Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Emory University on 07/28/15 For personal use only.
Special Report
Contemporary management of prosthetic valve endocarditis: principals and future outlook Expert Rev. Cardiovasc. Ther. 13(5), 501–510 (2015)
Cormac T O’Connor1 and Thomas J Kiernan*1,2 1 Cardiology Department, University Hospital Limerick, Co., Limerick, Ireland 2 University of Limerick, Dooradoyle, Co., Limerick, Ireland *Author for correspondence: [email protected]
Infective endocarditis involving prosthetic valves accounts for 20% of all endocarditis cases. Rising in prevalence due to increasing placement of valvular prostheses, prosthetic valve endocarditis (PVE) is more difficult to diagnose by conventional methods, associated with more invasive infection and increased mortality. This report explores the existing literature in identifying a direct approach to the management of PVE; such as adjuncts to establishing a diagnosis (for instance positron emission tomography/computed tomography and radiolabeled leukocyte scintigraphy), the trends in specific pathogens associated with PVE and the recommended antimicrobials for each. The patterns of disease requiring surgical intervention are also highlighted and explored. In addition, a 5-year outlook offers consolidated knowledge on epidemiological trends of both culprit organisms and population subgroups suffering (and projected to suffer) from PVE. KEYWORDS: infective endocarditis . management . prosthetic valve endocarditis . review . valve
Infective endocarditis (IE) is characterized by the infiltration and propagation of pathogens from the endocardial surface of the heart, typically involving valve-leaflet endocardium. In cases where the infected valve is prosthetic (i.e., mechanical or bioprosthetic), the disease is termed prosthetic valve endocarditis (PVE) (FIGURE 1). The number of valvular prostheses is increasing [1], and PVE now accounts for 10–30% of cases of IE [2]. This disease state is associated with an increased mortality compared with native valve endocarditis (NVE) [3,4]. This increasing incidence has been the subject of extensive ongoing research as its clinical importance increases. Epidemiology
Infection rates of valvular prostheses are at their highest within the first 3 months after surgery, falling in incidence thereafter [5]. Observational studies report an incidence of PVE between 1 and 3% at 1 year following valve surgery [6,7], with a 3–6% cumulative risk after 5 years follow-up [5,6]. A number of intrinsic characteristics have been shown to influence the development of PVE. informahealthcare.com
10.1586/14779072.2015.1035648
Time after surgery
PVE exists as two separate entities depending upon how soon infection occurs after valve surgery, namely early infection (within the first year after surgery) and late infection (more than 1 year after surgery) [4]. The definition of early PVE ranges from 12 h apart; or all of three or a majority of four separate cultures of blood (with first and last sample drawn at least 1 h apart) – Single positive blood culture for Coxiella burnetii or anti-Phase I IgG antibody titer >1:800
. .
. .
Predisposition, predisposing heart condition or history of intravenous drug abuse Pyrexia: temperature >38 C Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages and Janeway’s lesions Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, and rheumatoid factor microbiological evidence: positive blood culture but does not meet a major criterion as noted above† or serological evidence of active infection with organism consistent with IE
Evidence of endocardial involvement Echocardiogram positive for IE† defined as follows: oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation; or abscess; or new partial dehiscence of prosthetic valve; new valvular regurgitation (worsening or changing or preexisting murmur not sufficient)
Definite diagnosis: two major criteria, or one major and three minor criteria Possible diagnosis: one major and one minor criteria, or three minor criteria Rejected diagnosis: Firm alternative diagnosis explaining suspicion of IE; or resolution of IE syndrome with antibiotic therapy for ‡4 days; or no pathological evidence of IE at surgery or autopsy, with antibiotic therapy for ‡4 days; or does not meet criteria for possible IE as above. †
(TOE recommended for patients with prosthetic valves, rated at least “possible IE” by clinical criteria, or complicated IE (e.g., paravalvular abscess); TTE as first test in other patients). IE: Infective endocarditis.
