Infective endocarditis

This is a study note for educational purpose only. If you are here for medical advice please consult your doctor.

Introduction and risk factors

Infective endocarditis (IE) refers to infection of the endocardial surface of the heart. Heart valves are the most common site of endocarditis. However, the endocardium around the septal defect and mural endocardium (endocardium involving the walls of the chambers of the heart) can be affected.

Inflammation of the pericardium is called pericarditis and that of the myocardium is called myocarditis.  Infection is one of the common causes of this inflammation. 

Risk factors for endocarditis

There are two types. Some risk factors are directly related to heart – ‘cardiac factors’, while others are more general – ‘extra-cardiac factors’. Please see the information box below for a list of such factors.

Cardiac factors Extracardiac factors
1.       Past history of endocarditis

2.       Prosthetic valve

3.       Damaged heart valve/valve disease1

4.       Congenital heart disease2

1.       Intravenous drug abuse

2.       Indwelling intravenous line

3.       Immunosuppression

4.       A recent dental procedure, poor dentition, dental infection

5.       Old age

6.       Acute inflammatory bowel disease

7.       Extensive contact with healthcare setup.

1 Damaged heart valve- e.g rheumatic heart disease, mitral valve disease including mitral valve prolapse.

 

2 Congenital heart disease-Patent ductus arteriosus (PDA), Tetralogy of Fallot (ToF), ventricular septal defect (VSD), Bicuspid aortic valve (esp. in old age), coarctation of the aorta, pulmonary stenosis, idiopathic hypertrophic subaortic stenosis (aortic valve). Atrial septal defect (ASD) is usually not associated – as it is a low-pressure area.

 

Endothelial lining of the heart is usually resistant to bacterial or fungal infection. If the endothelial tissue is damaged, platelet and fibrin adhere to the damaged surface in an attempt to repair it. Pathogenic organisms find it easier to colonise these damaged and irregular areas of the endocardium.  Pathogens also find it easier to adhere to surfaces which are not native to our body like the prosthetic valve.

 

The normal flow of blood is also a deterrent against the adherence of the pathogens to the heart surface. Hence any disease which results in an irregular and turbulent flow (e.g regurgitation) can help the pathogens to adhere to the damaged surface.

 

Our immune system protects ourselves against an invading pathogen.  Bacteria enter our body on a regular basis in a small amount during daily activities like brushing teeth. These transient bacteremias are easily dealt with by our immune system. However, when the immunity is compromised (like patients on immunosuppressive medicine e.g. chemotherapy) or the number of bacteria entering the blood is too high or too frequent for the immune system to cope, bacteria can cause disease.

Please note: in some cases a predisposing factor may not be present. Highly virulent bacteria like Staphylococcus aureus are capable of attaching themselves to the healthy tissue (and damaged/artificial tissue as well). They invade the local tissue resulting in inflammation of the endothelium. This damaged inflamed endothelium attracts more platelet and fibrin resulting in vegetation (endocarditis).

Epidemiology of endocarditis

Age: 

The mean age of endocarditis has increased in the antibiotic era.

In 1926 the median age was 30 years. A recent report involving 2700 patients in 25 countries showed the median age is 57.9 years (50% of cases are in over 50 years of age).

The reduction in the number of rheumatic heart disease due to improved diagnosis and treatment of group A Streptococcus and higher prevalence of valvular disease in older people is the likely cause.

Gender:

Infective endocarditis is more common in men (1.7:1).

Valve involvement:

Mitral valve is most commonly affected in endocarditis.
Mitral>Aortic>Mitral and aortic combined>Tricuspid valve>Pulmonary valve.
Mitral valve endocarditis is more common in women (2:1)
Aortic valve endocarditis is more common in men (4:1)

Right-sided endocarditis is more common in intravenous drug abusers.

 

Aetiology

The most common causes of native valve endocarditis in non-intravenous drug users are currently S. aureus (28%), coagulase-negative staphylococci (9%), Streptococci (35%) and Enterococci (11%); 9% are culture-negative (Murdoch 2009).

Viridans Streptococcus (common in our mouth flora) is traditionally the commonest cause of endocarditis. However, in recent time the incident of Staphylococcus endocarditis is increasing.

Coxiella burnetii is the commonest cause of culture-negative endocarditis. (Raoult 2000)

Staphylococcus is the commonest cause of prosthetic valve endocarditis.

