• Summary
  Click here to print a Quick Reference Guide
• Background
• Clinical Diagnosis
• Investigation
• Treatment
• Non-Antimicrobial Treatment
• Empirical Antimicrobial Treatment
• Directed Antimicrobial Treatment (when microbiology results are known)
• Duration of Treatment
• Switch to oral agent(s)
• Treatment Failure

This guideline applies to patients with suspected or confirmed prosthetic valve endocarditis (PVE)

PVE should be considered in patients with a prosthetic heart valve and

1. fever, sweats, general malaise, weight loss, anorexia, leukocytosis or raised C-reactive protein
2. a febrile illness (temperature >38^oC) and a new regurgitant murmur, or
3. any of the above and a new embolic event (e.g. cerebral or limb ischaemia).
4. persistently positive blood cultures

NB not every patient with PVE has a murmur or a fever.

Initial investigations

3 sets of blood cultures taken at different times during the first 24 hours.
If patient has severe sepsis or septic shock, 2 sets of blood cultures at different times in the first hour, before starting empirical therapy.
Transoesophageal echocardiography (discuss with on call cardiology team).
Full blood count, C-reactive protein, Urea and electrolytes, liver function tests, urinalysis, ECG.

Treatment

Ideally antimicrobial therapy should be withheld pending blood culture results. If the patient has severe sepsis, septic shock or urgent empirical treatment is considered necessary:
Urgent empirical therapy: intravenous Vancomycin * see dosing guidelines plus Gentamicin* 1mg/kg 12 hourly plus oral Rifampicin* 600mg 12-hourly.

*dose adjustments may be necessary in patients with renal impairment. Dose frequency may need adjusting for Gentamicin according to levels. Low-dose Gentamicin is for synergistic activity: pre-dose levels should be maintained <1mg/l and 1 hour post-dose levels 3-5mg/l.

If there are concerns about renal function: Vancomycin can be replaced with Daptomycin or Teicoplanin  and Gentamicin can be replaced with Ciprofloxacin 

See full guideline for detail and treatment of specific organisms.

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Prosthetic heart valves are commonly implanted to replace native valves that have become severely dysfunctional as a result of numerous pathological processes including congenital abnormalities, rheumatic fever, mitral valve prolapsed and valve sclerosis. Other “anatomical” intra-cardiac medical devices, used to correct structural abnormalities, include prosthetic patches, annuloplasty rings, shunts and closure devices. The term “prosthetic valve endocarditis” (PVE) will be used in this guideline to include all these anatomical devices as well as replacement valves.

As with all indwelling medical devices there is a risk of infection at the time of insertion and an ongoing risk of infection while the device remains in situ. The reported rates of prosthetic valve endocarditis range from 0.1-2.3% per patient year.

Infection of a prosthetic valve is uncommon but very serious when it occurs, with life threatening consequences. The presence of man-made material in the heart provides a nidus for microbial pathogens to adhere to and establish a focus of infection. The establishment of infection on such materials takes the form of a “biofilm” comprising microbes, host-derived products and microbial extra-cellular polymers. The biofilm mode of growth provides an environment that is relatively protected from normal defense mechanisms. Thus, eradication of these infections is more difficult to achieve.

Infection of prosthetic heart valves and other anatomical devices share clinical, microbiological and treatment characteristics that enable some broad principles to be applied as a whole. This guideline concerns prosthetic valve infection and infection of anatomical devices.

Pacing systems and implanted defibrillators differ from the devices above in anatomical site, microbiology and method of insertion and removal. Infection of pacing systems, intra-cardiac defibrillators other “removable” devices are not covered in this guideline.

