This document discusses treatment options for vancomycin-resistant Enterococci (VRE) infective endocarditis. It presents a case of a patient with VRE endocarditis and reviews his treatment with linezolid and daptomycin. Linezolid and daptomycin are discussed as alternative treatment options for multidrug-resistant VRE infections when other antibiotics are not effective. The prevalence of linezolid resistance is analyzed, and the role of daptomycin in enterococcal infections is evaluated based on available literature.

1. Vancomycin- Resistant
Enterococci Infective
Endocarditis: Treatment Options
Hanna Yudchyts Pharm.D.
09/25/2013

2. Objective
• Introduce patient case
• Review treatment options for VancomycinResistant Enterococci (VRE) endocarditis
• Analyze prevalence of Linezolid resistance
• Discuss Daptomycin as a treatment option in
multidrug resistant endocarditis
• Evaluate treatment of selected patient

3. Patient Case

4. HPI/PMH
• SK is 32 year old male
• Past Medical History
– Human Immunodeficiency Virus (HIV)
– ESRD: hemodialysis (Tue, Thu, Sat)
– DVT in April 2013
• Began having fevers 1.5 months ago
• Cultures at HD center:
– Resistant Pseudomonas aeruginosa
• Antibiotics initiated
– Gentamycin + Vancomycin

5. HPI/PMH
• 07/29: HD catheter was removed and cultured
• Cultures revealed
– Gentamicin resistant Pseudomonas aeruginosa
– Vancomycin resistant Enterococci (VRE)
• Despite resistant cultures patient was continued
on same antibiotics for 4 weeks
• 08/28: repeated cultures revealed same
organisms
• Patient was advised to come to the hospital

6. HPI/PMH
• Patient complained of perianal abscess on
admission
• Smoker: 1 ppd x 15 years
• EtOH abuse: quit 2 years ago
• Denies IVDU
• Allergies
Penicillin anaphylaxis

7. Medications Prior to Admission
•
•
•
•
Emtricitabine (Emtriva®) 200 mg every 4 days
Darunavir (Prezista®) 600 mg every 12 hours
Ritonavir (Norvir®) 100 mg twice daily
Tenofovir (Viread®) 300 mg every 7 days

8. Laboratory Findings on Admission
127
88
23
3.3
26
9.44
85
CD4: 215 cells/mcL
Viral load 276 copies/mL
10.6
11.4
36
479

9. Transthoracic Echocardiogram (09/04)
• Mild to moderate aortic valve thickening and
suggestion of attached mildly mobile material
(vegetation) on aortic valve
• April 2013 study appears to show a normal
aortic valve
• Picture is highly suggestive for infective
endocarditis involving aortic valve

10. Therapy Initiated
• Bacteremia/ IE
– Linezolid 600 mg IV to be given after HD
– Metronidazole 500 mg IV to be given after HD
– Aztreonam 1000 mg IV one time, followed by 250 mg
every 12 hours
• HIV
–
–
–
–
–
Emtricitabine 200 mg every 3 days
Darunavir 600 mg every 12 hours
Ritonavir 100 mg twice daily
Tenofovir 300 mg every 7 days
Trimethoprim- Sulfamethoxazole DS (Tue, Thu, Sat)

11. Infective Endocarditis

12. Pathogens
• Most common pathogens: (≈ 80%)
– Streptococci
– Staphylococci
– Enterococci
• HACEK microorganisms (5-10%)
–
–
–
–
–
Haemophilus parainfluenzae/paraphophilus, influnzae
Actinobacillus actinomycetemcomitans
Cardiobacterium hominis
Eikenella corrodens
Kingella kingae/denitrificans
• Other: fungi, polymicrobial, culture negative

13. Risk Factors
Patient Factors
• > 60 y/o
• Male
• Injection drug use
• Poor dental hygiene
Comorbid Conditions
• Structural heart disease
• Valvular disease
• Congenital heart disease
• Prosthetic heart valve
• History of IE
• Presence of intravascular
devise
• Chronic hemodialysis
• HIV infection

15. Enterococci Endocarditis
• E. faecium are often multidrug- resistant
• Vancomycin resistant E. faecalis are usually
Penicillin susceptible
• Linezolid inhibits the growth of both E. faecalis
and E. faecium
• Quinupristin- dalfopristin (Synercid) only inhibits
E. faecium, since E. faecalis are intrinsically
resistant to it