Gram-negative bacteria are less common. HACEK* group of organisms are responsible for 3% of all endocarditis. Non-HACEK group like Pseudomonas, Acinetobacter, E coli are also rare.

Fungus (Candida albicans is the commonest) are responsible for 2-4% of cases of endocarditis.

* HACEK=
Haemophilus species,
Aggregatibacter actinomycetemcomitans, Aggregatibacter aphrophilus,
Cardiobacterium hominis,
Eikenella corrodens and
Kingella species

– slow growing gram-negative bacteria with demanding nutritional requirement.

Endocarditis presentation

Infective endocarditis is often classified as acute or subacute based on how the patient presents to the healthcare setup:
Acute endocarditis usually present with sign and symptoms developing over days to weeks and
subacute endocarditis over weeks to months.

Staphylococcus aureus endocarditis usually present as acute endocarditis while viridans Streptococcus endocarditis are subacute.

Endocarditis can present with various symptoms, many of them are non-specific. Hence it is a diagnostic challenge and high degree of suspicion is necessary.

Fever Fever is the commonest symptom (~90%).

Fever can be associated with a chill, weight loss and poor appetite, especially in subacute endocarditis.

 

Fever can be absent in older patient, immunocompromised and in those who have received an antibiotic.

Murmur Murmur is present in 85% of cases and new murmur in 48% of cases.
 Immunological or embolic phenomena
Roth’s spot Small retinal haemorrhage with a white centre.

It can also be seen in diabetes, leukaemia, hypertension, HIV retinopathy- hence it is not diagnostic of endocarditis.

Splinter haemorrhage Small blood clot under the fingernail.

It can be seen in Scleroderma, SLE, rheumatoid arthritis, psoriasis etc. Hence it is not diagnostic of endocarditis.

Janeway lesion Erythematous macular/nodular lesion on palm or sole (non-tender). These are caused by septic emboli.
Osler’s node Painful red raised lesion on hand and feet.

It can also be found in SLE, disseminated gonococcal infection etc. Hence it is not diagnostic of endocarditis.

Septic emboli to a distant organs Embolic phenomenon with fever -possibility of endocarditis should be considered.

Pic 1: Janeway lesion (Wikipedia)
Janeway lesionPic 2: Osler’s node (Wikipedia)

Osler's node

Pic 3: Splinter haemorrhage (Wikipedia)splinter haemorrhage

Endocarditis assessment (modified Duke’s criteria)

Patient with suspected endocarditis can be assessed using Duke’s criteria (modified).

Duke’s criteria are 70-80% sensitive for native valve endocarditis (lower for the prosthetic valve) and have a high negative predictive value.

The clinical judgement remains essential, especially in settings where the sensitivity of the modified Duke criteria is diminished, e.g. when blood cultures are negative, when too few blood culture sets have been taken, or when infection affects a prosthetic valve or the right side of the heart.

Modified Duke’s criteria 
Major diagnostic criteria
Blood culture a. Microorganism consistent with IE from 2 separate blood cultures:

– viridans Streptococci, Streptococcus gallolyticus (Streptococcus bovis), HACEK group, Staphylococcus aureus or community-acquired Enterococcus in the absence of a primary focus.

b. Microorganism consistent with IE from persistently positive blood cultures:

->/= 2 positive blood cultures of blood samples drawn >12 h apart or

-all of 3 or a majority of 4 or more separate cultures of blood (with first and last being drawn >/= 1 h apart)

 

Imaging a. Echocardiogram positive for IE:

– vegetation
– abscess, pseudoaneurysm, intracardiac fistula,
_ valvular perforation or an aneurysm,
-New partial dehiscence of the prosthetic valve

b. Abnormal activity around the site of prosthetic valve implantation detected by 18F-FDG PET/CT (only if the prosthesis was implanted for >3 months) or radiolabelled leukocytes SPECT/CT. *

c. Definitive paravalvular lesions by cardiac CT *

Coxiella a single positive blood culture for C. burnetii; or antiphase I IgG antibody titre 1:800
Minor diagnostic criteria**
Predisposition predisposing heart condition or intravenous drug use
Fever temperature 38.08C (100.48F)
Vascular phenomena (including those detected by imaging only*)
major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial haemorrhage, conjunctival haemorrhage, Janeway lesions.
Immunological phenomena glomerulonephritis, Osler’s nodes, Roth spots and rheumatoid factor
Microbiological phenomena positive blood culture but does not meet a major criterion as noted above  or serological evidence of active infection with organism consistent with IE
A Clinical criterion for definite infective endocarditis requires:

two major criteria; or

one major and three minor criteria; or

five minor criteria.