It is recommended to rationalize antimicrobial treatment as soon as specific organism characteristics are identified. Bactericidal treatment (preferred above bacteriostatic antimicrobials) is recommended for at least 6 weeks (by comparison to 2–6 weeks for NVE) [4,25]. Special considerations are given to disease states involving specific organisms.
recommended in addition to a b-lactam or vancomycin in severe infection. If, however, the organism is penicillin resistant (MIC of >0.12 mg/ml), AHA recommend 6 weeks of gentamicin in addition to the b-lactam or vancomycin as standard in this regime.
Staphylococcal infection
Fungal endocarditis is classified as a severe infection and is associated with mortalities as high as 80% [25]. Surgical repair is considered a standard aspect of curative care in addition to antimicrobial therapy [4]. Amphotericin B is the recommended empiric anti-fungal for PVE wherein a fungal culprit is identified [25]. See (TABLE 2) for a full list of antimicrobial protocols. See (TABLE 3) for typical organisms associated with patient subgroups.
Treatment depends upon the organism’s sensitivity to methicillin and other b-lactams. Vancomycin is recommended in those resistant to methicillin (MIC of >0.12 mg/ml) in addition to gentamicin and rifampicin. Flucloxacillin or oxacillin is recommended in cases of methicillin-susceptible staphylococcal infection (MIC of £0.12 mg/ml), in addition to gentamicin and rifampicin.
Fungal infection
Enterococcal infection
In the case of vancomycin-sensitive enterococcal infection, treatment involves the use of high-dose ampicillin with gentamicin or vancomycin together with gentamicin. Gentamicin is used for 6 weeks in enterococcal PVE due to reduced observed sensitivity to aminoglycosides. In cases of vancomycin- or gentamicin-resistant strains, recommended treatment will depend on the specific enterococcal organism (TABLE 2). Streptococcal infection
The treatment depends on the degree of penicillin sensitivity. If penicillin sensitive (MIC of £0.12 mg/ml), gentamicin is informahealthcare.com
Surgical intervention
Treatment of PVE has high failure rates with antimicrobial treatment alone, with 50% of patients in the European heart study proceeding to surgery [26]. These figures are observed elsewhere, with in addition to the 40–50% undergoing surgery, a reported further 20% of surgical candidates deemed suitable for surgery but unfit for the operating theater [10]. Surgical intervention is considered in high-risk cases where severe valvular dysfunction is present or where infection has spread beyond the valve surface. It is recommended that each patient is considered early for surgery as appropriate [4,25]. 503
Special Report
O’Connor & Kiernan
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Emory University on 07/28/15 For personal use only.
Table 2. Recommended Antimicrobial Therapy for PVE
[4,25].
Organism
Antibiotic
Dose
Duration
Unknown early PVE (culture negative)
1. Vancomycin 2. Rifampicin 3. Gentamicin ± cefepime
30 mg/kg iv. in 2 divided doses daily 1200 mg orally in 2 divided doses daily 3 mg/kg iv. in 2–3 divided doses daily 6 g iv. in 3 divided doses daily
