Upload
others
View
5
Download
0
Embed Size (px)
Citation preview
©2016 MFMER | slide-1
Antimicrobial Salvage Therapies for the Treatment of Methicillin-Resistant Staphylococcus aureus Infective EndocarditisKristen Knoph, PharmDPGY2 Pharmacotherapy ResidentPharmacy Grand RoundsSeptember 27, 2016
©2016 MFMER | slide-2
Objectives• Describe the pathophysiology of methicillin-
resistant Staphylococcus aureus (MRSA) infective endocarditis (IE)
• Review current guideline recommendations for the treatment of MRSA IE
• Discuss current literature evaluating antimicrobial salvage therapies
• Examine limitations of current salvage therapy options when considering penetration through the blood brain barrier
©2016 MFMER | slide-3
Epidemiology
05
101520253035404550
S. aureus CoNS VGS Enterococcus HACEK
Etio
logy
(%)
Microbiology in Infective Endocarditis
WorldwideNorth America
Murdoch et al. Arch Int Med. 2009;169(5):463-73
31%
43%
11%17%
6% 2%12% 9%
13%
0.3%
S. aureus: Staphylococus aureusCoNS: Coagulase-negative staphylococciVGS: Viridans group streptococciHACEK: Haemophilus spp., Aggregatibacter spp., Cardiobacterium hominis, Eikenella corrodens, Kingella spp.
©2016 MFMER | slide-4
Pathophysiology
Available at: http://www.mayoclinic.org/diseases-conditions/endocarditis/multimedia/endocarditis/img-20006116
©2016 MFMER | slide-5
Question 1• What is the most common causative organism
of infective endocarditis? • S. aureus• Enterococcus• Viridans group streptococcus• HACEK
©2016 MFMER | slide-6
Patient Case• 48 year old female admitted to an outside
hospital with acute disorientation, dizziness, and weakness
• 50 lb unintentional weight loss over the last 5 months with malaise and lethargy
• Superficial abscesses on scalp, back, and coccyx
• Labs• WBC: 21.0 cells x 109/L• Temperature: 39.0 C
©2016 MFMER | slide-7
Patient Case• PMH
• Recurrent MRSA skin infections• T2DM, recently diagnosed
• SH• Family members with CA-MRSA skin
infections• Medications: Metformin 500 mg BID• Allergies: NKDA
CA-MRSA: community-acquired MRSA
©2016 MFMER | slide-8
Patient Case• 8/2 CT Abdomen
• Pyelonephritis and perinephric abscess• Nephrostomy tube and percutaneous pigtail
catheter placed• 8/2 Blood cultures
• Preliminary results: gram-positive cocci in clusters
• Empiric treatment with vancomycin and ertapenem
CT: computerized tomography
©2016 MFMER | slide-9
Patient Case• 8/3 TEE
• 1.1 x 0.9 cm mass on the mitral valve• 1.8 x 0.9 multilobulated mass attached to the
cordae on the left ventricle• 1.1 x 1.1 cm mass in left atrium
TEE: Transesophageal echocardiogram
©2016 MFMER | slide-10
Question 2• According to the American Heart Association
guidelines, what is an appropriate initial antibiotic for the treatment of MRSA native-valve infective endocarditis?
• Continue vancomycin • Continue vancomycin and add rifampin plus
gentamicin • Change to daptomycin 6 mg/kg/day• Change to ceftaroline
©2016 MFMER | slide-11
American Heart Association (AHA) Infective Endocarditis Guidelines
Baddour LM et al. Circulation. 2015 Oct 13;132(15):1435-86
©2016 MFMER | slide-12
AHA/IDSA Guidelines• Goals of treatment
• Eradicate infection• Sterilize vegetations
• Prolonged antibiotic therapy is required• Focal infection• High bacterial density• Slow rate of bacterial growth within biofilms
Baddour LM et al. Circulation. 2015 Oct 13;132(15):1435-86
©2016 MFMER | slide-13
AHA/IDSA Guidelines
Therapy for MRSA Native Valve Endocarditis (NVE)
Regimen Dose Duration Evidence
Vancomycin Trough 10-20 mcg/mL 6 weeks I-C
Daptomycin ≥ 8 mg/kg/day 6 weeks IIb-B
Baddour LM et al. Circulation. 2015 Oct 13;132(15):1435-86
I-C: Benefit outweighs risk and treatment should be performed, based on expert opinionIIb-B: Benefit may be greater than or equal to the risk and treatment may be considered, based on evaluation in limited populations
©2016 MFMER | slide-14
Microbiology Results
8/4 Peripheral Blood Culture and Sensitivity
Organism: Staphylococcus aureus
Oxacillin >2 R Ceftaroline 0.5 S Clindamycin <=0.5 S
TMP/SMX <=.5/9.5 S Vancomycin 2 S Linezolid <=2 S
Daptomycin 1 S Mupirocin <=256 S Rifampin <=0.5 S
S: susceptibleR: resistantI: intermediateN: not susceptible
©2016 MFMER | slide-15
Microbiology Results
8/10 Peripheral Blood Culture and Sensitivity
Organism: Staphylococcus aureus
Oxacillin >2 R Ceftaroline 0.5 S Clindamycin <=0.5 S
TMP/SMX <=.5/9.5 S Vancomycin 4 I Linezolid <=2 S
Daptomycin 4 N Mupirocin <=256 S Rifampin <=0.5 S
S: susceptibleR: resistantI: intermediateN: not susceptible
©2016 MFMER | slide-16
Question 3• Given the culture and sensitivity results, what
modification should be made to the patient’s antibiotic regimen?