Possible infective endocarditis

1 major and 1 minor criterion, or

3 minor criteria.

Rejected:

Not fulfilling the above criteria.

Notes:

* These two criteria and provision for including imaging to diagnose embolic phenomenon were not included in original paper (proposing modified Duke’s criteria) by Li et al (2000), but was added to the 2015 European Society of Cardiology guideline for Endocarditis (see ref).

** Minor criteria for Echocardiogram (“Echocardiography finding consistent with IE but do not meet a major criterion as noted above”) has been omitted by the paper by Li (2000). It was a part of the original Duke’s criteria. BSAC (UK) guideline (2012) included this in the minor criteria. We did not include it here in favour of more recent ESC guideline.

BSAC guideline also includes provision for 16S PCR, which was not included in ESC guideline and we didn’t include it in this tutorial.

Investigation

Blood and other routine tests:

All cases of endocarditis must have

Full blood count- It is to establish a baseline and check for anaemia. It is non-specific and not diagnostic.
Urea and electrolytes and liver function test- baseline and monitoring,
C reactive protein- non-specific marker of infection/inflammation.
ECG- check for conduction disturbance.

Rheumatoid factor: positive in 30-50% cases, supporting evidence. It may develop later in the course of the disease, consider a repeat.
Urine- check for haematuria.

Microbiological test:

Blood culture:

This is the cornerstone of endocarditis investigation. In cases of endocarditis bacteraemia is continuous hence there is no need to take the blood culture during the fever. It is also not necessary to take the blood culture from different sites but meticulous aseptic technique must be used to reduce the risk of contamination.

It is also necessary to avoid taking culture through an IV line or groin sinus of an IVDU to avoid the risk of contamination.

Blood culture must be taken before giving antibiotics to the patient.

In patients with suspected IE and severe sepsis or septic shock at the time of presentation, two sets of optimally filled blood cultures should be taken at different times within 1 h prior to the commencement of empirical therapy, to avoid undue delay in commencing empirical antimicrobial therapy. (BSAC 2012).

In patients with a chronic or subacute presentation, three sets of optimally filled blood cultures should be taken from peripheral sites with ≥6 h between them prior to commencing antimicrobial therapy. (BSAC 2012)

These recommendations were made in the BSAC endocarditis guideline considering the practical implication of delaying therapy in a patient with infection although it doesn’t strictly adhere to the Duke’s criteria.

The bacteraemia is continuous in endocarditis hence it is expected that all the blood cultures should be positive. If only one set of many blood culture is positive it should be regarded with caution.

Other microbiology tests:

Serology:

Endocarditis due to Coxiella, Bartonella or Brucella is difficult or not possible to diagnose with blood culture. These organisms can be diagnosed with serology, however, they have limited availability and should be discussed with an infection specialist. Organisms like Chlamydia, Mycoplasma, are rare causes of endocarditis, which also need serology tests.

PCR:

Tissue from excised heart valve can be tested using broad range PCR technique.

Imaging technique:

Echocardiogram:
It is the most important imaging necessary in cases of endocarditis. two types of echocardiogram are commonly used transthoracic echocardiogram (TTE) and transoesophageal echocardiogram (TOE).
Sensitivity for the diagnosis of vegetations in native and prosthetic valves is 70% and 50%, respectively, for TTE and 96% and 92%, for TOE, respectively. Specificity has been reported to be around 90% for both TTE and TOE.

All cases of suspected endocarditis must have a transthoracic echocardiogram (ideally with 24 hours). (BSAC guideline 2012)
A TOE is recommended when –
1. clinically suspected endocarditis and non-diagnostic TTE
2. Suspected endocarditis with prosthetic valve/intracardiac device
3. even in cases of positive TTE to rule out local complication (expect in right-sided endocarditis with good quality TTE and unequivocal TTE findings)

If the initial TTE and TOE are non-conclusive and suspicion of endocarditis is high repeat TTE/TOE is recommended in 5-7 days. (ESC 2015)

During follow up echocardiogram is recommended if
1. New complication appears
2. If the patient is undergoing surgery (intraoperative echocardiogram)
3. On completion of therapy.

