 85%). For optimal outcome, surgery is required, especially when fever persists, fistulae develop, prostheses are dehisced and unstable, and invasive infection relapses after appropriate treatment. Cardiac rhythm must be monitored since high-grade heart block may require insertion of a pacemaker.

Uncontrolled Infection

Continued positive blood cultures or otherwise-unexplained persistent fevers (in patients with either blood culture–positive or –negative endocarditis) despite optimal antibiotic therapy may reflect uncontrolled infection and may warrant surgery. Surgical treatment is also advised for endocarditis caused by organisms for which experience indicates that effective antimicrobial therapy is lacking (e.g., yeasts, fungi, P. aeruginosa, other highly resistant gram-negative bacilli, Brucella species, and probably C. burnetii).

Aureus Endocarditis

The mortality rate for S. aureus PVE exceeds 50% with medical treatment but is reduced to 25% with surgical treatment. In patients with intracardiac complications associated with S. aureus PVE, surgical treatment reduces the mortality rate twentyfold. Surgical treatment should be considered for patients with S. aureus native aortic or mitral valve infection who have TTE-demonstrable vegetations and remain septic during the initial week of therapy. Isolated tricuspid valve endocarditis, even with persistent fever, rarely requires surgery.

Prevention of Systemic Emboli

Death and persisting morbidity due to emboli are largely limited to patients suffering occlusion of cerebral or coronary arteries. Echocardiographic determination of vegetation size and anatomy, although predictive of patients at high risk of systemic emboli, does not identify those patients in whom the benefits of surgery to prevent emboli clearly exceed the risks of the surgical procedure. Net benefits from surgery to prevent emboli are most likely when other surgical benefits can be achieved simultaneously—e.g., repair of a moderately dysfunctional valve or debridement of a paravalvular abscess. Only 3.5% of patients undergo surgery solely to prevent systemic emboli. Valve repair avoiding insertion of a prosthesis makes the benefit-to-risk ratio of surgery to address vegetations more favorable.

Timing of Cardiac Surgery

In general, when indications for surgical treatment of infective endocarditis are identified, surgery should not be delayed simply to permit additional antibiotic therapy, since this course of action increases the risk of death (Tables 124–6). After 14 days of recommended antibiotic therapy, excised valves are culture-negative in 99% and 50% of patients with streptococcal and S. aureus endocarditis, respectively. Recrudescent endocarditis on a new implanted prosthetic valve follows surgery for active NVE and PVE in 2% and 6–15% of patients, respectively. These frequencies do not justify the risk of adverse outcome with delayed surgery, particularly in patients with severe heart failure, valve dysfunction, and staphylococcal infections. Delay is justified only when infection is controlled and CHF is resolved with medical therapy.

Among patients who have experienced a neurologic complication of endocarditis, further neurologic deterioration can occur as a consequence of cardiac surgery. The risk of neurologic deterioration is related to the type of neurologic complication and the interval between the complication and surgery. Whenever feasible, cardiac surgery should be delayed for 2–3 weeks after a nonhemorrhagic embolic infarction and for 4 weeks after a cerebral hemorrhage. A ruptured mycotic aneurysm should be treated before cardiac surgery.

Antibiotic Therapy after Cardiac Surgery

Bacteria visible in Gram-stained preparations of excised valves do not necessarily indicate a failure of antibiotic therapy. Organisms have been detected on Gram's stain—or their DNA has been detected by PCR—in excised valves from 45% of patients who have successfully completed the recommended therapy for endocarditis. In only 7% of these patients are the organisms, most of which are unusual and antibiotic resistant, cultured from the valve. Despite the detection of organisms or their DNA, relapse of endocarditis after surgery is uncommon. Thus, when valve cultures are negative in uncomplicated NVE caused by susceptible organisms, the duration of preoperative plus postoperative treatment should equal the total duration of recommended therapy, with 2 weeks of treatment administered after surgery. For endocarditis complicated by paravalvular abscess, partially treated PVE, or cases with culture-positive valves, a full course of therapy should be given postoperatively.