6 6 2 6
Unknown late PVE (culture negative)
1. Co-Amoxiclav 2. Gentamicin OR 1. Amplicillin/sulbactam 2. Gentamicin
12 g iv. in 4 divided doses daily 3 mg/kg iv. in 2–3 divided doses daily
4–6 weeks 4–6 weeks
12g iv. in 4 divided doses daily 3 mg/kg iv. in 2–3 divided doses daily
4–6 weeks 4–6 weeks
Staphylococcal Species (methicillin sensitive)
1. Flucloxacillin or Oxacillin 2. Rifampicin 3. Gentamicin
12 g iv. in 4-6 divided doses daily 1200 mg orally in 2 divided doses daily 3 mg/kg iv. in 2–3 divided doses daily
6 weeks 6 weeks 2 weeks
Staphylococcal species (methicillin resistant)
1. Vancomycin 2. Rifampicin 3. Gentamicin
30 mg/kg iv. in 2 divided doses daily 1200 mg orally in two divided doses daily 3 mg/kg iv. in 2–3 divided doses daily
6 weeks 6 weeks 2 weeks
Enterococcal species
1. Amoxacillin 2. Gentamicin OR 1. Ampicillin 2. Gentamicin OR 1. Vancomycin 2. Gentamicin
200 mg/kg/day 4–6 doses daily 3 mg/kg iv. in 2–3 divided doses daily
6 weeks 6 weeks
200 mg/kg/day 4–6 doses daily 3 mg/kg iv. in 2–3 divided doses daily
6 weeks 6 weeks
30 mg/kg iv. in 2 divided doses daily 3 mg/kg iv. in 2–3 divided doses daily
6 weeks 6 weeks
1.2 g iv./p.o. in 2 divided doses daily
‡8 weeks
22.5 mg/kg iv. in 3 divided doses daily
‡8 weeks
2 g iv. in 4 divided doses daily 12 g iv. in 6 divided doses daily
‡8 weeks ‡8 weeks
4 g iv./im. in 2 equally divided doses daily 12 g iv. in 6 divided doses daily
‡8 weeks
1. Benzylpenicillin OR 1. Ceftriaxone OR 1. Vancomycin ± Gentamicin
24 million units iv. in 4–6 divided doses daily
6 weeks
2 g im./iv. as 1 dose daily
6 weeks
30 mg/kg iv. in 2 divided doses daily 3 mg/kg iv. in 2–3 divided doses daily
6 weeks 2 weeks
1. Benzylpenicillin 2. Gentamicin OR 1. Ceftriaxone 2. Gentamicin OR 1. Vancomycin 2. Gentamicin
24 million units iv. in 4–6 divided doses daily 3 mg/kg iv. in 2–3 divided doses daily
6 weeks 6 weeks
2 g im./iv. daily in 1 dose 3 mg/kg iv. in 2-3 divided doses daily
6 weeks 6 weeks
30 mg/kg iv. in 2 divided doses daily 3 mg/kg iv. in 2–3 divided doses daily
6 weeks 6 weeks
1. Ceftriaxone OR 2. Ampicillin OR 3. Ciprofloxacin
2 g iv./im in 1 dose daily
4 weeks
12 g iv. in 4 divided doses daily
4 weeks
1 g PO/800 mg iv. daily in 2 divided doses
6 weeks
Resistant Enterococcal species (penicillin, aminoglycoside (i.e., gentamicin) and glycopeptide (i.e., vancomycin) resistance)
Streptococcal species (Penicillin sensitive – MIC = £0.12 g/ml)
Streptococcal Species (Penicillin resistant – MIC = >0.12 ug/ml)
HACEK organisms†
Enterococcus faecium 1. Linezolid OR 2. Quinupristin-dalfopristin Enterococcus faecalis 1. Imipenem/cilastatin 2. Ampicillin OR 1. Ceftriaxone 2. Ampicillin
weeks weeks weeks weeks
†
Haemophilus parainfluenzae, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae.
504
Expert Rev. Cardiovasc. Ther. 13(5), (2015)
Contemporary management of PVE
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Emory University on 07/28/15 For personal use only.
Table 2. Recommended Antimicrobial Therapy for PVE
[4,25]
Special Report
(cont.).