• Continue daptomycin• Continue daptomycin and add ceftaroline• Change to linezolid• Change to ceftaroline
©2016 MFMER | slide-17
Antimicrobial Salvage Therapies for MRSA Infective Endocarditis
©2016 MFMER | slide-18
MRSA IE Treatment Challenges• No standard therapies exist for MRSA IE not
susceptible to vancomycin • hVISA: reduced susceptibility• VISA: intermediate resistance• VRSA: high-level resistance
Baddour LM et al. Circulation. 2015;132(15):1435-86Ghamrawi RJ et al. Cleve Clin J Med. 2015; 82(7):437-44
hVISA: Heterogeneous vancomycin-intermediate Staphylococcus aureusVISA: Vancomycin-intermediate Staphylococcus aureusVRSA: Vancomycin-resistant Staphylococcus aureus
©2016 MFMER | slide-19
MRSA IE Treatment Challenges• MRSA strains with reduced susceptibility to
vancomycin have reduced susceptibility to daptomycin
• Correlated with cell wall thickness
Cui L et al. Antimicrob Agents Chemother. 2006;50(3):1079-82
©2016 MFMER | slide-20
AHA/IDSA Guidelines
• Salvage therapies• Trimethoprim/sulfamethoxazole• Trimethoprim/sulfamethoxazole plus
daptomycin • Linezolid• Daptomycin plus β-lactam• Ceftaroline
Baddour LM et al. Circulation. 2015;132(15):1435-86
©2016 MFMER | slide-21
Use of Antistaphylococcal β-Lactams to Increase Daptomycin Activity in Eradicating Persistent Bacteremia Due to Methicillin-Resistant Staphylococcus aureus: Role of Enhanced Daptomycin BindingDhand et al. Clin Infect Dis. 2011 15;53(2):158-63
©2016 MFMER | slide-22
Study Design• Case series (n=7) of patients with persistent
MRSA bacteremia• DAP-ASBL after treatment with standard
therapy • Results: rapid clearance of bacteremia within 48
hours• Restoration of DAP susceptibility• Increases in DAP membrane binding• Reduction in membrane surface charge
Dhand et al. Clin Infect Dis. 2011 15;53(2):158-63DAP: daptomycinDAP-ASBL: daptomycin plus anti-staphylococcal β-lactam
©2016 MFMER | slide-23
Ceftaroline fosamil• Fifth generation cephalosporin
• High affinity for PBP 2A• FDA approved for SSTI and CAP
• Dose: 600 mg IV Q12H• Used off-label to treat severe MRSA infections
Ghamrawi RJ et al. Cleve Clin J Med. 2015; 82(7):437-44PBP: penicillin binding proteinSSTI: skin and soft tissue infectionsCAP: community-acquired pneumonia
©2016 MFMER | slide-24
In Vivo Efficacy of Ceftaroline (PPI-0903), a New Broad-Spectrum Cephalosporin, Compared with Linezolid and Vancomycin against Methicillin Resistant and Vancomycin-Intermediate Staphylococcus aureus in a Rabbit Endocarditis Model
Jacqueline C et al. Antimicrob Agents Chemother. 2007;51(9):3397-400
©2016 MFMER | slide-25
Study Design• Rabbit endocarditis model• Efficacy against methicillin-resistant and
vancomycin-intermediate S. aureus• Ceftaroline • Linezolid • Vancomycin• No treatment (control)
Jacqueline C et al. Antimicrob Agents Chemother. 2007;51(9):3397-400
©2016 MFMER | slide-26
Results
Jacqueline C et al. Antimicrob Agents Chemother. 2007;51(9):3397-400
MRSA hVISA
● Control♦ Linezolid■ Vancomycin▲ Ceftaroline
©2016 MFMER | slide-27
The Use of Ceftaroline Fosamil in Methicillin-Resistant Staphylococcus aureus Endocarditis and Deep-seated MRSA InfectionsLin et al. J Infect Chemother. 2013;19(1):42-9
©2016 MFMER | slide-28
Ceftaroline fosamil• Case series (n=10) of ceftaroline for MRSA
NVE and other MRSA infections after treatment failure with vancomycin
• Ceftaroline 600 mg IV Q8H
• 5 cases with MRSA NVE• 4 cases had clear blood cultures after 3-7
days• 3 cases had clinical cure
Lin et al. J Infect Chemother. 2013;19(1):42-9NVE: native valve endocarditis
©2016 MFMER | slide-29
Treatment Course
Daptomycin
Repeat TEE
First negative blood culture
8/158/6 8/11
Ceftaroline
©2016 MFMER | slide-30
Treatment Course
Ceftaroline
Daptomycin
Negative blood culture
CPK: 960 mcg/L
Transfer to Mayo Clinic,
blood cultures positive
8/17 8/228/19
CPK: creatine phosphokinase
©2016 MFMER | slide-31
Additional Testing• 8/19 MRI Brain
• Numerous septic emboli with ring-enhancing abscesses in the right parietal lobal and left centrum semiovale
©2016 MFMER | slide-32
Question 4What modification to the antibiotic regimen would be appropriate to improve penetration into the central nervous system?
