Vancomycin- Resistant
Enterococci Infective
Endocarditis: Treatment Options

Hanna Yudchyts Pharm.D.
09/25/2013
Objective
• Introduce patient case
• Review treatment options for VancomycinResistant Enterococci (VRE) endocarditis
• Ana...
Patient Case
HPI/PMH
• SK is 32 year old male
• Past Medical History
– Human Immunodeficiency Virus (HIV)
– ESRD: hemodialysis (Tue, Th...
HPI/PMH
• 07/29: HD catheter was removed and cultured
• Cultures revealed
– Gentamicin resistant Pseudomonas aeruginosa
– ...
HPI/PMH
• Patient complained of perianal abscess on
admission
• Smoker: 1 ppd x 15 years
• EtOH abuse: quit 2 years ago
• ...
Medications Prior to Admission
•
•
•
•

Emtricitabine (Emtriva®) 200 mg every 4 days
Darunavir (Prezista®) 600 mg every 12...
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
3...
Transthoracic Echocardiogram (09/04)
• Mild to moderate aortic valve thickening and
suggestion of attached mildly mobile m...
Therapy Initiated
• Bacteremia/ IE
– Linezolid 600 mg IV to be given after HD
– Metronidazole 500 mg IV to be given after ...
Infective Endocarditis
Pathogens
• Most common pathogens: (≈ 80%)
– Streptococci
– Staphylococci
– Enterococci

• HACEK microorganisms (5-10%)
–
...
Risk Factors
Patient Factors
• > 60 y/o
• Male
• Injection drug use
• Poor dental hygiene

Comorbid Conditions
• Structura...
Enterococci Endocarditis
• E. faecium are often multidrug- resistant
• Vancomycin resistant E. faecalis are usually
Penici...
Therapy for multidrug Resistant
Enterococcal Endocarditis
• Linezolid therapy resulted in 77% cure rate
• Synercid therapy...
Therapy for Native or Prosthetic Valve Enterococcal Endocarditis
Caused by Strains Resistant to Penicillin, Aminoglycoside...
KS Microbiology Results
Source

Blood

Wound deep buttock

Organism

Vancomycin-Resistant
E. faecalis

Vancomycin-Resistan...
Linezolid
Class

Oxazolidinone

MOA

Inhibits the bacterial ribosomal translation process by selectively
binging to a site...
Linezolid Resistant Enterococci:
Literature Reports
1.

2.
3.

4.
5.
6.

Linezolid- resistant Enterococci: report of the f...
LEADER Surveillance Program
• 2011
– Susceptibility rate at 99.8%

• 2010
– Susceptibility rate at 99.6%
– 12 Enterococci ...
Treatment course in SK
• 09/05: Linezolid, Metronidazole, Aztreonam were
discontinued
• Daptomycin 500 mg IV daily was sta...
Role of Daptomycin in
Enterococcal infections
• Active against > 98% of Enterococci tested
• Data from randomized controll...
Susceptibility of Enterococci to antibiotic agents in multicenter, comparative studies worldwide
Daptomycin in Infective Endocarditis
• Case reports of Daptomycin for IE caused by
Enterococcus have yielded various outco...
Case Reports of Endocarditis due to VancomycinResistant Enterococci Treated with Daptomycin
AGE/ SEX

UNDERLYING
CONDITION...
Treatment Progression
• Pharmacist intervention:
– Daptomycin dose adjustment: 500 mg IV q 48 h
– Emtricitabine 200 mg PO ...
Conclusion
• Treatment options for VRE endocarditis are
limited
• Individual case reports of Linezolid resistant
Enterococ...
References
•

•

•
•

•

Flamm R., Mendes R., Ross J., et al. Linezolid Surveillance Results for the United
States: LEADER...
References
•
•
•
•
•

•
•

Morales G., Picazo J., Baos E., et al. Resistance to Linezolid is Mediated by the cfr
gene in t...
Vancomycin- Resistant Enterococci Infective Endocarditis: Review of Linezolid and Daptomycin as treatment options.
Vancomycin- Resistant Enterococci Infective Endocarditis: Review of Linezolid and Daptomycin as treatment options.
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Vancomycin- Resistant Enterococci Infective Endocarditis: Review of Linezolid and Daptomycin as treatment options.