Organism
Antibiotic
Dose
Duration
Fungal PVE
1. Amphotericin B
0.7–1.5 mg/kg iv. daily in 1 dose
As directed by Infectious diseases specialist
Brucella species
1. Doxycycline 2. Co-trimoxazole 3. Rifampicin
200 mg p.o. daily in 1 single dose 1920 mg p.o daily in 2 divided doses 300–600 mg p.o. daily in 1 single dose
3 months (success defined as antibody titer 18 months (success defined as anti-Phase I IgG titer
Special Report
Contemporary management of prosthetic valve endocarditis: principals and future outlook Expert Rev. Cardiovasc. Ther. 13(5), 501–510 (2015)
Cormac T O’Connor1 and Thomas J Kiernan*1,2 1 Cardiology Department, University Hospital Limerick, Co., Limerick, Ireland 2 University of Limerick, Dooradoyle, Co., Limerick, Ireland *Author for correspondence: [email protected]
Infective endocarditis involving prosthetic valves accounts for 20% of all endocarditis cases. Rising in prevalence due to increasing placement of valvular prostheses, prosthetic valve endocarditis (PVE) is more difficult to diagnose by conventional methods, associated with more invasive infection and increased mortality. This report explores the existing literature in identifying a direct approach to the management of PVE; such as adjuncts to establishing a diagnosis (for instance positron emission tomography/computed tomography and radiolabeled leukocyte scintigraphy), the trends in specific pathogens associated with PVE and the recommended antimicrobials for each. The patterns of disease requiring surgical intervention are also highlighted and explored. In addition, a 5-year outlook offers consolidated knowledge on epidemiological trends of both culprit organisms and population subgroups suffering (and projected to suffer) from PVE. KEYWORDS: infective endocarditis . management . prosthetic valve endocarditis . review . valve
Infective endocarditis (IE) is characterized by the infiltration and propagation of pathogens from the endocardial surface of the heart, typically involving valve-leaflet endocardium. In cases where the infected valve is prosthetic (i.e., mechanical or bioprosthetic), the disease is termed prosthetic valve endocarditis (PVE) (FIGURE 1). The number of valvular prostheses is increasing [1], and PVE now accounts for 10–30% of cases of IE [2]. This disease state is associated with an increased mortality compared with native valve endocarditis (NVE) [3,4]. This increasing incidence has been the subject of extensive ongoing research as its clinical importance increases. Epidemiology
Infection rates of valvular prostheses are at their highest within the first 3 months after surgery, falling in incidence thereafter [5]. Observational studies report an incidence of PVE between 1 and 3% at 1 year following valve surgery [6,7], with a 3–6% cumulative risk after 5 years follow-up [5,6]. A number of intrinsic characteristics have been shown to influence the development of PVE. informahealthcare.com
10.1586/14779072.2015.1035648
Time after surgery
PVE exists as two separate entities depending upon how soon infection occurs after valve surgery, namely early infection (within the first year after surgery) and late infection (more than 1 year after surgery) [4]. The definition of early PVE ranges from 12 h apart; or all of three or a majority of four separate cultures of blood (with first and last sample drawn at least 1 h apart) – Single positive blood culture for Coxiella burnetii or anti-Phase I IgG antibody titer >1:800
. .
. .
Predisposition, predisposing heart condition or history of intravenous drug abuse Pyrexia: temperature >38 C Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages and Janeway’s lesions Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, and rheumatoid factor microbiological evidence: positive blood culture but does not meet a major criterion as noted above† or serological evidence of active infection with organism consistent with IE
Evidence of endocardial involvement Echocardiogram positive for IE† defined as follows: oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation; or abscess; or new partial dehiscence of prosthetic valve; new valvular regurgitation (worsening or changing or preexisting murmur not sufficient)
Definite diagnosis: two major criteria, or one major and three minor criteria Possible diagnosis: one major and one minor criteria, or three minor criteria Rejected diagnosis: Firm alternative diagnosis explaining suspicion of IE; or resolution of IE syndrome with antibiotic therapy for ‡4 days; or no pathological evidence of IE at surgery or autopsy, with antibiotic therapy for ‡4 days; or does not meet criteria for possible IE as above. †
(TOE recommended for patients with prosthetic valves, rated at least “possible IE” by clinical criteria, or complicated IE (e.g., paravalvular abscess); TTE as first test in other patients). IE: Infective endocarditis.
