Endovascular Infections (endocarditis, septic thrombophelbitis, mycotic aneurysm)

1. Description of the problem

What every clinician needs to know

Endovascular infections (EI) including endocarditis, septic thrombophlebitis and mycotic aneurysms should be suspected in any patient with prolonged bacteremia greater than 72 hours after starting appropriate antimicrobial therapy. Often these infections present with a constellation of clinical findings that will guide the clinician to the source of bacteremia. Endocarditis is much more common than septic thrombophlebitis or mycotic aneurysms. Risk factors for endocarditis include injection drug use, structural valvular disease (rheumatic heart disease), prosthetic heart valves, history of infective endocarditis, healthcare-associated catheter-related bacteremia, and hemodialysis requiring intravascular catheters.

Clinical features

Clinical features of endocarditis may include fever, malaise, myalgias, arthralgias, chest pain, back pain, dyspnea, unintentional weight loss, night sweats, and neurologic symptoms. Clinical features of septic thrombophlebitis may include all of the above, and in addition, erythema and tenderness near the involved vessel. Septic pulmonary emboli may be present, often complicated by pneumonia. Clinical manifestations of mycotic aneurysms depend on the site of the aneurysm. If the aorta is involved, fever, back pain and abdominal pain are common. If the aneurysm is a complication of endocarditis, stroke or subarachnoid hemorrhage may be the presenting symptoms.

Key management points

Management: Empiric antibiotic therapy should be started against the likely organisms. Likely organisms in decreasing order of frequency are Staphylococcus aureus, Streptococcus viridans, Enterococcus, coagulase-negative staphylococci, Streptococcus bovis, gram-negative bacilli, HACEK organisms, and fungi.

2. Emergency Management

Emergency management for patients suspected of having an endovascular infection includes stabilizing the patient with fluid resuscitation and empiric antibiotic therapy. Multiple blood cultures should be obtained prior to starting empiric antibioitics, but there should be no delay in getting antibiotics started. Source control is of paramount importance in managing these infections, and every effort should be made to pinpoint the source using imaging techniques including transthoracic and transesophageal echography and angiography if indicated.

Surgery is indicated in patients with severe heart failure, uncontrolled infection, persistent bacteremia despite appropriate antibiotic therapy, fungal endocarditis, progressive heart block, periannular abscess extensions, and unstable prosthetic valves. Other relative indications for surgery include vegetations larger than 10mm and culture-negative prosthetic valve endocarditis with fever greater than 10 days. Timing of surgery depends on hemodynamic optimization, not duration of antibiotic therapy or sterilization of blood cultures. Prognosis for injection drug users depends on successful drug rehabilitation.

Management points not to be missed

1. Fluid resuscitation, blood cultures, antibiotics

2. Imaging studies

3. Source control/surgery

3. Diagnosis

Duke Clinical Criteria: 2 major or 1 major + 3 minor, or 5 minor

Major

a) typical organisms in two separate blood cultures (eg, S viridans, Sbovis, S aureus, HACEK, Enterococcus) without another primary source

b) persistent bacteremia greater than 12 hours

c) 3 out of 3 or 3 out of 4 positive blood cultures with the first and last culture being drawn more than 1 hour apart

d) oscillating intracardiac mass on valve or supporting structure, or in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation

e) abscess

f) new partial dehiscence of a prosthetic valve

g) new valvular regurgitation

Minor

a) predisposing cardiac condition or intravenous drug use

b) fever (>38.0C)

c) vascular phenomena including emboli, mycotic aneurysm, intracerebral bleed, conjunctival hemorrhage, Janeway lesions

d) immune phenomena including glomerulonephritis, Roth spots, Osler nodes, positive rheumatoid factor

e) positive blood cultures not meeting above diagnostic criteria

f) abnormal cardiac echogram, but not diagnostic

Diagnostic and confirmatory tests

The diagnoses of thrombophlebitis and mycotic aneurysms are made with imaging studies including ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI). Confirmation of the diagnosis is made by culturing an organism from the blood.

