Post on 21-Sep-2020
Thomas Holland, MD
Hilton Head, SC
July 2017
S. aureus Bacteremia:
What an internist needs to know. And
also maybe some things that are just
nice to know
• Consulting: The Medicines Company, Basilea Pharmaceutica
• Scientific Advisory Board: Motif Bio
• Adjudication committee: Achaogen
• Grant support: NIH, FDA
• Royalties: UpToDate
• Employment: Duke University
Disclosures
Patient GJ
• I am contacted via the transfer center re: a 63yo male with recent
transmetatarsal amputation for diabetic foot infection, now admitted
with fevers and found to have MRSA bacteremia. He has a pacemaker;
TTE does not show any vegetation. Despite appropriately dosed
vancomycin, blood cultures are persistently positive for the past 8
days. His foot looks okay. What should be done?
A) Switch vancomycin to daptomycin
B) Add ceftaroline
C) Transfer to a center where his cardiac device can be removed
D) Just wait longer
Patient GJ
• I am contacted via the transfer center re: a 63yo male with recent
transmetatarsal amputation for diabetic foot infection, now admitted
with fevers and found to have MRSA bacteremia. He has a pacemaker;
TTE does not show any vegetation. Despite appropriately dosed
vancomycin, blood cultures are persistently positive for the past 8
days. His foot looks okay. What should be done?
A) Switch vancomycin to daptomycin
B) Add ceftaroline
C) Transfer to a center where his cardiac device can be removed
D) Just wait longer
Outline
• S. aureus is different
• Changing epidemiology of S. aureus bacteremia
• Diagnostic workup – complicated vs uncomplicated infection
• TEE or no TEE
• Optimal treatment considerations
• Discuss the data behind the value of an ID consult
Outline
• S. aureus is different
• Changing epidemiology of S. aureus bacteremia
• Diagnostic workup – complicated vs uncomplicated infection
• TEE or no TEE
• Optimal treatment considerations
• Discuss the data behind the value of an ID consult
Not all bloodstream infections are the same
• A young woman presents with sepsis due to
pyelonephritis, and she has E. coli bacteremia. What is
the appropriate antibiotic approach?
A) Vancomycin + zosyn
B) Intravenous ceftriaxone until culture results are
available, then narrow to oral therapy
C) Prescribe one week of oral Cipro
D) Call an ID consult
Not all bloodstream infections are the same
• A young woman presents with sepsis due to
pyelonephritis, and she has E. coli bacteremia. What is
the appropriate antibiotic approach?
A) Vancomycin + zosyn
B) Intravenous ceftriaxone until culture results are
available, then narrow to oral therapy
C) Prescribe one week of oral Cipro
D) Call an ID consult
• But one week of oral antibiotics for S.
aureus bacteremia would absolutely,
unequivocally, no-doubt-about-it be the
wrong approach
• S. aureus bacteremia is different
Case fatality rates for SAB are high
Kaasch et al, J Infect. 2014 Mar;68(3):242-51
Outline
• S. aureus is different
• Changing epidemiology of S. aureus bacteremia
• Diagnostic workup – complicated vs uncomplicated infection
• TEE or no TEE
• Optimal treatment considerations
• Discuss the data behind the value of an ID consult
SAB epidemiology
• Annual incidence in the US is ~38-45 per 100,000
person-years1
• Rates are much higher in specific subpopulations – e.g.
hemodialysis
• Rates roughly stable over time, though proportion due to
MRSA is declining
1 Holland, Epidemiology of Staphylococcus aureus Bacteremia in Adults. UpToDate 2017
Copyright © 2014 American Medical
Association. All rights reserved. Kallen et al, JAMA. 2010;304(6):641-647.
MRSA bacteremia incidence is decreasing
Outline
• S. aureus is different
• Changing epidemiology of S. aureus bacteremia
• Diagnostic workup – complicated vs uncomplicated infection
• TEE or no TEE
• Optimal treatment considerations
• Discuss the data behind the value of an ID consult
The most important aspect of S. aureus bacteremia treatment is to make the right diagnosis
S. aureus Bacteremia
• Key Issue: Complicated or Uncomplicated?