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  • Treated with Coumadin 3 mg x 4 monthscultures at HD center: Resistant Pseudomonas aeruginosa
  • Allergic to penicillin, important in treatment of endocarditis
  • Prezista, Norvir – PI, Emtriva, Vired- NRTI
  • Slightly hyponatremic, hypokalemic, choloride levels decreased Mac prophylaxis is needed when cd4 is < 50Prophylaxis should be administered to all HIV-infected patients with a CD4 count of <200 cells/µL or a history of oral thrush. PCP prophylaxis may be indicated for patients with CD4 counts of >200 cells/µL in the presence of a CD4 percentage <14%, or a history of an AIDS-defining illness.
  • Mac prophylaxis is needed when cd4 is < 50Prophylaxis should be administered to all HIV-infected patients with a CD4 count of <200 cells/µL or a history of oral thrush. PCP prophylaxis may be indicated for patients with CD4 counts of >200 cells/µL in the presence of a CD4 percentage <14%, or a history of an AIDS-defining illness.
  • Duke criteria is used for diagnosis of endocarditis. To have a definite diagnosis of endocordities either pathological or clinical criteria have to be met. Pathological: histological examination of vegetation showed endocarditis. Clinical: 2 major criteria or 1 major+ 3 minor, or 5 minor criteria * Exclude single positive cultures for coagulase-negative staphylococci and organism that do not cause endocarditis.
  • SK MIC for vancomycin was 32. Two main subtypes of Enterococcispp are E. faecium and E. faecalis. E. faecium is usually more resistant and lead to poor outcomes, where E. faeclis respond to treatment better.
  • Linezolid therapy resulted in the cure of 77% of 22 course of therapy in patient with VRE. Synercid therapy was effective in 4 out of 9 patients with endocarditis caused by VRECure with antimicrobial therapy alone is < 50 %
  • Monitoring Linezolid: thrombocytopeniaQuinupristin- dalfopristin: severe myalgias
  • Oxazolidinone class is the first new class of anitibacterail agents that have been introduced since 1980
  • Linezolid,daptomycin and tigecycline were the most active agents tested against enterococci with susceptibility rates at 99.9, 99.4, 99.6 % respectively. 4 were in NYC, 1 in Rochester
  • Susceptibility studies have shown, active again > 98 enterococci tested irrepsectively of their susceptibility to other agents. Lack of cross-resistance reflects that daptomycin has a mode of action distinct from those of other antibiotics.
  • 2002-08 USA > 99.9% of 4496 E. faecalis and > 99.5% of 2875 E. faecium isolates were susceptible to daptomycin, with MIC 1 and 4 respectively. These results were confirmed by European surveillance carried out between 2005-2007 that included 3385 strains of enterococci, which showed a daptomycin susceptibility rate of 100%, with the MIC to E. faecalis and E.faecium being 1 and 2 respectively.
  • Various outcomes included death.
  • Vancomycin- Resistant Enterococci Infective Endocarditis: Review of Linezolid and Daptomycin as treatment options.

    1. 1. Vancomycin- Resistant Enterococci Infective Endocarditis: Treatment Options Hanna Yudchyts Pharm.D. 09/25/2013
    2. 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. 3. Patient Case
    4. 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. 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. 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. 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. 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. 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. 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. 11. Infective Endocarditis
    12. 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. 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
    14. 14. 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
    15. 15. 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
    16. 16. 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
    17. 17. 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
    18. 18. 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
    19. 19. 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
    20. 20. 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.
    21. 21. 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
    22. 22. 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
    23. 23. Susceptibility of Enterococci to antibiotic agents in multicenter, comparative studies worldwide
    24. 24. 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.
    25. 25. 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
    26. 26. 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
    27. 27. 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
    28. 28. 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.
    29. 29. 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.

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