Corey, G. Ralph MD
Infectious disease physicians, nurses, hospital epidemiologists, clinical microbiologists, pharmacists, public health officials, practicing physicians, and other healthcare professionals interested in the treatment of serious infections due to methicillin-resistant Staphylococcus aureus (MRSA).
Describe the utility of history taking, physical examination, blood cultures, echocardiography, and selected imaging studies in establishing the diagnosis of bacteremia and/or endocarditis.
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Credit is based on the approximate time it should take to read this publication and complete the assessment and evaluation. A minimum assessment score of 80% is required. Publication date is September 1, 2011. Requests for credit or contact hours must be postmarked no later than March 1, 2012, after which this material is no longer certified for credit.
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Marla Dalton, PE (managing editor) reported no relevant financial relationships.
G. Ralph Corey, MD (faculty) served as an advisor or consultant for Astellas Pharma, Cempra Pharmaceuticals, Cerexa, Inc, Cubist Pharmaceuticals, GlaxoSmithKline, Inimex Pharmaceuticals, Merck & Co, Targanta Therapeutics, and Trius Therapeutics; and received grants for clinical research from Cempra Pharmaceuticals, Cerexa, Inc, Innocoll, and Theravance, Inc.
Thomas M. File, Jr, MD (reviewer) served as an advisor or consultant for Astellas/Theravance, Cerexa/Forest, Merck, Nabriva, Pfizer Inc, and Tetraphase; and received grants for clinical research from Cerexa, Cempra, Pfizer Inc, and The Medicines Company.
Marguerite Jackson, PhD, RN (reviewer) owns stock, stock options, or bonds from Cellestis, Inc.
Susan J. Rehm, MD (senior editor) served as an advisor or consultant for Merck and Pfizer, Inc; served as a speaker for Genentech; and received grants for clinical research from Cubist Pharmaceuticals, Inc.
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Staphylococcus aureus is a ubiquitous organism whose ability to adapt to its environment makes it a constant challenge for both the body's host defenses and antibiotic development. Over the past 2 decades, we have witnessed an epidemic of S. aureus infections including skin and soft tissue infections, hospital-acquired pneumonia, and bacteremia. Fueled by a new bacterial strain, USA300, S. aureus has become the predominant community-acquired bacteria causing skin and skin structure infections. In addition, this organism has demonstrated its ability to cause necrotizing pneumonia in patients infected with influenza. More recently, community-associated methicillin-resistant S. aureus (CA-MRSA) has moved into hospitals, resulting in hospital-acquired pneumonia and healthcare-associated bacteremia. As a result of changing increasingly invasive medical practice, S. aureus bacteremia (SAB) is being recognized more and more frequently. Complications of SAB can be difficult to identify, and the appropriate length of therapy is critical for favorable outcomes. The role of infectious disease specialists in treating patients with SAB is becoming increasingly important.1 The objectives of this discussion are to (1) to identify the danger that SAB poses and to quantify the risks of the illness to the patient; (2) to conduct a proper evaluation, which includes a bedside evaluation, appropriate laboratory tests, and imaging procedures; and (3) based on these results, determine the category (uncomplicated vs. complicated) and consequent length of therapy for SAB.