Uncomplicated S. aureus Bacteremia
Uncomplicated MRSA Bacteremia
DEFINITION
• Exclude endocarditis with echocardiography
• Defervesce in 72h
• Follow-up blood culture negative
• No prosthetic material (pacer, valve, arthroplasty)
• No evidence of metastatic infection
TREATMENT: at least 2 weeks with vancomycin or daptomycin (6mg/kg IV) from date of negative cultures
Uncomplicated SAB is Uncommon
Screen: Enroll Rate
ABSSSI ~ 4 : 1
Skin & Skin Structure Infection Trials
Screen Enroll Rate
ASSURE Stryjewski
~2000 60 33 : 1
SABATO Kaasch
2100 75 28 : 1
NIH Algorithm Fowler
15,000 500 30 : 1
Blood Stream Infection Trials
If you think you have a case of
uncomplicated SAB….
You are probably
wrong
Complicated S. aureus Bacteremia
Fowler, et al. Arch Intern Med. 2003;163:2066-2072.
Complicated SAB is Complicated
n=89 n=54 n=41 n=22 n=18 n=17 n=13 n=12 n=16
12%
7.4%
5.7%
3% 2.5% 2.4%
2.2% 1.7% 2.4%
Pati
en
ts (
%)*
Infective endocarditis
Septic arthritis
Deep-tissue abscess
Vertebral osteomyelitis
Epidural abscess
Septic thrombophlebitis
Psoas abscess
Meningitis
Other complications
Identifying Complicated SAB: the physical exam
matters
• Helpful when Present
• Not Always Present
1 point
Community-acquired Skin examination suggesting acute systemic infection Persistent fever at 72 hours
2 points
Positive follow-up blood cultures at 48-96 hours Fowler, Arch Intern Med, 2003;163:2066-72.
15
30
40
70
80
90
0
20
40
60
80
100
0 1 2 3 4 5
Score
Pro
ba
bil
ity
, %
Identifying Complicated SAB Scoring Systems Matter
SAB + Arthroplasty = 28% Joint Infection
Murdoch et al Clin Infect Dis 2001; 32:647-9.
Tande et al Am J Med 2016; 221:e11-20.*
SAB + Prosthetic Valve = 51% Valve Infection El-Adhab Am J Med 2005; 118:225-9.
SAB + Pacemaker/ICD = 45% Device Infection Chamis Circulation 2001; 104: 1029
.
SAB + Central Line = 71% Thrombophlebitis Crowley Crit Care Med 2008;36:385-90
.
Identifying Complicated SAB: Clinical Context Matters
S. aureus Bacteremia + Prosthesis = Trouble
* All community-acquired/onset, 97% symptomatic
Lessons Learned: Clinical Identifiers of Complicated SAB
• Things to bank on:
All SAB is Complicated SAB until proven otherwise
• Things to always do:
Get follow-up blood cultures
Get an echo
• Things to look for:
Persistent bacteremia
Persistent fever
Community acquisition
Clinical evidence of complications
• Things to Fear:
Pain
Prostheses
Outline
• S. aureus is different
• Changing epidemiology of S. aureus bacteremia
• Diagnostic workup – complicated vs uncomplicated infection
• TEE or no TEE
• Optimal treatment considerations
• Discuss the data behind the value of an ID consult
Does everybody need a TEE? Maybe not.
• In our 2014 review, 9 studies looked at this
– All observational
– Variable rates of performing TEE – 12%-82% - and
who gets a TEE is not random
– More TEEs = more IE diagnoses
– Caveats
• do patients with IE detectable only by TEE have the same
natural history/outcomes?
• Echo technology is not static
• You may already be planning to treat for a long time
Holland, Arnold, and Fowler. JAMA 2014
Use of a Simple Criteria Set for Guiding Echocardiography in Nosocomial
S. aureus Bacteremia
- Europe - USA
- Prolonged bacteremia >4 days
- Intracardiac devices (PV, ICD, PCM)
- Hemodialysis dependence
- Spinal infection/nonvertebral osteomyelitis
Kaasch AJ, Fowler, VG, et al. Clin Infect Dis. 2011; 53:1–9
Relative frequency of infective endocarditis by number of positive criteria in
patients with nosocomial SAB
Kaasch AJ, Fowler, VG, et
al. Clin Infect Dis. 2011;
53:1–9
Use of a Simple Criteria Set for Guiding TEE in Nosocomial S. aureus
Bacteremia
Outline
• S. aureus is different
• Changing epidemiology of S. aureus bacteremia
• Diagnostic workup – complicated vs uncomplicated infection
• TEE or no TEE
• Optimal treatment considerations
• Discuss the data behind the value of an ID consult
Limited high quality trial data
Holland et al, JAMA 2014
Treatment Principle #1: Source Control
• The patient at the beginning of this talk had incurable
infection, unless his device was removed
• Find the abscess, the infected hardware, the joint that
needs to be washed out…. that is the most important
thing
Treatment Principle #2: Pick the right antibiotic
• For MSSA – always use a beta-lactam
• 79% lower mortality hazard with nafcillin or cefazolin,
compared to vancomycin
• Vancomycin is clearly an inferior drug for MSSA
bacteremia
BMC Infectious Diseases 2011;11:279
What if my patient is penicillin-allergic?
