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The following protocol is intended to be a useful and practical guide to empirical and pathogen directed antimicrobial therapy of infective endocarditis (IE) in adult patients. It has been in use for a number of years at the Instituto Nacional de Cardiologia, a referral center for cardiac surgery located in Rio de Janeiro, Brazil. The institute belongs to the national health system and annually, approximately 270 valve replacement surgeries in adults are performed; there are 8000 outpatient visits to the Heart Valve Disease Department, and 25 cases of definite IE according to the modified Duke criteria in adults are admitted. Around 2/3 of patients referred for surgery are from other hospitals.

The protocol has been updated regularly, with incorporation of the relevant published literature; the last update was on May 2018. The main sources used were the British guidelines (Gould et al., 2012), the American guidelines (Baddour et al., 2015) and the European guidelines (Habib et al., 2015), but several other references provided evidence for its construction.

1.Collecting blood cultures

Blood cultures must be collected by peripheral vein puncture. The protocol used is as follows:

A)            The patient is stable, and has not used antibiotics previously:

Draw 20 ml of blood at moments 0, 1 hour and 6 hours. Use for the first set an aerobic and one anaerobic bottle per set, and in the third set, 2 aerobic bottles. Do not start antibiotics yet. If blood cultures remain negative after 72 hours, collect another 4 bottles and at the same time, collect blood for Bartonella spp and Coxiella burnetii   serologies and polymerase chain reaction (PCR). Start empirical treatment then.

 B)          If the patient is stable but is on antibiotics, we recommend these are stopped for at least 72 hours (ideally for 1 week). After this time, collect 6 blood culture bottles (two at 0, two at 1 hour and two at 6 hours, as described in A).

C1)         The patient is unstable, and has not used antibiotics: collect 4 bottles (2 sets), with a 30 minute interval between them. Start empirical treatment taking into account whether the patient has an acute onset of signs and symptoms (usually of days, certainly less than a month) or a subacute onset (more than 4 weeks of the start of signs and symptoms), if it is a native valve endocarditis or prosthetic valve IE and whether the patient has been exposed to healthcare (see below).

C2)         The patient is unstable, and is on antibiotics: keep the antibiotics and collect blood cultures immediately, as in C1 (4 bottles in total, with a 30 minute interval). Discuss antibiotic change with the  infectious diseases specialist.                  

2.Echocardiogram

Organize a transthoracic echocardiogram (TTE) if IE involves native valves, and a transesophageal echocardiogram if IE involves prosthetic valves, intracardiac devices, if there is atrioventricular block or if  TTE has not been helpful.

3.Other important investigations

Full blood count, C-reactive protein levels,  erythrocyte sedimentation rate (ESR), renal function, routine electrolytes, urinalysis, tomographic scans of the brain and abdomen if IE is left- sided.

4.intravenous access

If the diagnosis of IE is definite or probable, and the patients will be treated as such, consider early the insertion of a peripherally inserted central catheter (PICC). PICCs are the type of intravenous line that have been associated with less adverse events and that have the longer duration of routinely used IV access in the scenario of antibiotic treatment of IE, potentially lasting weeks if adequately cared for.            

Antimicrobial Treatment

Infective endocarditis requires surgical treatment when left-sided in around 40 to 50% of patients.  Therefore, antimicrobial treatment is just a part of the treatment strategy.  Though IE is a severe infection, response to antimicrobials usually occurs in 3 to 5 days. Therefore, failure to respond to antimicrobial treatment usually indicates complications such as perivalvular abscess, intra-abdominal abscess, problems with intravenous lines or antibiotic hypersensitivity.

The following are treatment guidelines used in our institution:

 

Native valve or late-onset prosthetic valve IE with a subacute course

“Subacute” defined as that situation where signs and symptoms have developed insidiously over more than 4 weeks.

Rationale: coverage for viridans group streptococci. Greater commercial availability of ampicillin than of penicillin.

 

In case  viridans group streptococci are confirmed:

a)If the patient will be submitted to cardiac surgery: maintain ampicillin and stop gentamicin.     Gentamicin should be continued only if there is intermediate resistance to penicillin, defined as an MIC  between 0.12 and 0.5 mcg/ml. In this case, it will be maintained  as a once daily infusion, for 2 weeks.

If the patient has uncomplicated viridans group IE, that is, no valvular dysfunction, no abscess and no embolic lesions, the total duration of combined ampicillin and gentamicin treatment will be 2 weeks .

b)If the patient will not undergo surgery:  keep ampicillin and gentamicin.

The goal of associating gentamicin is to shorten the duration of IE treatment. However, if the patient has a surgical indication, the infectious focus of infection will be removed, and duration of treatment will be decided according to the macroscopic surgical findings as well as the histopathology of the excised valve.  Stopping gentamicin will avoid further kidney injury. Kidney dysfunction occurs in around 33% of patients with IE and post valve replacement surgery hemodialysis is necessary for 10% .

c)When the patient is discharged from the cardiac postoperative unit to the ward, change ampicillin to ceftriaxone 2 grams once daily, till the completion of antibiotic treatment.

In case  Enterococcus is confirmed:

Check for aminoglycoside resistance and confirm if gentamicin may be used.

If the patient is to have cardiac surgery: keep ampicillin, stop gentamicin and start ceftriaxone 2 grams every 12 hours instead.

If the patient is not surgical:  keep gentamicin for 2 to 3 weeks in patients with native valve IE, associated to ampicillin (which will be kept for 4 to 6 weeks).

Alternatively, ampicillin may be associated with ceftriaxone all along the course of treatment (6 weeks in all).