THE NATURE OF SAB
S. aureus is a unique and versatile organism. The organism contains attachment proteins on its surface, which allow it to cause metastatic infection in a variety of sites and increases its virulence. Some of these proteins include fibronectin-binding protein, collagen-binding protein, and elastin-binding protein. S. aureus will bind to sites of endovascular damage where platelet-fibrin thrombi have formed. These binding proteins may play a more important role than the toxins (enterotoxin B, TSST-1, and α-toxin) in the pathogenesis of staphylococcal invasion.2
S. aureus is not like other catheter-associated pathogens. Other bacteria-causing bloodstream infections are able to cause septic shock (gram-negative bacilli) or have high prevalence of antibiotic resistance (coagulase-negative staphylococci) or invade immunocompromised hosts (Candida species). The important distinction between S. aureus and other pathogens is that S. aureus is frequently associated with metastatic infections, making it a dangerous organism (Table 1).3
SAB is a highly lethal condition, even among patients with catheter-related infections. Studies have shown that metastatic infections with S. aureus occurred in 34% of patients with SAB; and even in catheter-related bloodstream infections, 14% of patients suffered from metastatic infections. Endocarditis occurred in 1 of 8 patients with SAB, and the 12-week mortality rate in patients with SAB was 24%.4,5
IMPORTANT PATIENT HISTORY CONSIDERATIONS: COMPLICATED SAB
The primary objective for the infectious disease physician is to determine the extent of staphylococcal infection. The origin of the infection is not as critical as defining where the infection has settled in the body. The key historical points to ascertain from the patient are summarized in Table 2. Determining the setting in which the bacteremia was acquired is the first step in determining the risk of SAB. For example, patients in the community with SAB have a high likelihood of having endocarditis. These patients are likely to have had the illness without treatment for a longer period than those patients who acquired their infection in the hospital setting. This prolonged SAB increases the chances of having metastatic infection.6 A second risk factor for complicated SAB, indeed the highest risk factor of acquiring S. aureus endocarditis, is a previous episode of endocarditis. Intravascular hardware/prolonged catheter placement, especially dialysis, also puts a patient at risk of acquiring complicated SAB.
Historical research has shown that heart structure, valve abnormalities, and turbulence (ie, pressure gradients, as in mitral insufficiency and aortic insufficiency) were important factors necessary for the occurrence of endocarditis.7,8 However, these factors may not be necessary for SAB because S. aureus can attach to normal valves. In contrast, Streptococcus viridians requires damaged valves and turbulence for attachment.
The presence of intravascular hardware such as a pacemaker is another risk factor for complicated SAB. Atomic force microscopy has shown that there is a strong distinction between the binding-force signature of S. aureus isolates of patients with an infected cardiac prosthesis and the S. aureus isolates from the nares of healthy patients.9 The strength of force between invasive S. aureus and hardware suggests that patients with implanted medical devices have a greater risk of acquiring complicated SAB. The presence of other prosthetic hardware is also an important risk factor for invasive S. aureus infection. In a prospective study of 53 patients with prosthetic joints and 27 patients with other orthopedic prosthetic devices who developed SAB, the risk of prosthetic device infection was 28% overall.10
KEY PHYSICAL EXAMINATION FINDINGS
S. aureus can infect any tissue of the body including the skin, eyes (fundi and conjunctivae), heart, lungs, bones/muscles/joints, kidneys, liver, and spleen. SAB can manifest in the eye as cotton wool exudates and Roth spots, which are retinal hemorrhages with white centers.11 Embolic phenomena are also classic manifestations of SAB (Fig. 1). However, as physicians are diagnosing endocarditis earlier, these symptoms are detected less frequently. Vertebral osteomyelitis and psoas abscesses are also common manifestations of SAB mainly because these areas have high blood flow, which is a risk factor for S. aureus colonization.
The key objective in obtaining laboratory tests is to differentiate uncomplicated from complicated SAB. The follow-up blood culture is the most important laboratory test for diagnosing SAB. A positive follow-up blood culture is an indication of complicated disease. A second test, which may help differentiate uncomplicated from complicated disease, is a urinalysis. Obtaining a urinalysis in patients without a Foley catheter is important, especially if it demonstrates hematuria and pyuria. These findings may indicate small microabscesses in the kidney, a sign of complicated disease.
ECHOCARDIOGRAMS AND OTHER IMAGING PROCEDURES
Transthoracic esophageal echocardiograms (TEE) are favored over transthoracic echocardiograms (TTE) in detecting the cardiac complications of SAB.12 The use of TEE to determine duration of therapy for intravascular catheter-associated SAB has been shown to be a cost-effective alternative to 2- or 4-week empirical therapy.13 The value of TEE in predicting embolic events has also been reported.14 Some researchers have recommended that TTE should be the diagnostic procedure of choice for endocarditis and that TEE should be reserved for patients who have prosthetic valves and in whom TTE is either inadequate or indicates an intermediate probability of endocarditis. However, this study did not use the Duke criteria for infective endocarditis, and clinically defining an "intermediate probability" of endocarditis can be challenging.15
In diagnosing SAB, routine radiographic studies may not be particularly helpful. Bone x-rays may be useful; however, the physician needs to consider that osteomyelitis may take some time to show up on x-ray. Computed tomography has been shown to be valuable for identifying abscesses and osteomyelitis and may detect more emboli than are clinically apparent. Magnetic resonance imagining (MRI) is often helpful in detecting early osteomyelitis as well as central nervous system emboli/infection. With regard to cardiac imaging, MRI of the heart is neither sensitive nor specific for the diagnosis of endocarditis; however, both computed tomography and MRI may provide ancillary information when vascular graft infection is suspected.