• Continue ceftaroline • Add linezolid• Add rifampin• Add minocycline
©2016 MFMER | slide-33
Central Nervous System Penetration of Antimicrobial Agents for MRSA
©2016 MFMER | slide-34
CNS Penetration• Drug delivery to the CNS
• Molecular size• Lipophilicity• Plasma protein binding• Affinity of active transport mechanisms• Meningeal inflammation
Nau R et al. Clin Microbiol Rev. 2010;23(4):858-83CNS: central nervous system
©2016 MFMER | slide-35
IDSA Guidelines
Liu et al. Clin Infect Dis. 2011; 52(3):e18-55
MRSA brain abscess, subdural empyema, spinal epidural abscess
IV vancomycin for 4-6 weeks B-II
Some experts recommend the addition of rifampin 600 mg daily or 300-450 mg twice daily B-III
Alternatives:Linezolid 600 mg PO/IV twice daily and TMP-SMX 5 mg/kg/dose IV every 8-12H
B-IIC-III
B-II: Moderate evidence, based on results of non-randomized, controlled clinical trialsB-III: Moderate evidence, based on expert opinionC-III: Poor evidence, based on expert opinion
©2016 MFMER | slide-36
Ceftaroline CNS Penetration• Ceftaroline in a rabbit meningitis model against
E. coli and K. pneumoniae
Stucki et al. Antimicrob Angents Chemother. 2013; 57(12):5808-10
020406080
100120
Serum CSF
AU
C0-
8(m
g·h/
L)
Inflamed Meninges
020406080
100120
Serum CSF
AU
C0-
8(m
g·h/
L)
Non-Inflamed Meninges
Penetration (%)15.1 ± 9.7
Penetration (%)3.17 ± 1.29
CNS: central nervous systemCSF: cerebrospinal fluid
©2016 MFMER | slide-37
Antibiotic CSF penetration
AUCCSF/AUCS AcceptableCSF:MIC?
Uninflamedmeninges
Inflamed meninges
Vancomycin 0.14 0.3 Yes
Linezolid 0.9 Not available Yes
Rifampin 0.22 Not available Yes
Tetracycline (doxycycline) 0.2 0.2 Yes
Nau et al. Clin Microbiol Rev. 2010;23(4):858-83
AUC: area under the curveCSF: cerebrospinal fluidS: serumMIC: minimum inhibitory concentration
©2016 MFMER | slide-38
Treatment Course
Ceftaroline
MinocyclineLinezolid
8/30
8/30Discharge
8/20CPK: 960
mcg/L
8/22 8/278/19
8/26 WBC: 2.0 x109/L
Platelets: 140 x109/L
CPK: creatine phosphokinaseWBC: white blood cell
©2016 MFMER | slide-39
Patient Case Recommendations• MRSA NVE treatment
• Initial treatment with vancomycin• Daptomycin• Daptomycin plus ceftaroline• Ceftaroline
• Septic emboli to the brain• Initial treatment with linezolid• Minocycline
©2016 MFMER | slide-40
Conclusions• MRSA is a highly virulent organism and is
associated with high morbidity and mortality• Vancomycin is recommended as first line-
therapy for MRSA NVE• No standard therapies exist for MRSA IE not
susceptible to vancomycin • Treatment of septic emboli requires careful
consideration of antimicrobial CNS penetration
©2016 MFMER | slide-41
Questions & Discussion