4. Specific Treatment

Empiric therapy for acute endocarditis should take into consideration the most likely pathogens (Methicillin-resistant staphylococcus aureus (MRSA), methicillin-sensistive staphylococcus aureus (MSSA)and streptococci and enterococci): vancomycin 15mg/kg intravenous (IV) q 12h is appropriate for most patients.

Empiric subacute endocarditis: ampicillin/sulbactam 3g IV q 6h + gentamicin or tobramycin 1mg/kg IV q 8h; or vancomycin 15mg/kg q 12h + ceftriaxone 2g IV q 12h or gentamicin/tobramycin 1mg/kg IV q8 h. Culture and sensitivity results will define further therapy.

Specific therapy for native valve endocarditis

Viridans streptococci and S bovis susceptible to penicillin: Aqueous penicillin G 12 to 18 million units per 24 h IV either continuously or in 4 or 6 equally divided doses; or ceftriaxone 2g per 24 h IV; or vancomycin 15mg/kg q 12h IV. Therapy should continue for 4 weeks. Selected uncomplicated patients with no evidence of extracardiac or intracardiac complications and no pre-existing otic or renal disease could be treated with a shorter course: Aq peniciilin or ceftiaxone as above + gentamicin 1mg/kg IV q 8h x 2 weeks.

Viridans streptococci and and S bovis resistant to penicillin: Aqueous penicillin 24 million units per 24h IV either continuously or in 4 or 6 equally divided doses or ceftriaxone 2g per 24h IV x 4 weeks, PLUS gentamicin 1mg/kg IV q 8h x 2 weeks; or vancomycin 15mg/kg q 12h IV x 4 weeks.

Enterococci strains susceptible to penicillin, gentamicin, and vancomycin: gentamicin 1mg/kg q 8h IV for 4 to 6 weeks plus one of the following: aqueous penicillin G 18 to 30 million units q 24h IV either continuously or in four or six equally divided doses for 4 to 6 weeks or ampicillin 12g q 24h IV in six equally divided doses for 4 to 6 weeks or vancomycin 15mg/kg q 12h IV for 6 weeks.

Enterococci strains resistant to penicillin and susceptible to aminoglycoside and vancomycin: Gentamicin 1mg/kg q 8h IV for 6 weeks plus either ampicillin-sulbactam 12g per 24h IV in four equally divided doses for 6 weeks or vancomycin 15mg/kg q 12h IV for 6 weeks.

Enterococci strains resistant to penicillin, aminoglycoside, and vancomycin: E. faecium: Linezolid 600mg q 12h IV or PO doses for 8 weeks or more or quinupristin-dalfopristin 22.5mg/kg per 24h IV in three equally divided doses for 8 weeks or more.

Staphylococci susceptible to oxacillin: Nafcillin or oxacillin 2g q 4h IV for 6 weeks, plus optional addition of gentamicin 1mg/kg q 8h IV or intramuscular (IM) for 3 to 5 days. Alternative: Cefazolin 2g q 6h IV for 6 weeks, plus optional addition of gentamicin 1mg/kg per 8 h IV or IM for 3 to 5 days.

For tricuspid valve endocarditis with vegetation less than 2 cm, no emboli besides lung, and negative blood cultures by day 4, could use nafcillin or oxacillin 2g q 4h IV plus gentamicin 1mg/kg q 8h IV or IM for 2 weeks.

Staphylococci resistant to oxacillin: vancomycin 15 mg/kg q 12 x 6 weeks; goal trough greater than 15 to 20mcg/mL.

Pseudomonas aeruginosa: tobramycin 2.5 mg/kg q 8h plus piperacillin 4g IV q4 or ceftazadime 2g IV q 8h for 4 to 6 weeks.