PREDICTORS OF COMPLICATED SAB
The key to defining treatment of SAB is to categorize patients into uncomplicated and complicated infection. In a prospective observational cohort of 724 adult hospitalized patients with SAB, Fowler et al16 determined that the strongest predictor of complicated SAB was a positive follow-up blood culture at 48 to 96 hours (odds ratio, 5.6). Other independent predictors of complicated SAB were community onset (odds ratio, 3.1), persistent fever at 72 hours (odds ratio, 2.2), and skin lesions (odds ratio, 2.0).
The probability of acquiring complications associated with SAB has been determined using a scoring system based on the sum of individual risk factor points (one point each for skin findings, persistent fever at 72 hours, and community onset; 2 points for a positive blood culture at 48 to 96 hours.)16
LENGTH OF TREATMENT FOR SAB
When determining the length of treatment for SAB, clinicians need to remember that the origin of the bacteremia is not predictive of outcome.16 Focusing on short-term therapy for catheter-related infection ignores the fact that (1) the origin of bacteremia is not predictive of outcome and that (2) 39% of infectious endocarditis cases are healthcare-associated infections.17
The most prudent approach to treatment of SAB is to treat all patients for at least 4 weeks. Infectious disease specialists and other physicians experienced in the treatment of endocarditis may choose to treat patients with SAB for a short-term period only in specific well-defined cases.1,3 These cases include catheter-associated bacteremia if the catheter is removed, a follow-up negative blood culture, lowering of fever in 72 hours, normal TEE, no prosthetic material in joints or intravascular space, no evidence of thrombophlebitis, and no symptoms suggestive of metastatic infection.1,3
The conduct of clinical trials in patients with uncomplicated SAB is difficult. For example, in a study by Raad et al18 that evaluated the efficacy of dalbavancin in catheter-related bloodstream infections, 2600 patients were screened to enroll 75 patients; 23 of these patients had S. aureus. The progressive algorithm in Figure 2 (GR Corey, satellite symposium preceding the 47th Annual IDSA Meeting on October 28, 2009 in Philadelphia, PA) shows that in another clinical trial of treatment for uncomplicated SAB, only 105 of 1282 screened patients were eligible for enrollment. Because of post-randomization criteria excluding patients with a positive follow-up blood culture, persistent fever over 72 hours, and a positive TEE, the number of evaluable patients dropped to 26.
In summary, the evaluation of a patient with SAB is a major undertaking, which should be conducted by infectious disease specialists. Patients should be categorized as having either uncomplicated or complicated S. aureus infections. A careful history and physical examination should be conducted to determine the need for further testing. The TEE should be used in the majority of adult patients with SAB because of the limited imaging characteristics of TTE. This is especially true in large patients and those with prosthetic valves. Clinical trials in SAB are difficult to conduct because of the large numbers of patients needed to identify and enroll those with uncomplicated disease. Finally, regarding length of treatment for SAB, all patients, except for those who meet specific well-defined criteria, should be treated for 4 weeks.
1. Lahey T, Shah R, Gittzus J, et al. Infectious diseases consultation lowers mortality from Staphylococcus aureus bacteremia. Medicine (Baltimore). 2009;88(5):263-267.
2. Lowy FD. Staphylococcus aureus infections. N Engl J Med. 1998;339(8):520-532.
3. Corey GR, Stryjewski ME, Everts RJ. Short-course therapy for bloodstream infections in immunocompetent adults. Int J Antimicrob Agents. 2009;34(suppl 4):S47-S51.