Extracardiac Complications

Splenic abscess develops in 3–5% of patients with endocarditis. Effective therapy requires either image-guided percutaneous drainage or splenectomy. Mycotic aneurysms occur in 2–15% of endocarditis patients; one-half of these cases involve the cerebral arteries and present as headaches, focal neurologic symptoms, or hemorrhage. Cerebral aneurysms should be monitored by angiography. Some will resolve with effective antimicrobial therapy, but those that persist, enlarge, or leak should be treated surgically if possible. Extracerebral aneurysms present as local pain, a mass, local ischemia, or bleeding; these aneurysms are treated by resection.

Outcome

Older age, severe comorbid conditions and diabetes, delayed diagnosis, involvement of prosthetic valves or the aortic valve, an invasive (S. aureus) or antibiotic-resistant (P. aeruginosa, yeast) pathogen, intracardiac and major neurologic complications, and an association with health care adversely affect outcome. Death and poor outcome often are related not to failure of antibiotic therapy but rather to the interactions of comorbidities and endocarditis-related end-organ complications. Overall survival rates for patients with NVE caused by viridans streptococci, HACEK organisms, or enterococci (susceptible to synergistic therapy) are 85–90%. For S. aureus NVE in patients who do not inject drugs, survival rates are 55–70%, whereas 85–90% of injection drug users survive this infection. PVE beginning within 2 months of valve replacement results in mortality rates of 40–50%, whereas rates are only 10–20% in later-onset cases.

Prevention

In the past, in an effort to prevent endocarditis (long a goal in clinical practice), expert committees have supported systemic antibiotic administration prior to many bacteremia-inducing procedures. In the absence of human trials, a reappraisal of the indirect evidence for antibiotic prophylaxis for endocarditis by the American Heart Association has culminated in guidelines that reverse prior recommendations and restrict prophylactic antibiotic use. At best, the benefit of antibiotic prophylaxis is minimal. Most endocarditis cases do not follow a procedure. In case-control studies, dental treatments—widely considered as predisposing to endocarditis—occur no more frequently before endocarditis than in matched controls. Furthermore, the frequency and magnitude of bacteremia associated with dental procedures and routine daily activities (e.g., tooth brushing and flossing) are similar. Because dental procedures are infrequent, exposure of cardiac structures to bacteremic oral-cavity organisms is notably greater from routine daily activities than from dental care. The relation of gastrointestinal and genitourinary procedures to subsequent endocarditis is more tenuous than that of dental procedures. In addition, cost-effectiveness and cost-benefit estimates suggest that antibiotic prophylaxis represents a poor use of resources.

Studies in animal models suggest that antibiotic prophylaxis may be effective. Thus it is possible that rare cases of endocarditis are prevented. Weighing the potential benefits, potential adverse events, and costs associated with antibiotic prophylaxis, the American Heart Association and the European Society of Cardiology now recommend prophylactic antibiotics (Tables 124–7) only for those patients at highest risk for severe morbidity or death from endocarditis (Tables 124–8). Maintaining good dental hygiene is essential. Prophylaxis is recommended only when there is manipulation of gingival tissue or the periapical region of the teeth or perforation of the oral mucosa (including surgery on the respiratory tract). Prophylaxis is not advised for patients undergoing gastrointestinal or genitourinary tract procedures. High-risk patients should be treated before or when they undergo procedures on an infected genitourinary tract or on infected skin and soft tissue. The British Society for Antimicrobial Chemotherapy continues to recommend prophylaxis for at-risk patients undergoing selected gastrointestinal and genitourinary procedures. In contrast, the National Institute for Health and Clinical Excellence in the United Kingdom found no convincing evidence that antibiotic prophylaxis was cost effective and advised discontinuation of the practice (see www.nice.org.uk/guidance/CG64).