Candida: amphotericin B 0.8 to 1.0mg/kg/day IV plus flucytosine 100 to 150mg/kg/day divided q 6h plus surgery. Alternative: Fluconazole 400mg IV/day plus surgery.

HACEK: ceftriaxone 2g q 24h IV x 4 weeks or ampicillin-sulbactam 3g IV q 6h x 4 weeks or ciprofloxacin 400mg IV q 12h or 500mg PO q 12h X 4 to 6 weeks.

Culture-negative: ampicillin-sulbactam 3g IV q 6h x 4 to 6 weeks plus gentamicin 1mg/kg q 8h IV or IM or vancomycin 15mg/kg q 12h plus gentamicin 1mg/kg IV q 8h plus ciprofloxacin 750mg PO q 12h or 400mg IV q 12h x 4 to 6 weeks.

Specific therapy for prosthetic valve endocarditis (PVE)

Penicillin-susceptible streptococci species: AQ penicillin G 24 million units IV q 24 by continuous infusion or q 4 to 6 hours in divided doses; or cefttriaxone 2g IV q 24 +/- gentamicin 3mg/kg q 24h. Alternatively vancomycin 15mg/kg q 12. Therapy should continue for 6 weeks.

Penicillin-resistant streptococci: AQ penicillin or ceftriaxone as above +gentamicin 3mg/kg IV q 24h. Therapy should continue for 6 weeks.

S aureus (MSSA): naficillin or oxacillin 2g IV q 4h x 6 weeks plus rifampin 300mg IV or PO q 8h x 6 weeks plus gentamicin 1mg/kg IV q 8h x 2 weeks.

S aureus (MRSA): vancomycin 15mg/kg q 12 h x at least 6 weeks plus rifampin 300mg IV or PO q 8h x 6 weeks plus gentamicin 1mg/kg IV q 8h x 2 weeks.

Enterococci strains susceptible to penicillin, gentamicin, and vancomycin: gentamicin 1mg/kg q 8h IV for 4 to 6 weeks plus one of the following: aqueous penicillin G 18 to 30 million units q 24h IV either continuously or in 4 or 6 equally divided doses for 4 to 6 weeks or ampicillin 12g q 24h IV in 6 equally divided doses for 4 to 6 weeks or vancomycin 15mg/kg q 12h IV for 6 weeks; alternative: vancomycin 15mg/kg IV q 12h.

Enterococci strains resistant to penicillin and susceptible to aminoglycoside and vancomycin: Gentamicin 1mg/kg q 8h IV for 6 weeks plus either ampicillin-sulbactam 12g q 24h IV in four equally divided doses for 6 weeks or vancomycin 15mg/kg q 12h IV for 6 weeks.

Enterococci strains resistant to penicillin, aminoglycoside, and vancomycin:
E faecium: Linezolid 600mg q12h IV or PO doses for 8 weeks or more, or quinupristin-dalfopristin: 22.5mg/kg per 24h IV in 3 equally divided doses for 8 weeks or more; or daptomycin 6 to 10mg/kg/day IV for more than 8 weeks.

HACEK: ceftriaxone 2g q 24h IV x more than 6 weeks or ampicillin-sulbactam 3g IV q 6h for more than 6 weeks or ciprofloxacin 400mg IV q 12h or 750mg PO or 400mg IV q 12h x 6 weeks. Use quinolones only if patient is intolerant to ceftriaxone or ampicillin-sulbactam.

Culture-negative (<1y): vancomycin 15mg/kg q 12h x 6 weeks, plus gentamicin 1mg/kg IV q 8h x 2 weeks, plus cefipime 2g IV q 8h x 6 weeks plus rifampin 300mg IV or PO q 8h x 6 weeks.

Culture-negative (>1y): ceftriaxone 2g IV q 24h plus gentamicin 1mg/kg IV q 8h plus doxycycline 100mg IV/PO q 12h.