Prosthetic valve endocarditis (PVE) is usually caused by bacteria but occasionally involves fungi. Infections can be divided into “early prosthetic valve endocarditis” (EPVE) or “late prosthetic valve endocarditis” (LPVE) depending on the time period between valve insertion and presentation with infection. EPVE is usually defined as infection occurring up to one-year after surgery and LPVE one year and beyond. The incidence of LPVE is lower for mechanical than for bioprosthetic heart valves.¹ The risk of early PVE is highest in those undergoing replacement surgery for active infective endocarditis and may be up to 5%.

The most common pathogens causing EPVE are Staphylococcus aureus, coagulase negative staphylococci and enterococci and the inference is that the infection is acquired at the time of surgery or soon after. LPVE tends to be caused by staphylococci, enterococci and streptococci and is referred to by some as community acquired infection. A multitude of other pathogens infect cardiac prostheses, some of the most important being: corynebacteria, propionibacteria, Pseudomonas species, “coliforms” (e.g. Escherichia coli) and Candida species. Rarely, difficult to culture bacteria such as Mycobacterium spp. and Legionella spp. are involved. The value of separating PVE into early and late types is that there are implications regarding the likely infecting organism and therefore the choice of initial antimicrobial therapy. National guidelines covering the treatment and investigation of common causes of PVE have been published.²

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In the past, endocarditis has been a difficult condition to diagnose because of its protean clinical manifestations and frequent lack of localizing symptoms or signs. Diagnosis has been improved by echocardiography and more sensitive microbiological methods but diagnostic difficulties persist. The Duke criteria (and recent modifications) are diagnostic criteria that are increasingly used in clinical practice.^3,4

Details on the categorisation of patients using this diagnostic schema are given in the accompanying guideline on native valve endocarditis (NVE). The Duke criteria do not usually allow an immediate diagnosis to be confirmed or rejected but they remain the most widely used and accepted objective framework used as an aid to diagnosing this difficult and challenging condition.² There are no clinical findings that are specific for a particular pathogen and the cornerstones of diagnosis are the demonstration of a persistent bacteraemia (or fungaemia) using blood cultures and evidence of vegetations on echocardiography.

The methods used and the approach to diagnosis in cases of PVE is essentially identical to that used in native valve endocarditis (NVE) but with extra emphasis on the need for transoesophageal echocardiography (TOE) to be used early in all cases of suspected PVE unless there is a clear contra-indication to this procedure.

PVE can be caused by low-grade pathogens (including coagulase negative staphylococci) and may present with a very mild clinical illness, often with few classical signs of infection. Diagnosis is dependent on a low index of suspicion and appropriate investigation.
There are a multitude of different clinical presentations of PVE but it should be considered in patients with a fever, sweats, general malaise, leukocytosis or raised C-reactive protein and a prosthetic heart valve or intra-cardiac device. A fever (>38^oC) is usually present, being detected in 94% of episodes in one series.⁵ The diagnosis should be considered in patients:

1. with a febrile illness (temperature >38^oC) and a new regurgitant murmur relating to a prosthetic valve(s) or at risk lesion e.g. VSD patch repair, or
2. a protracted history of sweats, weight loss, anorexia or malaise and an at-risk cardiac lesion which includes intra-cardiac devices, or,
3. any of the above and a new embolic event (e.g. cerebral or limb ischaemia).

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Recommendations:

Three sets of blood cultures should be taken at different times during the first 24 hours in all patients with suspected PVE, unless severe sepsis is present. Evidence level B

If the patient has severe sepsis or septic shock, two sets of blood cultures should be taken at different times in the first hour, during initial resuscitation before starting empirical therapy. Evidence level D

If initial blood cultures are negative, a set of three further blood cultures should be taken after one week without antimicrobial therapy, or sooner, if there is recurrence of fever and this is considered clinically appropriate. Evidence level D

If blood cultures are negative a Legionella urinary antigen test and a mycobacterial blood culture should be sent to Microbiology. Evidence level C

In patients who require valve surgery, valve tissue should be sent for microscopy, culture and broad range PCR as appropriate. Evidence level B.

