Vancomycin- Resistant Enterococci Infective

Endocarditis: Treatment Options

Hanna Yudchyts Pharm.D.09/25/2013

Objective

• Introduce patient case • Review treatment options for Vancomycin-

Resistant Enterococci (VRE) endocarditis• Analyze prevalence of Linezolid resistance• Discuss Daptomycin as a treatment option in

multidrug resistant endocarditis • Evaluate treatment of selected patient

Patient Case

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

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

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

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

127

3.3

88

26

23

9.4485 10.6

11.4

36479

Laboratory Findings on Admission

CD4: 215 cells/mcLViral load 276 copies/mL

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

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)

Infective Endocarditis

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

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

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

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

•Linezolid 600 mg q 12 h IV/PO

•Quinupristin- dalfopristin 22.5 mg/kg/day IV in 3 equally divided doses

Enterococcus faecium

•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

Enterococcus faecalis

Therapy for Native or Prosthetic Valve Enterococcal Endocarditis Caused by Strains Resistant to Penicillin, Aminoglycoside, and

Vancomycin

Treatment ≥ 8 weeks

KS Microbiology ResultsSource Blood Wound deep buttock

Organism Vancomycin-Resistant E. faecalis

Vancomycin-Resistant E. faecalisE. Coli (sparse amount)

Sensitivity Sensitive• Ampicillin• Chloramphenicol• Linezolid (MIC=2)

Resistant• Streptomycin• Gentamicin• Amikacin

LinezolidClass 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/mLI: 4 mcg/mLR: ≥ 8 mcg/mL

Linezolid Resistant Enterococci: Literature Reports

1. Linezolid- resistant Enterococci: report of the first isolates in the United Kingdom

2. Emergence of linezolid resistance in the vancomycin- resistant Enterococcus faecium multilocus sequence typing C1 epidemic lineage

3. Response to emerging infection leading to outbreak of linezolid- resistant enterococci

4. Antimicrobial Resistance to Linezolid5. Increasing incidence of linezolid- intermediate or resistant ,

vancomycin- resistant enterococcus faecium strains parallels increasing linezolid consumption

6. Linezolid- resistant, vancomycin resistant enterococcus faecium infection in patients without prior exposure to linezolid

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.

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

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

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 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.

Case Reports of Endocarditis due to Vancomycin- Resistant 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

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

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

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.

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 linezolid- intermediate

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.