Anticoagulation is controversial but indicated for patients with mechanical valves. Bioprosthetic valves do not require anticoagulation.

Surgery

Indications: moderate to severe heart failure, unstable prosthesis, uncontrolled infection, persistent bacteremia despite antibiotics, endocarditis with certain organisms (fungi, S aureus, Pseudomonas), periannular extension, relapse. Relative indications include vegetations greater than 10cm, culture-negative PVE with unexplained fever greater than 10 days.

Special consideration for tricuspid valve

May consider valvectomy or vegetectomy; aortic or mitral valve requires replacement. Some surgeons are unwilling to operate on drug addicts unless there is assurance for drug rehabilitation. Prognosis for valve replacement without drug rehabilitation is quite poor.

Timing of surgery depends on optimizing hemodynamic parameters, not sterilization of blood cultures or duration of antibiotic therapy. Low risk of infecting new valve. In the setting of neurologic complication, hemorrhagic transformation is decreased by delaying surgery if hemodynamics permit.

Specific therapy for mycotic aneurysms

Four to six weeks of parenteral antimicrobial therapy directed at the cultured or likely organism is recommended for the treatment of a mycotic aneurysm. A longer duration of treatment should be considered if biochemical parameters of inflammation (C-reactive protein [CRP] ,erythrocyte sedimentation rate [ESR] and white cell count) do not return to normal. The initial choice of therapy depends upon the most probable infecting organisms for the involved site. Subsequent decisions should be made after the organism(s) have been cultured and sensitivity testing performed. Some authors recommend that life-long oral suppressive antibiotics follow the intravenous course for organisms that are difficult to treat.

Surgery for mycotic aneurysms depends on the anatomic site and the availability of a homograft. In some cases the best surgical approach can only be determined at the time of surgical exploration.

5. Disease monitoring, follow-up and disposition Instruction

If surgery is undertaken, the length of administration of antibiotics after surgery is determined by operative findings. With evidence of ongoing infection, treat with the standard course of therapy postoperatively. If infection has been well controlled, the length of preoperative and postoperative courses can be added for a sum total of 6 to 8 weeks.

Patients should be followed up with imaging and laboratory tests including WBC, ESR, CRP, and blood cultures until they are negative.

Complications include aminoglycoside-induced ototoxicity or nephrotoxicity, secondary bacteremia due to central vascular lines, mediastinitis or early postoperative prosthetic valve endocarditis, intravenous catheter-associated phlebitis, drug fever, allergic or idiosyncratic reactions to various antimicrobial agents. and bleeding due to disturbances in coagulation caused by anticoagulants (in prosthetic valve endocarditis).

Pathophysiology

A variety of microorganisms can cause infective endocarditis (IE), but staphylococci and streptococci account for the majority of cases. The International Collaboration on Endocarditis-Prospective Cohort Study identified the microbiologic etiology in 2781 patients from 58 sites in 25 countries with definite endocarditis as defined by Duke criteria. Most patients had native valve IE (72%) and 23% were healthcare associated.

Overall, staphylococci were the etiologic agents in744 of 1779 (42%) and streptococci in 712 (40%). The pathogens included:S aureus— 31%Viridans group streptococci — 17%Enterococci — 11%Coagulase-negative staphylococci — 11%S bovis — 7%Other streptococci — 5%Non-HACEK gram-negative bacteria — 2%Fungi — 2%HACEK— 2%. Organisms in this category include a number of fastidious gram-negative bacilli: Haemophilus aphrophilus; Actinobacillusactinomycetemcomitans; Cardiobacterium hominis;Eikenella corrodens; and Kingella kingae.

The remaining cases included culture-negative endocarditis (8%), polymicrobial (1%), and a variety of other organisms (3%).

The higher incidence of S aureuscompared with viridans group streptococci is probably because this study was conducted in large, tertiary care centers and may not reflect the epidemiology of IE in more rural communities.