16. Therapy for multidrug Resistant
Enterococcal Endocarditis
• Linezolid therapy resulted in 77% cure rate
• Synercid therapy was effective in 4 out of 9
patients
• Double β- lactam combinations only been used in
a small number of patients
• Clinical results of daptomycin therapy are needed
• Surgery is often indicated, since cardiac valve
replacement may be the only chance of cure in
some patients

17. Therapy for Native or Prosthetic Valve Enterococcal Endocarditis
Caused by Strains Resistant to Penicillin, Aminoglycoside, and
Vancomycin
Enterococcus
faecium
• Linezolid 600 mg q 12 h IV/PO
• Quinupristin- dalfopristin 22.5 mg/kg/day IV in 3
equally divided doses
Enterococcus
faecalis
• Imipenem/cilastatin 2 g/24h IV in 4 equally divided
doses + Ampicillin 12 g/24h IV in 6 equally divided
doses
• Ceftriaxone 4 g/24h IV/IM in 2 equally divided
doses + Ampicillin 12g/24h IV in 6 equally divided
doses
Treatment ≥ 8 weeks

18. KS Microbiology Results
Source
Blood
Wound deep buttock
Organism
Vancomycin-Resistant
E. faecalis
Vancomycin-Resistant
E. faecalis
E. Coli (sparse amount)
Sensitivity
Sensitive
• Ampicillin
• Chloramphenicol
• Linezolid (MIC=2)
Resistant
• Streptomycin
• Gentamicin
• Amikacin

19. Linezolid
Class
Oxazolidinone
MOA
Inhibits the bacterial ribosomal translation process by selectively
binging to a site on the 23S ribosomal RNA of the 50S subunit,
thereby preventing initiation complex formation with the 70S
ribosomal subunit
Spectrum
Good
• MSSA, MRSA
• Streptococci
• Enterococci (VRE)
• Nocardia
Moderate
• Atypicals
Poor
• Gram- negative, anaerobes
MIC standards
S: ≤ 2 mcg/mL
I: 4 mcg/mL
R: ≥ 8 mcg/mL

20. Linezolid Resistant Enterococci:
Literature Reports
1.
2.
3.
4.
5.
6.
Linezolid- resistant Enterococci: report of the first isolates in the
United Kingdom
Emergence of linezolid resistance in the vancomycin- resistant
Enterococcus faecium multilocus sequence typing C1 epidemic
lineage
Response to emerging infection leading to outbreak of linezolidresistant enterococci
Antimicrobial Resistance to Linezolid
Increasing incidence of linezolid- intermediate or resistant
, vancomycin- resistant enterococcus faecium strains parallels
increasing linezolid consumption
Linezolid- resistant, vancomycin resistant enterococcus faecium
infection in patients without prior exposure to linezolid

21. LEADER Surveillance Program
• 2011
– Susceptibility rate at 99.8%
• 2010
– Susceptibility rate at 99.6%
– 12 Enterococci were found resistant
– 5 of them were in New York State
Antimicrob. Agents Chemother. February 2013 vol. 57 no. 2 1077-1081.

22. Treatment course in SK
• 09/05: Linezolid, Metronidazole, Aztreonam were
discontinued
• Daptomycin 500 mg IV daily was started
– Cultures: Vancomycin-Resistant E. faecalis
– Linezolid MIC of 2
– Decrease in platelets: 479 334
• 09/10: SK underwent aortic valve replacement

23. Role of Daptomycin in
Enterococcal infections
• Active against > 98% of Enterococci tested
• Data from randomized controlled trials is
limited
• Extensive clinical experience
– Staphylococcal bacteremia
– Right sided endocarditis
– Skin and soft tissue infections
– Bone and joint infections

24. Susceptibility of Enterococci to antibiotic agents in multicenter, comparative studies worldwide

25. Daptomycin in Infective Endocarditis
• Case reports of Daptomycin for IE caused by
Enterococcus have yielded various outcomes
• It is unclear whether cases of treatment
failure were due to underlying co- morbidities
or failure of the medication
J Antimicrob Chemother 2010; 65: 1126-1136.