Echo might be considered during treatment as a follow up for uncomplicated endocarditis by the clinical team based on the clinical situation.

New and other investigations:

Histology of excised tissue: 

3D TOE – better estimation of vegetation size.

Multislice CT scan (MSCT) – Possibly equivalent and in some cases superior to TOE in diagnosing endocarditis and its complications.

MRI – to diagnose cerebral embolic complications.

Radiolabelled WBC SPECT/CT and 18F-FDG PET/CT: These scans may have a role as a supplementary test in suspected endocarditis without diagnostic confirmation from other conventional tests.

Treatment

(This is for educational purpose and for medical and infection trainees only. It is not medical advice. You must consult your doctor if you are looking for medical advice)

Treatment of endocarditis is complex and prolonged, mostly 4-6 weeks. It is very important to establish a microbiological diagnosis so that the best narrow spectrum antibiotic can be used specifically directed towards the pathogen.

Please consult latest BSAC/ESC guideline for update

It is very important to make every effort to obtain recommended number of blood culture before starting antibiotic unless patient present with sepsis, which makes early antibiotic prescription necessary (please see the blood culture in investigation section). If the patient is stable it may be possible to delay the antibiotic to obtain the blood culture. However, an infection specialist should be involved.

In some cases, antibiotic treatment is not adequate and valve surgery must be considered.

1. Empirical treatment.

2. Antibiotic choice for Staphylococcal endocarditis.

3. Antibiotic choice for Streptococcal endocarditis.

4. Antibiotic choice for Enterococcal endocarditis.

5. Antibiotic choice for other types of endocarditis.

6. Other modalities of treatment.

Empirical treatment(before blood culture is positive)

In some cases, it might become necessary to start treatment of endocarditis before the blood culture result is available. For example, if the patient is septic.

In these cases, it is important to thoroughly evaluate the patient to look for any other potential source of infection, the severity of infection, type of the valve affected and risk for an unusual or resistant organism. Always review the previous microbiology results to check for any resistant organisms like methicillin-resistant Staphylococcus aureus (MRSA), extended spectrum beta-lactamase producing organism (ESBL), carbapenemase producing organism (CPE), vancomycin-resistant Enterococcus (VRE) etc.

It is important to discuss with the microbiologist/infection specialists as they are aware of the resistance pattern of the local flora and are able to help with the decision making process.

These empirical treatments are directed towards most common causes of endocarditis.

In cases of indolent presentation main organisms to consider are – Streptococci, Enterococci and HACEK organism.
In cases, severe sepsis Staphylococcus aureus and gram-negative organisms must be considered.

Endocarditis: indication Drug regimen Notes
Native valve endocarditis:

Indolent presentation

Amoxicillin 2g 4hrly IV

 

And

 

Gentamicin 1mg/kg ideal body weight (IBW) (optional)

Native valve endocarditis:
Severe sepsis (no risk factors for Enterobacteriaceae or Pseudomonas **) 

Or

 

Indolent presentation and patient is allergic to penicillin

Vancomycin IV *α
(dose according to local guideline) 

And

 

Gentamicin 1mg/kg IBW BD

 

In this case, Staphylococcus aureus must be considered.

 

If there are concerns about nephrotoxicity gentamicin can be replaced by Ciprofloxacin

 

 

Native valve endocarditis:
Severe sepsis and risk factors for multiresistant Enterobacteriaceae or Pseudomonas
Vancomycin IVα

 

And

 

Meropenem 2g TDS IV

Prosthetic valve endocarditis Vancomycin IV*α

And

Rifampicin 300-600mg BD IV/PO

And

Gentamicin 1mg/kg IBW

 

A lower dose of rifampicin must be used in severe renal impairment.