Epidemiology

Sex and age have an impact on the incidence of endovascular infections (EI). Men predominate in most case series, with male-to-female ratios ranging from 3:2 to 9:1. New trends in the epidemiology of endocarditis have occurred during the past 30 years. Most of these changes relate to the numbers and types of susceptible hosts, rather than to shifts in the virulence of the infecting microorganisms.

Endocarditis has increasingly become a disease of the elderly. More than one half of all cases in the United States and Europe occur in patients over the age of 60, and the median age of patients has increased steadily during the past 40 years. This trend is probably due to two factors: the decline in the incidence and importance of rheumatic heart disease as a risk factor and the increasing proportion of elderly subjects in the general population who are more likely both to develop degenerative valve disease and to require valve replacement, which is associated with an increased risk.

Characteristics of patients with S aureus EI vary by region. In the International Collaboration on Endocarditis-Prospective Cohort Study, patients in the United States were significantly more likely to be hemodialysis dependent, to have diabetes, to have a presumed intravascular device source, to receive vancomycin, to be infected with methicillin-resistant S aureus(MRSA), and to have persistent bacteremia.

Prognosis

Many studies have evaluated the mortality rates of EI, specifically endocarditis. The in-hospital mortality rate is between 18 and 23 percent, while the 6-month mortality is between 22% and 27%. Many studies have attempted to identify predictors of death, however, since most patients will have several of the following co-morbid conditions, quantifying this is difficult. Mortality is higher in patients with S aureus, heart failure, embolic events, perivalvular abscess, large vegetation size, female gender, contraindication to surgery, low serum albumin, persistent bacteremia.

What's the evidence?

Baddour, LM, Wilson, WR, Bayer, AS. “Infective endocarditis: 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: endorsed by the Infectious Diseases Society of America”. Circulation. vol. 111. 2005. pp. e394-434. (The third edition of an infective endocarditis "treatment" document developed by the American Heart Association under the auspices of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease of the Young. It updates recommendations for diagnosis, treatment, and management of complications of infective endocarditis. Tables have been included that provide input on the use of echocardiography during diagnosis and treatment.)

“ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons”. J Am Coll Cardiol. vol. 48. 2006. pp. e1-148. (Guidelines for management of patients with valvular heart disease, including patients with prosthetic valves.)

Wilson, WR, Karchmer, AW, Dajani, AS, Taubert, KA. “Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci,and HACEK microorganisms. American Heart Association”. JAMA. vol. 274. 1995. pp. 1706-13. (Guidelines for the treatment of endocarditis in adults caused by the following microorganisms: viridans streptococci and other streptococci, enterococci, staphylococci, and fastidious gram-negative bacilli of the HACEK group. Published studies of the treatment of patients with endocarditis and the collective clinical experience of this group of experts. As a useful aid to the practicing clinician, the writing group developed a consensus opinion regarding management of endocarditis caused by the most commonly encountered microorganisms and regarding those cases due to infrequent causes of endocarditis.)

Chambers, HF, Korzenlowski, OM, Sande, MA. “Staphylococcus aureus endocarditis: clinical manifestations in addicts and nonaddicts”. Medicine (Baltimore). vol. 62. 1983. pp. 170-7. (Major differences include 1) better prognosis in the addict population; 2) high rate of tricuspid valve involvement; 3) high frequency of pulmonary complications in the addict population.)

Cosgrove, SE, Vigliani, GA, Fowler, VG. “Initial low-dose gentamicin for
bacteremia and endocarditis is nephrotoxic”. Clin Infect Dis. vol. 48. 2009. pp. 713-21. (This is a prospective cohort study of safety data from a randomized, controlled trial of therapy for S aureus bacteremia and native valve infective endocarditis involving 236 patients from 44 hospitals in 4 countries. Patients either received standard therapy (antistaphylococcal penicillin or vancomycin) plus initial low-dose gentamicin (n=116) or received daptomycin monotherapy (n = 120). They measured renal adverse events and clinically significant decreased creatinine clearance in patients (1) in the original randomized study arms and (2) who received any initial low-dose gentamicin, either as a study medication or before enrollment.