TOE should be undertaken as soon as possible in cases of suspected PVE, unless contraindicated. Evidence level A

An initial negative TOE should be repeated after 7-10 days if the initial scan is negative or equivocal. Evidence level B.

If a patient with PVE, who had been progressing satisfactorily, suddenly deteriorates TOE should be repeated as a matter of urgency. Evidence level B.

FBC should be measured at baseline and repeated weekly during therapy. Evidence level D

CRP should be measured at baseline and repeated weekly during therapy. Evidence level D

U&E and LFT’s should be measured at baseline and weekly during therapy (or more frequently if renal function is unstable). Evidence level D

Evidence review/justification
blood cultures are a fundamental component of the diagnosis of endocarditis and are positive in 95% of cases.² In order to demonstrate a sustained bacteraemia and because bacteria that are known to be common blood culture contaminants can also cause endocarditis (e.g. coagulase negative staphylococci and propionibacteria) multiple blood culture sets are required. Three sets of blood cultures will give a microbiological diagnosis 95% of the time.²

blood culture request forms must specify that PVE is suspected to allow prolonged incubation if required.

The peripheral white blood cell count may be normal or elevated in patients with PVE and is therefore not particularly useful in confirming a clinical diagnosis. A full blood count (FBC) is indicated however to determine if the patient is anaemic and to establish a baseline peripheral white blood cell count since several of the antimicrobials used in treatment can cause leukopaenia.

C-reactive protein (CRP) is a sensitive test, being raised in >95% of patients with endocarditis,⁶ but it is non-specific. A raised CRP provides supportive evidence of infection, rather than confirming the diagnosis, and can be used to monitor response to treatment.^6,7 It is superior to the Erythrocyte Sedimentation Rate (ESR) which is slower to change than the CRP.

Urea and electrolytes (U&E), liver function tests (LFT’s) are necessary baseline tests. Results will influence choice and dose of antimicrobials as well as enabling monitoring fluid balance, nutritional status etc.

When antimicrobials have been given prior to admission, blood cultures should be taken as recommended above. If the patient is clinically stable without signs of severe sepsis or septic shock and is not in heart failure antimicrobials can be withheld pending blood culture results. If routine blood cultures are negative, but clinical suspicion of PVE remains high, consider Legionella or mycobacterial infection.

Echocardiography is another fundamental component of the diagnosis of endocarditis. It serves to confirm the presence of an “at-risk” heart valve lesion or other structural abnormality. The demonstration of the pathological lesion of endocarditis, a vegetation, is central to the diagnosis. A vegetation is defined as an oscillating intra-cardiac mass attached to a valve leaflet or mural endocardium. Echocardiography also allows evaluation of cardiac function which will be crucial in the assessment of the patient’s ability to undergo cardiac surgery. Transthoracic echocardiography (TTE) is suboptimal in the evaluation of PVE because of its limited ability to allow a full examination of prosthetic materials, especially metallic valves, which generate large echo reflections which greatly limit visualization of these structures and their immediate surrounding components. This obscuration of the intracardiac structures is overcome by transoesophageal echocardiography (TOE). American and European guidelines mandate that TOE be undertaken as soon as possible in cases of suspected PVE.

Infections of metallic prostheses is usually associated with the sewing cuff or thrombi related to the sewing ring. Accordingly, periprosthetic leaks, ring abscesses, fistulae and direct myocardial invasion by the infected material are typical findings and are most reliably detected by TOE. In contrast, the pathogenesis of infections of bioprostheses is similar to that of native valves with the infection occurring in relation to the valve cusps (which may develop perforations and other signs of destruction) with a lower tendency to invade the sewing cuff or to cause periprosthetic/paravalvuar leaks.

An important addition to the foregoing is the need to consider repeating the TOE 7-10 days after the first negative or inconclusive study but the clinical suspicion of IE remains high. Non-specific perivalvuar thickening may be the forerunner of cavitation, perivalvualr abscesses, dehiscence or significant valvular regurgitation.