** Risk factors are – antibiotic use, prolonged and/or recent hospital stay, severe illness, recent surgery, bladder catheterisation or other invasive medical devices, residence in a long-term care facility, international travel, and age 65 years and older (Tham et al, 2013). Patients with past history of multiresistant bacteria, both infection and colonisation, must also be considered at high risk of having a multiresistant organism.
α Daptomycin 6mg/kg body weight IV OD can replace vancomycin if the patient has an allergy to vancomycin.
This is based on the British Society of Antimicrobial Chemotherapy (BSAC) guideline on Endocarditis (please see reference)

Streptococcal endocarditis

The treatment depends upon how sensitive the Streptococcus is to the penicillin. The microbiology laboratory should check this for you and microbiologist will be able to help you with this information. British society of Antimicrobial Chemotherapy (BSAC) has produced guideline to help to choose the appropriate antibiotic –

Penicillin-susceptible (penicillin MIC ≤0.125 mg/L – discuss with microbiologist)
1. Benzylpenicillin* 1.2 g q4h IV 4-6 weeks
2. Ceftriaxone 2 gm OD IV/IM 4-6 weeks not advised for patients at risk of C. difficile infection; suitable for outpatient antibiotic therapy (OPAT).
3. Benzylpenicillin*

and

gentamicin**

1.2 g q4h IV

 

1 mg/kg q12h iv

2 weeks not advised for patients with-
PVE,
extra-cardiac foci of infection,
any indications for surgery,
high risk of nephrotoxicity or
at risk of C. difficile
4. Ceftriaxone

And

Gentamicin**

2 gm OD IV/IM

 

1 mg/kg q12h iv

2 weeks
Relatively resistant to penicillin (penicillin MIC >0.125 to ≤0.5 mg/L – Discuss with microbiologist)
1. Benzylpenicillin*

and

gentamicin

2.4 g q4h iv 4–6 IV

 

1 mg/kg q12h iv

4 – 6 weeks

 

2 weeks

Penicillin allergy
1. Vancomycin**

and

gentamicin

1 g q12h 4–6 IV

 

1 mg/kg q12h iv

 4-6 weeks

≥2 weeks

2. Teicoplanin**

 

 

 

And

Gentamicin**

10 mg/kg body weight every 12 h

then 10 mg/kg daily

 

1 mg/kg q12h iv

 

4-6 weeks

≥2 weeks

 preferred option when a high risk of nephrotoxicity

.* Amoxicillin 2 g every 4 –6 h may be used in place of benzylpenicillin 1.2–2.4 g every 4 h.
** Vancomycin, Teicoplanin and gentamicin level should be monitored according to local protocol
Daptomycin is new antibiotic often used for the treatment of endocarditis- this should always be discussed with an infection specialist due to limited experience of this drug.

NotePenicillin-resistant (penicillin MIC >0.5 mg/L) – The guideline for Enterococcus endocarditis must be followed for these group of patients (see next section).

Staphylococcal endocarditis

Staphylococcus aureus is the commonest cause of endocarditis.

The treatment is slightly different for native and prosthetic valve endocarditis. In cases of native valve endocarditis if the organism is sensitive flucloxacillin monotherapy is adequate. Addition of another antibiotic does not give any additional benefit. However, if Flucloxacillin cannot be given a second antibiotic should be added as these non-beta lactam antibiotics are considered less active against Staphylococcus aureus, and may lead to treatment failure or the Staph aureus may become resistant to the antibiotic.

It is generally more difficult to treat prosthetic valve endocarditis, hence longer duration or multidrug combination may be required.

Endocarditis of native valve Duration  
Methicillin-sensitive Staphylococcus aureus (MSSA) Flucloxacillin 2gm IV
4hrly  or  6 hrly
4 weeks if >85kg BW – 4 hourly
Methicillin-resistant Staphylococcus aureus (MRSA)

Or

Penicillin allergy

Vancomycin 1 gm BD IV

And

Rifampicin 300–600 mg BD PO

4 weeks

 

4 weeks

Modify dose according to renal function and maintain pre-dose level 15–20 mg/L

Lower dose if creatinine clearance <30 mL/min

MRSA and

 

vancomycin-resistant/intolerance/allergy

Daptomycin 6 mg/kg OD IV

and

Rifampicin 300–600 mg BD PO

or

Gentamicin 1 mg/kg IV BD

4 weeks

 

4 weeks

 

4 weeks

Monitor CK, baseline and weekly, monitor renal function and dose accordingly
Prosthetic valve endocarditis
MSSA Flucloxacillin 2gm IV 4hrly or 6 hrly IV

And

Gentamicin 1mg/kg IV BD

And

Rifampicin 300-600 mg BD PO

6 weeks

 

 

6 weeks

 

6 weeks

MRSA

 

or

 

penicillin allergy

Vancomycin 1gm iv BD

And

Rifampicin 300–600 mg BD PO

And

Gentamicin 1 mg/kg BD IV

6 weeks

 