Howden, BP, Ward, PB, Charles, PG. “Treatment outcomes for serious infections caused by methicillin-resistant with reduced vancomycin susceptibility”. Clin Infect Dis. vol. 38. 2004. pp. 521-8. (Although infections caused by methicillin-resistant S aureuswith reduced vancomycin susceptibility (SA-RVS) have been reported from a number of countries, including Australia, the optimal therapy is unknown. The authors reviewed the clinical features, therapy, and outcomes of 25 patients with serious infections due to SA-RVS in Australia and New Zealand. Antibiotic therapy, especially linezolid with or without rifampicin and fusidic acid, in conjunction with surgical debulking is effective therapy for the majority of patients with serious infections (including endocarditis) caused by SA-RVS.)

Sakoulas, G, Eliopoulos, GM, Alder, J, Eliopoulos, CT. “Efficacy of daptomycin in experimental endocarditis due to methicillin-resistant “. Antimicrob Agents Chemother. vol. 47. 2003. pp. 1714-8. (In this study, the authors compared the efficacy of daptomycin with that of vancomycin, each with or without rifampin, in a model of experimental aortic valve endocarditis due to MRSA. The infecting strain (MRSA strain 32) was susceptible to daptomycin, vancomycin, and rifampin. Comination therapy, vegetation bacterial counts were as follows: daptomycin at 40 mg/kg, 4.6 +/- 1.6; rifampin, 3.6 +/- 1.3; vancomycin plus rifampin, 3.3 +/- 1.1; daptomycin plus rifampin, 2.9 +/- 0.8. The difference between daptomycin and daptomycin plus rifampin was statistically significant (P= .006). These results support the continued evaluation of daptomycin for serious MRSA infections, including infective endocarditis.)

Tleyjeh, IM, Abdel-Latif, A, Rahbi, H. “A systematic review of population-based studies of infective endocarditis”. Chest. vol. 132. 2007. pp. 1025-35. (Fifteen population-based investigations with 2371 IE cases from seven countriesThe decline in IE cases with underlying RHD became nonsignificant, but the proportion of IE patients undergoing valve surgery increased 7% per decade , and those with underlying prosthetic valve increased 7% per decade. There were no significant temporal trends in the causative organisms. Available studies suggest a changing distribution of underlying valvular heart disease in patients with IE and an increase in its surgical treatment.)

Hill, EE, Herijgers, P, Claus, P. “Infective endocarditis: changing epidemiology and predictors of 6-month mortality: a prospective cohort study.”. Eur Heart J. vol. 28. 2007. pp. 196-203. (Compared with older series, we observed more prosthetic valve IE nosocomial IE, and surgery. S aureus and E faecaliswere predominant microorganisms. Age, staphylococci, and a contraindication to surgery predicted 6-month mortality. Nearly half of deaths had a contraindication to surgery. Six-month mortality did not differ significantly between patients who received surgical treatment and those who received medical treatment without a contraindication to surgery.)

Wang, A, Athan, E, Pappas, PA. “International Collaboration on Endocarditis-Prospective Cohort Study Investigators. Contemporary clinical profile and outcome of prosthetic valve endocarditis”. JAMA. vol. 297. 2007. pp. 1354-61. (Prospective, observational cohort study conducted at 61 medical centers in 28 countries, including 556 patients with definite PVE. Prosthetic valve endocarditis accounts for a high percentage of all cases of infective endocarditis in many regions o fthe world. S aureusis now the leading cause of PVE. Healthcare-associated infection significantly influences the clinical characteristics and outcome of PVE. Complications of PVE strongly predict in-hospital mortality, which remains high despite prompt diagnosis and the frequent use of surgical intervention.)

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