Tables 124–7 Antibiotic Regimens for Prophylaxis of Endocarditis in Adults with High-Risk Cardiac Lesionsa,b



A. Standard oral regimen

1. Amoxicillin: 2 g PO 1 h before procedure

B. Inability to take oral medication

1. Ampicillin: 2 g IV or IM within 1 h before procedure

C. Penicillin allergy

1. Clarithromycin or azithromycin: 500 mg PO 1 h before procedure

2. Cephalexinc: 2 g PO 1 h before procedure

3. Clindamycin: 600 mg PO 1 h before procedure

D. Penicillin allergy, inability to take oral medication

1. Cefazolinc or ceftriaxonec: 1 g IV or IM 30 min before procedure

2. Clindamycin: 600 mg IV or IM 1 h before procedure
a Dosing for children: for amoxicillin, ampicillin, cephalexin, or cefadroxil, use 50 mg/kg PO; cefazolin, 25 mg/kg IV; clindamycin, 20 mg/kg PO, 25 mg/kg IV; clarithromycin, 15 mg/kg PO; and vancomycin, 20 mg/kg IV.
b For high-risk lesions, see Tables 124–8. Prophylaxis is not advised for other lesions.
c Do not use cephalosporins in patients with immediate hypersensitivity (urticaria, angioedema, anaphylaxis) to penicillin.
Source: W Wilson et al: Circulation, published online 4/19/2007.


Tables 124–8 High-Risk Cardiac Lesions for Which Endocarditis Prophylaxis Is Advised before Dental Procedures

Prosthetic heart valves
Prior endocarditis
Unrepaired cyanotic congenital heart disease, including palliative shunts or conduits
Completely repaired congenital heart defects during the 6 months after repair
Incompletely repaired congenital heart disease with residual defects adjacent to prosthetic material
Valvulopathy developing after cardiac transplantation



Further Readings

Aksoy O et al: Early surgery in patients with infective endocarditis: A propensity score analysis. Clin Infect Dis 44:364, 2007[PMID: 17205442]


Baddour LM et al: Diagnosis, antimicrobial therapy, and management of complications. A statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association. Circulation 111:e394, 2005


Bannay A et al: The impact of valve surgery on short- and long-term mortality in left-sided infective endocarditis: Do differences in methodological approaches explain previous conflicting results? Eur Heart J epub ahead of print, Feb 9, 2009 (http://eurheartj.oxfordjournal.org/content/early/2009/02/09/eurheartj.ehp008)


Benito N et al: Health care–associated native valve endocarditis: Importance of non-nosocomial acquisition. Ann Intern Med 150:586, 2009[PMID: 19414837]


Cosgrove SE et al: Initial low-dose gentamicin for Staphylococcus aureus bacteremia and endocarditis is nephrotoxic. Clin Infect Dis 48:713, 2009[PMID: 19207079]


Durack DT: Prevention of infective endocarditis, in Principles and Practice of Infectious Diseases, 7th ed, GL Mandell et al (eds). Philadelphia, Elsevier Churchill Livingstone, 2010, pp 1143–1151


Fowler VG Jr et al: Endocarditis and intravascular infections, in Principles and Practice of Infectious Diseases, 7th ed, GL Mandell et al (eds). Philadelphia, Elsevier Churchill Livingstone, 2010, pp 1067–1112


Habbib G et al: Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009). Eur Heart J 30:2369, 2009


Murdoch DR et al: Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century. Arch Intern Med 169:463, 2009[PMID: 19273776]


Rybak MJ et al: Vancomycin therapeutic guidelines: A summary of consensus recommendations from the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis 49:325, 2009[PMID: 19569969]


Thuny F et al: The timing of surgery influences mortality and morbidity in adults with severe complicated infective endocarditis: A propensity analysis. Eur Heart J epub ahead of print, March 26, 2009 (http://eurheartj.oxfordjournal.org/content/early/2009/03/26/eurheartj.ehp089)


Wilson W et al: Prevention of infective endocarditis. Guidelines from the American Heart Association. A guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 116:1736, 2007[PMID: 17446442]







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