In patients with prosthetic valve enterococcal IE who will be treated conservatively, caution is recommended: use gentamicin 1 mg/kg 8- hourly and treat for 6 weeks. 

 

 

 Rationale:  Bartonella spp, Coxiella and  HACEK are possible etiologic agents. Send away blood for Coxiella burnetii and Bartonella serologies. It is very important to establish diagnosis as treatment for Coxiella is long, around 18 months.

 

“Acute” defined as that situation where signs and symptoms have developed abruptly and usually over days, but  less  than 4 weeks.

Rationale: Coverage for methicillin sensitive (MSSA) and resistant S. aureus (MRSA).

Further action:

- Stop vancomycin when blood culture results are available (usually after 48 to 72 h) if MSSA is isolated;

- If the patient has a prosthesis and MSSA is isolated, associate gentamicin once daily with the dose of 3 to 5 mg/kg for 2 weeks, and rifampin  300mg  PO 8 hourly (after 5 days of oxacillin) for the whole course of treatment;

- If  MRSA is isolated, stop oxacillin and keep  vancomycin;

- If MRSA is isolated and the patient has a prosthesis, associate gentamicin once daily with the dose of 3 to 5 mg/kg for 2 weeks, and rifampin 300mg PO 8 hourly (after 5 days of vancomycin) for the whole course of treatment;

- After the 3^rd  dose of vancomycin, pre-dose serum levels must be checked and dose adjusted according to protocol.

- If MRSA is isolated and there are any of the following: vancomycin MIC >1.5, moderate to severe renal dysfunction (creatinine clearance, CrCl, between 30 and 50 ml/min) and vancomycin allergy

use Daptomycin 8 to 10 mg/kg IV once daily

- If the CrCl is < 30 ml/min or the patient is on hemodialysis, give daptomycin at an attack dose of 10 mg/kg and then use 4 mg/kg/day once daily.

- If daptomycin is used for native valve IE, consider associating oxacillin or gentamicin or ceftaroline (please consult infectious disease specialist).

- If daptomycin is used for prosthetic valve IE, associate gentamicin and rifampin.

- If blood cultures remain negative in this acute scenario, consult ID specialist and discuss the case individually.

Acute onset of infective endocarditis affecting a recently implanted valve prosthesis

 

Important: The patient needs to be weighed so that the correct dose is given. The loading dose of vancomycin is 25 mg/kg.

After the 3rd dose, pre -dose serum levels of vancomycin must be done and dose adjusted according to protocol.

Rationale: coverage for coagulase negative staphylococci, for MRSA, for enterobacteria that are extended spectrum lactamase (ESBL) producers  and for Candida spp when valve replacement has occurred less than 2 months. Starting rifampin after 5 days is to minimize the risk of staphylococci developing resistance.

It is very important to draw blood cultures specifically for fungi, as Candida spp may grow in usual culture media but may take longer to do so and the yield is not optimal. If available, ask for serum β (1-3)-glucan.

Consult with the ID specialist for therapeutic adjustment of antimicrobials when a pathogen has been isolated. For non-resistant Gram negative organisms, preference will be given to the use of a β-lactam combined with an aminoglycoside. 

If Candida spp, is isolated, liposomal amphotericin B (3-5mg/Kg/day) or an equinocandin (caspofungin, anidulafungin or micafungin)  may be used; discuss with the ID specialist.

If blood cultures are negative, keep vancomycin, gentamicin and rifampin, and consider maintaining antifungal therapy (consult ID).

 

                   Post-operative antibiotics for IE

General rules

1)Do not send valves for cultures, except in blood culture negative endocarditis. Send all surgical specimens for histopathology (HP).

2)Use, as a gold standard, histopathology of valves to guide antibiotic duration following valve replacement surgery. Results should be available 1 week after surgery.

3)Culture results should be obtained in BCNE but sensitivity of valve culture is low, around 15%. Also, there may be a problem with false positive results in valve culture. If the same organism is grown from valve and blood, keep antibiotics for 4 weeks post-surgery.

 

-Duration of antibiotic treatment for fungi and Gram negative organisms will be decided on a case- by- case basis.

Other recommendations:

Gentamicin:

- Gentamicin must be diluted and infused over 45 minutes to avoid risk of muscle paralysis.

- Weigh the patient and calculate the dose; use the real weight except if  body mass index (BMI) is >30, when ideal body weight should be used;

-  Check pre-dose levels of gentamicin prior to the second dose;

-  Desirable pre-dose serum levels are 1 to 1.5 mcg/ml;

- Monitor serum levels once weekly in stable patients, and twice weekly in unstable ones. Correct the dose according to protocol.

Vancomycin

- Vancomycin must be diluted and infused over at least one hour to avoid the red man syndrome and to minimize the risks of phlebitis

-Check pre-dose serum levels one hour before the 4th dose;

- Monitor serum levels once weekly in stable patients, and twice weekly in unstable ones. Correct the dose according to protocol.

-Doses above 4 grams per day are associated with considerable chance of nephrotoxicity and alternative treatment with daptomycin should be considered.

Daptomycin

- Patients using daptomycin should have creatine phosphokinase (CPK) levels checked once a week.

-  CPK levels should also be checked if the patient complains of myalgia.

-  CPK levels > 1000 IU/L (5 times the upper limit of normal) in a patient with myalgia or muscle weakness, or > 2000 IU/L irrespective of symptoms, are considered high. In these cases, daptomycin must be stopped.

 

Peer-review: Internal

Conflict of interest: None to declare

Authorship: G. I. F. B., B. Z., R. Q.G., C.C.L. contributed equally to preparation of manuscript

Acknowledgement and funding: Cristiane C. Lamas receives a research grant from Fundacaao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ; number # E26/202.782/2015).