It is recommended to rationalize antimicrobial treatment as soon as specific organism characteristics are identified. Bactericidal treatment (preferred above bacteriostatic antimicrobials) is recommended for at least 6 weeks (by comparison to 2–6 weeks for NVE) [4,25]. Special considerations are given to disease states involving specific organisms.
recommended in addition to a b-lactam or vancomycin in severe infection. If, however, the organism is penicillin resistant (MIC of >0.12 mg/ml), AHA recommend 6 weeks of gentamicin in addition to the b-lactam or vancomycin as standard in this regime.
Staphylococcal infection
Fungal endocarditis is classified as a severe infection and is associated with mortalities as high as 80% [25]. Surgical repair is considered a standard aspect of curative care in addition to antimicrobial therapy [4]. Amphotericin B is the recommended empiric anti-fungal for PVE wherein a fungal culprit is identified [25]. See (TABLE 2) for a full list of antimicrobial protocols. See (TABLE 3) for typical organisms associated with patient subgroups.
Treatment depends upon the organism’s sensitivity to methicillin and other b-lactams. Vancomycin is recommended in those resistant to methicillin (MIC of >0.12 mg/ml) in addition to gentamicin and rifampicin. Flucloxacillin or oxacillin is recommended in cases of methicillin-susceptible staphylococcal infection (MIC of £0.12 mg/ml), in addition to gentamicin and rifampicin.
Fungal infection
Enterococcal infection
In the case of vancomycin-sensitive enterococcal infection, treatment involves the use of high-dose ampicillin with gentamicin or vancomycin together with gentamicin. Gentamicin is used for 6 weeks in enterococcal PVE due to reduced observed sensitivity to aminoglycosides. In cases of vancomycin- or gentamicin-resistant strains, recommended treatment will depend on the specific enterococcal organism (TABLE 2). Streptococcal infection
The treatment depends on the degree of penicillin sensitivity. If penicillin sensitive (MIC of £0.12 mg/ml), gentamicin is informahealthcare.com
Surgical intervention
Treatment of PVE has high failure rates with antimicrobial treatment alone, with 50% of patients in the European heart study proceeding to surgery [26]. These figures are observed elsewhere, with in addition to the 40–50% undergoing surgery, a reported further 20% of surgical candidates deemed suitable for surgery but unfit for the operating theater [10]. Surgical intervention is considered in high-risk cases where severe valvular dysfunction is present or where infection has spread beyond the valve surface. It is recommended that each patient is considered early for surgery as appropriate [4,25]. 503
Special Report
O’Connor & Kiernan
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Emory University on 07/28/15 For personal use only.
Table 2. Recommended Antimicrobial Therapy for PVE
[4,25].
Organism
Antibiotic
Dose
Duration
Unknown early PVE (culture negative)
1. Vancomycin 2. Rifampicin 3. Gentamicin ± cefepime
30 mg/kg iv. in 2 divided doses daily 1200 mg orally in 2 divided doses daily 3 mg/kg iv. in 2–3 divided doses daily 6 g iv. in 3 divided doses daily
6 6 2 6
Unknown late PVE (culture negative)
1. Co-Amoxiclav 2. Gentamicin OR 1. Amplicillin/sulbactam 2. Gentamicin