6 weeks

 

≥2 weeks

 

 

 

Continue gentamicin for the full course if there are no signs or symptoms of toxicity

MRSA and

 

vancomycin-resistant/intolerance/allergy

Daptomycin 6 mg/kg OD IV

and

Rifampicin 300–600 mg BD PO

and

Gentamicin 1 mg/kg IV BD

6 weeks

 

6 weeks

 

≥2 weeks

 

 

Continue gentamicin for the full course if there are no signs or symptoms of toxicity

Enterococcal Endocarditis

 

Amoxicillin sensitive
(MIC ≤4 mg/L)and
Penicillin-sensitive
(MIC ≤4 mg/L)

and

Gentamicin MIC ≤128 mg/L

amoxicillin 2 g 4 hrly IV

or

penicillin 2.4 g 4 hrly IV

and

gentamicin 1 mg/kg BD IV

4-6 weeks

 

4-6 weeks

 

4-6 weeks

6 weeks for prosthetic valve endocarditis

 

There should be a low threshold for stopping gentamicin if renal function deteriorating or toxicity appears

Amoxicillin resistant/ penicillin resistant

Or

Penicillin allergy

And

Vancomycin sensitive
(MIC ≤4 mg/L)

Vancomycin 1gm iv BD *

And

Gentamicin 1 mg/kg BD IV

4-6 weeks

 

4-6 weeks

6 weeks for prosthetic valve endocarditis

 

There should be a low threshold for stopping gentamicin if renal function deteriorating or toxicity appears

 

·         *Teicoplanin can replace vancomycin if teicoplanin MIC ≤2 mg/L

Amoxicillin sensitive

But

Gentamicin MIC>128 mg/L

Amoxicillin 2 gm 4 hrly >6 weeks European Society of Cardiology guideline recommends using cephalosporin with amoxicillin in these cases.
Antibiotic choice for other types of endocarditis.

This section is for endocarditis caused by relatively rare causes. Treatment of these infections is complicated and advice from an infection specialist must be sought.

Endocarditis treatment for HACEK group of organisms:
(HACEK = Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella)

These organisms may produce beta-lactamase enzyme which can inactivate amoxicillin. The laboratory should test for it but it is difficult to test and these bacteria are difficult to grow.

If beta-lactamase test is negative

Amoxicillin 2gm 4 hrly IV (4 weeks for native valve and 6 weeks for prosthetic valve endocarditis)

with gentamicin 1mg/kg BW IV BD (2 weeks).

If beta-lactamase test is positive

Ceftriaxone 2gm IV OD (4 weeks for NVE, 6 weeks for PVE)

or Ciprofloxacin (as an alternative)

Q fever

Very difficult to treat and infection specialist must be involved.

The recommended regimen is doxycycline and hydroxychloroquine for ≥18 months.

Follow up with serology for a minimum of 2 years after discontinuation of treatment.

Bartonella

This is the organism that causes trench fever, risk factor being homelessness and alcoholism. It is one of the causes of culture-negative endocarditis.

Doxycycline 100 mg BD 4 weeks and Gentamicin 1mg/kg BW TDS.

Other gram-negative organism including Enterobacteriaceae/ Pseudomonas

A combination of a beta-lactam and an aminoglycoside (once daily dose) based on sensitivity result.

Fungal endocarditis

Antifungal therapy for Candida:
liposomal amphotericin B (or other lipid formulations) ~
with or without flucytosine 

or 

an echinocandin at high doses;  

Aspergillus endocarditis,

voriconazole is the drug of choice
some experts recommend the addition of an echinocandin or amphotericin B.

Other modalities of treatment

Surgery:

Surgical opinion must be sought in

1. All prosthetic valve endocarditis.

2. Endocarditis with heart failure (urgent/emergency)

3. Uncontrolled infection (consider urgent referral) – abscess, false aneurysm, enlarging vegetation, persistent fever/positive blood culture 10 days after starting an appropriate antibiotic, endocarditis by a fungal or multi-resistant organism.