26. Case Reports of Endocarditis due to VancomycinResistant Enterococci Treated with Daptomycin
AGE/ SEX
UNDERLYING
CONDITIONS
PATHOGEN (ALL
VAN-RESISTANT)
PRIOR ANTIBIOTICS
OUTCOME
64 F
HD, prosthetic valve
Enterococcus spp.
None
Expired
51 M
Not reported
Enterococcus spp.
VAN
Expired
25 F
SLE, ESRD
E. faecium
LZA
Expired
62 M
DM, CAD, PAD, ESRD
E. faecium
VAN, LZD, MEM,
FLC
Recovered
60 M
DM
E. faecium
CEF, VAN
Recovered
13 M
GVHD, pancreatitis
E. faecium
VAN, MEM, GEN
Expired
70 M
Renal failure (HD)
E. faecium
LZD
Failure
HD- haemodialysis; CEF- cefepime, FLC- fluconazole, GEN- gentamicin,
GVHD- graft versus host disease, LZD- linezolid, MEM- meropenem,
J Antimicrob Chemother. 2010 June; 65(6):
1126-1136

27. Treatment Progression
• Pharmacist intervention:
– Daptomycin dose adjustment: 500 mg IV q 48 h
– Emtricitabine 200 mg PO q 4 days
•
•
•
•
Patient remained afebrile
Repeat blood culture were negative
09/16 TTE results were found normal
Patient was discharged

28. Conclusion
• Treatment options for VRE endocarditis are
limited
• Individual case reports of Linezolid resistant
Enterococci are described in the literature
• According to LEADER surveillance
program, Linezolid has high susceptibility results
• Daptomycin has extensive activity against
Enterococci
• Randomized controlled trials are required to
evaluate Daptomycin efficacy in VRE endocarditis

29. References
•
•
•
•
•
Flamm R., Mendes R., Ross J., et al. Linezolid Surveillance Results for the United
States: LEADER Surveillance Program 2011. Antimicrob. Agents Chemother.
February 2013 vol. 57 no. 2 1077-1081.
Canton R., Ruiz- Garbajosa P., Chaves R., et al. A potential role of daptomycin in
enterococcal infecions: what is the evidence?. J Antimicrob Chemother 2010; 65:
1126-1136
Auckland C., Teare L., Cooke F., et al. Linezolid- resistant Enterococci: report of the
first isolates in the United Kingdom. J Antimicrob Chemother (2002) 50, 743-746.
Bonora M., Solbiati M., Stepan E., et al. Emergence of linezolid resistance in the
vancomycin- resistant Enterococcus faecium multilocus sequence typing C1
epidemic lineage. J Clinical Microbiology; Mar 2006: 1153-1155.
Flamm R., Farrell D., Mendes R., et al. LEADER Surveillance program results for
2010: an activity and spectrum analysis of linezolid using 680 clinical isolates from
Unites States (61 medical centers). Diagnostic Microbiology and Infectious Disease;
74 (2002): 54-61.

30. References
•
•
•
•
•
•
•
Morales G., Picazo J., Baos E., et al. Resistance to Linezolid is Mediated by the cfr
gene in the first report of an outbreak of linezolid- resistant Staphylococcus
aureus. Clinical Infectious Diseases 2010; 50: 821-825.
Kainer M., Devasia R., Jones T., et al. Response to emerging infection leading to
outbreak of linezolid- resistant enterococci. Emerging Infectious Diseases. Available
at www.cdc.gov/eid
Meka V., Gold H. Antimicrobial Resistance to Linezolid. Clinical Infectious Diseases
2004; 39: 1010-5.
www.uptodate.com
Scheetz M., Knechtel S., Malczynski M., et al. Increasing incidence of linezolidintermediate or resistant , vancomycin- resistant enterococcus faecium strains
parallels increasing linezolid consumption. Antimicrobial Agents and
Chemotherapy, June 2008: 2256-2259.
Rahim S., Pillai S., Gold H., et al. Linezolid- resistant, vancomycin resistant
enterococcus faecium infection in patients without prior exposure to linezolid.
Clinical Infectious Diseases 2003; 36: e146-8.
Baddour L., Wilson W., Bayer A., et al. Infective Endocarditis. Infectious Disease
Society of America 2005; 111: e394- e433.