12 g iv. in 4 divided doses daily 3 mg/kg iv. in 2–3 divided doses daily
4–6 weeks 4–6 weeks
12g iv. in 4 divided doses daily 3 mg/kg iv. in 2–3 divided doses daily
4–6 weeks 4–6 weeks
Staphylococcal Species (methicillin sensitive)
1. Flucloxacillin or Oxacillin 2. Rifampicin 3. Gentamicin
12 g iv. in 4-6 divided doses daily 1200 mg orally in 2 divided doses daily 3 mg/kg iv. in 2–3 divided doses daily
6 weeks 6 weeks 2 weeks
Staphylococcal species (methicillin resistant)
1. Vancomycin 2. Rifampicin 3. Gentamicin
30 mg/kg iv. in 2 divided doses daily 1200 mg orally in two divided doses daily 3 mg/kg iv. in 2–3 divided doses daily
6 weeks 6 weeks 2 weeks
Enterococcal species
1. Amoxacillin 2. Gentamicin OR 1. Ampicillin 2. Gentamicin OR 1. Vancomycin 2. Gentamicin
200 mg/kg/day 4–6 doses daily 3 mg/kg iv. in 2–3 divided doses daily
6 weeks 6 weeks
200 mg/kg/day 4–6 doses daily 3 mg/kg iv. in 2–3 divided doses daily
6 weeks 6 weeks
30 mg/kg iv. in 2 divided doses daily 3 mg/kg iv. in 2–3 divided doses daily
6 weeks 6 weeks
1.2 g iv./p.o. in 2 divided doses daily
‡8 weeks
22.5 mg/kg iv. in 3 divided doses daily
‡8 weeks
2 g iv. in 4 divided doses daily 12 g iv. in 6 divided doses daily
‡8 weeks ‡8 weeks
4 g iv./im. in 2 equally divided doses daily 12 g iv. in 6 divided doses daily
‡8 weeks
1. Benzylpenicillin OR 1. Ceftriaxone OR 1. Vancomycin ± Gentamicin
24 million units iv. in 4–6 divided doses daily
6 weeks
2 g im./iv. as 1 dose daily
6 weeks
30 mg/kg iv. in 2 divided doses daily 3 mg/kg iv. in 2–3 divided doses daily
6 weeks 2 weeks
1. Benzylpenicillin 2. Gentamicin OR 1. Ceftriaxone 2. Gentamicin OR 1. Vancomycin 2. Gentamicin
24 million units iv. in 4–6 divided doses daily 3 mg/kg iv. in 2–3 divided doses daily
6 weeks 6 weeks
2 g im./iv. daily in 1 dose 3 mg/kg iv. in 2-3 divided doses daily
6 weeks 6 weeks
30 mg/kg iv. in 2 divided doses daily 3 mg/kg iv. in 2–3 divided doses daily
6 weeks 6 weeks
1. Ceftriaxone OR 2. Ampicillin OR 3. Ciprofloxacin
2 g iv./im in 1 dose daily
4 weeks
12 g iv. in 4 divided doses daily
4 weeks
1 g PO/800 mg iv. daily in 2 divided doses
6 weeks
Resistant Enterococcal species (penicillin, aminoglycoside (i.e., gentamicin) and glycopeptide (i.e., vancomycin) resistance)
Streptococcal species (Penicillin sensitive – MIC = £0.12 g/ml)
Streptococcal Species (Penicillin resistant – MIC = >0.12 ug/ml)
HACEK organisms†
Enterococcus faecium 1. Linezolid OR 2. Quinupristin-dalfopristin Enterococcus faecalis 1. Imipenem/cilastatin 2. Ampicillin OR 1. Ceftriaxone 2. Ampicillin
weeks weeks weeks weeks
†
Haemophilus parainfluenzae, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae.
504
Expert Rev. Cardiovasc. Ther. 13(5), (2015)
Contemporary management of PVE
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Emory University on 07/28/15 For personal use only.
Table 2. Recommended Antimicrobial Therapy for PVE
[4,25]
Special Report
(cont.).
Organism
Antibiotic
Dose
Duration
Fungal PVE
1. Amphotericin B
0.7–1.5 mg/kg iv. daily in 1 dose
As directed by Infectious diseases specialist
Brucella species
1. Doxycycline 2. Co-trimoxazole 3. Rifampicin
200 mg p.o. daily in 1 single dose 1920 mg p.o daily in 2 divided doses 300–600 mg p.o. daily in 1 single dose
3 months (success defined as antibody titer 18 months (success defined as anti-Phase I IgG titer