4. for prevention of embolism – large vegetation (>10mm) on the mitral/aortic valve with embolic episode despite appropriate antibiotic therapy. (urgent)

5 Isolated large vegetation (>15mm)- urgent

Ref:
1. Habib et al, 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC), Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM), European Heart Journal, Volume 36, Issue 44, 21 November 2015, Pages 3075–3128,

2. Li et al, Proposed Modifications to the Duke Criteria for the Diagnosis of Infective Endocarditis, Clinical Infectious Diseases, Volume 30, Issue 4, 1 April 2000, Pages 633–638,

3. Durack DT,  Lukes AS,  Bright DK. Duke Endocarditis ServiceNew criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings, Am J Med , 1994, vol. 96 (pg. 200-9) (Pubmed)

4. Gould et al, Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the Working Party of the British Society for Antimicrobial Chemotherapy, J Antimicrob Chemother 2012; 67: 269 –289

Basic microbiology: gram positive and gram negative organisms

Gram staining is one of the basic staining technique used in microbiology laboratories. It was discovered by Hans Christian Gram in 1884. This technique uses bacterial property of having peptidoglycan in their cell wall.

Hence, bacteria lacking a cell wall cannot be stained using this method – e.g. Mycoplasma.

Gram staining process
1. Make a smear on a glass slide using bacterial colony, heat fix.
2. Put a crystal violet (blue dye)
3. Put iodine (to fix the dye)
4. Decolourise using ethanol/acetone – If the bacteria have large amount of peptidoglycan in their cell wall, i.e. they have a thick cell wall, they will retain the blue dye, these are gram positive organisms.
5. Put a red/pink stain (safranin, neutral red etc) – bacteria with a thin cell wall with small amount of peptidoglycan, would have lost the blue stain in the previous stage. These will appear red, these are gram negative.

Here is a video showing how to do gram stain
This is national standard (SMI) for gram stain (and other staining methods) – if you are interested

So gram positive organisms are blue, gram negatives are red.
Occasionally it becomes difficult in some bacteria as they may stain inconsistently – we call them gram variable (we would exclude them from this discussion).

We classify bacteria based on their shape and how they appear in relation to each other.
Common shapes are –
round = coccus (pl. cocci)
long rod like = bacillus (pl. bacilli)
(There is a genus of bacteria called Bacillus – do not confuse these two terms. Genus Bacillus is indeed a bacillus shaped bacteria but, there are other bacteria with this shape – E coli, Klebsiella, Clostridium etc).
However, some bacteria may appear somewhat in the middle of these two categories – they are called coccobacilli.

These bacteria may form a particular type of configuration, which help us to make an educated guess of their genus.  They may form cluster, chains, pairs, Chinese letter appearance. However, it is difficult, if not impossible, to predict the species of gram stain only.

Here are some examples:
Gram positive cocci in cluster:
Staphylococcus aureus, 
Staphylococcus epidermidis, Staphylococcus capitis, Staphylococcus lugdunensis, Staphylococcus saprophyticus, Staphylococcus simulans etc.
Gram positive cocci in chains
Streptococcus pyogenes (Group A Strep), Streptococcus agalactiae (Group B Strep), Streptococcus dysgalactiae (Group C/G Strep), Streptococcus gallolyticus (Group D Strep), Streptococcus anginosus (milleri) group, 
Gram positive cocci in pairs:
Pneumococcus (Streptococcus pneumoniae), Streptococcus from mouth flora (These are alpha haemolytic Strep - Strep salivarius, Strep sanguinis, Strep oralis, Strep mitis, Strep mutans etc).

Enterococcus (Enterococcus faecalis, E faecium etc) usually present as short chain or in pairs
Gram positive rod/bacilli
Bacillus cereus, Bacillus anthracis (causes anthrax), Clostridium difficile, Clostridium tetany (causes tetanus), Clostridium botulinum, Clostridium perfringens, Clostridium novyi (causes gas gangrene)
Listeria (meningitis, neonatal infection etc)
Corynebacterium sp. (causes diphtheria but also some species live on our skin and normally harmless)
  

Gram negative cocci:
Acinetobacter, Moraxella - they can often be seen as coccobacilli

Neisseria meningitidis (diplococci - two coccus together), Neisseria gonorrhoea (diplococci).
Gram negative rod/bacilli
Escherichia coli, Klebsiella, Enterobacter, Serratia, Salmonella, Shigella, Yersinia, Proteus, Morganella

Some gram negative bacilli may have typical appearance-
Campylobacter (curved gram negative rod)

Vibrio e.g Vibrio cholerae (comma shaped)


Fusobacterium nucleatum (an anaeorobic bacteria from the mouth) - needle shaped
Yeast- like Candida, appears gram positive.

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