Additionally, if a patient who had been progressing satisfactorily suddenly deteriorates then urgent reassessment with TTE or TOE is appropriate. The question of repeating a TOE in this setting should be discussed with the Echo Dept. and/or a member of the Endocarditis Service.

If surgery is required, microbiological examination of heart valve tissue/explanted device provides an opportunity to confirm or identify the pathogen causing the infection. If tissue is culture-negative it should be processed by “broad range” (16S ribosomal RBA gene) PCR which may enable identification of the causative organism.²

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With an appropriate choice and duration of antimicrobial therapy a significant proportion of cases can be cured. If a cure can be achieved with antimicrobial therapy this avoids the risks associated with open cardiac surgery for a re-do valve replacement. The risks of attempted medical therapy (see below) need to be balanced against the risks of device removal on a case-by-case basis.
Clinical findings that indicate failure of medical therapy in a patient who has had at least 10 days of appropriate antimicrobials include:

1. failure of a raised temperature to settle
2. failure of the inflammatory markers to fall
3. failure of the patient’s symptoms to improve

A continuing picture of severe sepsis warrants review at an earlier stage.
In any of these situations referral for consideration of cardiac surgery is necessary.

Indications for Surgery in PVE
The timing of surgical intervention must be determined on an individual basis. Any patient with a confirmed diagnosis of PVE should be discussed with the Consultant Cardiothoracic Surgeon on-call that day. That person then becomes the assigned surgeon and any consideration of surgical treatment must be discussed with him/her. Surgery is more common in early PVE because of the associated valve dehiscence. The indications for surgical intervention are similar to those for NVE and include:

1. evidence of uncontrolled infection (see above)
2. worsening heart failure
3. recurrent embolisation i.e. 1 or more events either prior to or during antimicrobial therapy. This is most likely to occur in the first 2 weeks of the illness and the risk is increased by vegetation size (>10mm) and the presence of hypermobile vegetation(s), particularly if located on the anterior mitral valve leaflet
4. cerebral embolus provided that there is no intracerebral haemorrhage and that the interval between the event and surgery is less than 72h so that the blood-brain barrier can be expected to remain intact
5. periprosthetic dehiscence, perforation, fistula formation or large perivalvular ascess with or without heart failure
6. fungal infection
   

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Recommendation
Antimicrobials should not be started until after blood cultures have been taken (see blood culture section above).
Evidence level B

Recommended therapy: intravenous Vancomycin * see dosing guidelines plus Gentamicin* 1mg/kg 12 hourly plus oral Rifampicin * 600mg 12-hourly.2

*dose adjustments may be necessary in patients with renal impairment. Dose frequency may need adjusting for Gentamicin according to levels. Low-dose Gentamicin is for synergistic activity: pre-dose levels should be maintained <1mg/l and 1 hour post-dose levels 3-5mg/l.

In patients with acute kidney injury Teicoplanin  (Initially 10mg /kg dosing) or Daptomycin (8mg/kg, interval adjusted according to renal function) can be used in place of Vancomycin . Ciprofloxacin  can be used in place of Gentamicin.²

Justification
A microbiological diagnosis enables administration of directed antimicrobial therapy, avoiding the need for broad-spectrum, potentially toxic therapeutic combinations or erroneous empirical therapy. Outcomes are better if the pathogen is known. In patients who have been administered antimicrobials before blood cultures have been taken, the chance of obtaining a microbiological diagnosis is reduced, highlighting the need to withhold treatment until appropriate investigations have been carried out.²

Therapy will be altered depending on the need for prosthetic valve removal. In the absence of clear indications for surgery (see above), a trial of six weeks antimicrobial therapy should be given.