4. Fowler VG, Olsen MK, Corey GR, et al. Clinical identifiers of complicated Staphylococcus aureus bacteremia. Arch Intern Med. 2003;163(17):2066-2072.
5. Fowler VG, Justice A, Moore C. Risk factors for hematogenous complications of intravascular catheter-associated Staphylococcus aureus bacteremia. Clin Infect Dis. 2005;40(5):695-703.
6. Nolan CM, Beaty HN. Staphylococcus aureus bacteremia. Current clinical patterns. Am J Med. 1976;60(4):495-500.
7. Weinstein L, Schlesinger JJ. Pathoanatomic, pathophysiologic, and clinical correlations in endocarditis (second of two parts). N Engl J Med. 1974;291(21):1122-1126.
8. Weinstein L. "Modern" infective endocarditis. JAMA. 1975;233(3):260-263.
9. Yongsunthon R, Fowler VG Jr, Lower BH, et al. Correlation between fundamental binding forces and clinical prognosis of Staphylococcus aureus infections of medical implants. Langmuir. 2007;23(5):2289-2292.
10. Murdoch DR, Roberts SA, Fowler VG Jr, et al. Infection of orthopedic prostheses after Staphylococcus aureus bacteremia. Clin Infect Dis. 2001;32(4):647-649.
11. Bouza E, Cobo-Soriano R, Rodriguez-Créixems M, et al. A prospective search for ocular lesions in hospitalized patients with significant bacteremia. Clin Infect Dis. 2000;30(2):306-312.
12. Fowler VG Jr, Li J, Corey GR, et al. Role of echocardiography in evaluation of patients with Staphylococcus aureus bacteremia: experience in 103 patients. J Am Coll Cardiol. 1997;30(4):1072-1078.
13. Rosen AB, Fowler VG Jr, Corey GR, et al. Cost-effectiveness of transesophageal echocardiography to determine the duration of therapy for intravascular catheter-associated Staphylococcus aureus bacteremia. Ann Intern Med. 1999;130(10):810-820.
14. Di Salvo G, Habib G, Pergola V, et al. Echocardiography predicts embolic events in infective endocarditis. J Am Coll Cardiol. 2001;37(4):1069-1076.
15. Lindner JR, Case RA, Dent JM, et al. Diagnostic value of echocardiography in suspected endocarditis. An evaluation based on the pretest probability of disease. Circulation. 1996;93(4):730-736.
16. Fowler VG Jr, Olsen MK, Corey GR, et al. Clinical identifiers of complicated Staphylococcus aureus bacteremia. Arch Intern Med. 2003;163(17):2066-2072.
17. Fowler VG Jr, Miro JM, Hoen B, et al. Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA. 2005;293(24):3012-3021.
18. Raad I, Darouiche R, Vazquez J, et al. Efficacy and safety of weekly dalbavancin therapy for catheter-related bloodstream infection caused by gram-positive pathogens. Clin Infect Dis. 2005;40(3):374-380.
A minimum assessment score of 80% is required.
1) S. aureus can be distinguished from other line-associated pathogens by its increased ability to cause:
A. Septic shock
B. Metastatic infection
D. Blood culture contamination
2) Important considerations for determining the risk and extent of S. aureus bacteremia do NOT include:
A. The origin of the infection
B. Community versus healthcare-associated setting
C. Previous episode of endocarditis
3) Physical examination findings in patients with S. aureus bacteremia may include which of the following:
A. Roth spots
B. Psoas abscess
C. Embolic phenomena
D. All of the above
4) The recommended length of therapy for treatment of S. aureus bacteremia may be 2 weeks in which of the following cases?
A. Normal TEE and positive follow-up blood culture
B. Persistent fever in 72 hours and no symptoms suggestive of metastatic infection
C. Catheter-associated bacteremia with catheter removed and no symptoms suggestive of metastatic infection
D. Normal TEE and persistent fever in 72 hours
5) The strongest predictor of complicated S. aureus bacteremia is:
A. Community-onset disease
B. Persistent fever at 72 hours
C. Positive follow-up blood culture at 48 to 96 hours
D. Skin lesions
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