A wide range of pathogens with varying antimicrobial susceptibilities can cause prosthetic valve endocarditis or pacing lead infection. Empirical therapy may be needed in two clinical situations:

1. A patient with severe sepsis or septic shock in whom it would be inappropriate to wait for blood culture results before starting antimicrobial therapy.
2. A patient with clinical and echocardiographic findings suggestive of endocarditis but negative blood cultures.
   

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Staphylococcal PVE
For methicillin-susceptible staphylococci a combination of intravenous Flucloxacillin 2g 6-hourly$ in combination with oral Rifampicin * 600mg 12-hourly and intravenous Gentamicin* 1mg/kg 12 hourly is recommended. Gentamicin should ideally be given for at least 2 weeks.

$ use 4-hourly Flucloxacillin regimen if patient >85kg.
For methicillin-resistant staphylococci a combination of intravenous Vancomycin * see dosing guidelines in combination with oral Rifampicin * 600mg 12-hourly and intravenous Gentamicin* 1mg/kg 12 hourly is recommended. Gentamicin should ideally be given for at least 2 weeks.

For patients intolerant of Vancomycin (or risk of nephrotoxicity) or with vancomycin-resistant staphylococci, Daptomycin (see LTHT daptomycin guideline) can be used instead of Vancomycin at a dose of 8mg/Kg every 24 hours.

Daptomycin requires creatinine kinase (CK) levels at baseline and then weekly throughout treatment (or every three days if patient is at a high risk of developing myopathy). Daptomycin is eliminated primarily by the kidneys, therefore baseline creatinine clearance and regular monitoring of renal function is advised.

Use regimen for meticillin-resistant staphylococci in patients with a genuine penicillin allergy and consider desensitization.

*Doses may need adjustment in patients with renal impairment. Dose frequency for Gentamicin may need adjusting according to levels. Low-dose Gentamicin is for synergistic activity: pre-dose levels should be maintained <1mg/l and 1 hour post-dose levels 3-5mg/l.

Enterococcal PVE
For Amoxicillin-susceptible enterococci intravenous Amoxicillin 2g 4-hourly plus intravenous Gentamicin* 1mg/kg 12-hourly is recommended. Gentamicin should be continued so long as there are no signs of toxicity and the isolate is susceptible.

For Amoxicillin-resistant enterococci a combination of intravenous Vancomycin see dosing guidelines with intravenous Gentamicin* 1mg/kg 12 hourly (for the duration of therapy) is recommended.

*Low-dose Gentamicin is for synergistic activity: pre-dose levels should be maintained <1mg/l and 1 hour post-dose levels 3-5mg/l.

NB. Synergy may be lost in isolates with high-level resistance to Gentamicin.

In a genuinely-penicillin-allergic patient, use the regimen for Amoxicillin-resistant enterococci.

Other regimens may be required where isolates are resistant to these regimens or toxicity /poor clinical response to therapy occurs.

Streptococcal endocarditis
For penicillin-susceptible streptococci (MIC≤0.125 mg/L) intravenous Benzyl penicillin  1.2g 4 hourly.

For streptococci with reduced susceptibility to penicillin (MIC >0.125-≤0.5mg/L) a combination of intravenous Benzyl penicillin  2.4g 4-hourly with Gentamicin* 1mg/kg 12 hourly for the first 2 weeks of therapy is recommended.

For penicillin-resistant streptococci (>MIC 0.5mg/L) see enterococcal regimens.

For penicillin-allergic patients a combination of intravenous Vancomycin see dosing guidelines with intravenous Gentamicin* 1mg/kg 12 hourly is recommended.

Enterobacteriaceae.
Treat case-by-case based on susceptibility.

Pseudomonas aeruginosa
Treat case-by-case based on susceptibility.
Fungi
Treat case-by-case based on susceptibility.
Antimicrobial allergy
contact Microbiology for advice if not stated above.

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The presence of a brain abscess, intracardiac abscesses or vertebral osteomyelitis usually requires treatment with six weeks antimicrobials.

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