• Your patient probably is not penicillin allergic • <5% of reported penicillin allergies are confirmed when skin testing is
done
• Yeah, but what if my patient gives a good allergy story?
Blumenthal et al. Clin Infect Dis 2015;61(5):741-749.
Beta lactam is better
Blumenthal et al. Clin Infect Dis 2015;61(5):741-749.
If no history of anaphylaxis, cefazolin is
clearly better
Blumenthal et al. Clin Infect Dis 2015;61(5):741-749.
Nafcillin or cefazolin?
• Historically, nafcillin was the drug of choice
– More data
– Inoculum effect
– Narrower spectrum than cefazolin
• But….. it has downsides compared to cefazolin:
– More adverse drug events
– More $$$
– Less convenient dosing schedule
Cefazolin is probably better
• Retrospective cohort of 3,167 patients with MSSA bacteremia at
16 VAMCs
• Receipt of cefazolin associated with 37% lower 30d mortality
and 23% lower 90d mortality
• Conclusion: use cefazolin for MSSA bacteremia
– Caveats:
• Nafcillin for CNS infections
• Deep-seated infections?
• This is nonrandomized data
McDanel et al, Clin Infect Dis 2017
MRSA Bacteremia Treatment Options
• Vancomycin and daptomycin are the only two FDA-
approved agents for MRSAB
• Daptomycin is safe and probably more effective at
higher-than-approved doses
Fowler, NEJM 2006 – the only high-quality trial
data (so far)
• Open label RCT, N=246
• Dapto 6mg/kg/day vs standard therapy (vanc or beta-lactam, each with gent)
• Daptomycin non-inferior to vancomycin for SAB (success: daptomycin 53/120 [44%] vs vancomycin 48/115 [42%]; absolute difference 2.4; 95% CI -10.2-15.1)
• Right-sided endocarditis (success: daptomycin 41/90 [46%] vs vancomycin 37/91 [41%]; absolute difference 4.9; 95% CI -9.5-19.3)
• Success in only 3/18 patients (9 in each group) with L-sided IE
Fowler et al, NEJM 2006;355(7):653-65.
Limited data for other abx in bacteremia
• Linezolid – all data of low quality
• TMP/SMX – worse than vanc in small RCT in 1992, all failures in MSSA. Paul et al tried again and TMP/SMX did not meet noninferiority criteria
• Dalbavancin – adults with G+ CRBSI (only 14 MRSA)
• Telavancin – uncomplicated bacteremia “proof-of-concept” study: N=9 MRSAB
• Ceftaroline – retrospective report of 129 patients with SAB, 78.2% success rate reported
• Fosfomycin + imipenem as rescue therapy in complicated MRSAB or IE
• Dapto + ceftaroline
Markowitz, Annals of Int Med, 1992;117:390-398. Paul et al, BMJ 2015; 350:h2219. Goldberg, J Antimicrob Chemother 2010;65:1779-83. Raad, CID 2005;40:374-80. Stryjewski, BMC Infect Dis 2014;14:289 Del Rio, CID 2014 Sakoulas, Clin Ther 2014
Stepdown therapy?
• Once a patient is doing well, can you step down to oral
therapy? Or long-acting glycopeptide?
• I don’t know. If you are doing these things, you are in a
data-free zone
How else can we improve outcomes in
SAB?
Outline
• S. aureus is different
• Changing epidemiology of S. aureus bacteremia
• Diagnostic workup – complicated vs uncomplicated infection
• TEE or no TEE
• Optimal treatment considerations
• Discuss the data behind the value of an ID consult
Why do we need an ID consult when we have guidelines that spell out the recommended approach?
Do Guidelines for MRSA Matter?
• Multisite retrospective
comparison of 28-day all
cause mortality in 1675
patients with MRSA
bacteremia before and after
UK National MRSA
Treatment Guidelines
P = 0.73
Brindle et al J Antimicrob Chemotherap 2009; 64: 1111–3
Does Expertise Matter? ID Consultants Improve Outcome of S. aureus Bacteremia
Paulsen et al. Open Forum Infect Dis.2016;3(2):ofw048
What about telephone consultation?
• Forsblom Clin Infect Dis 2013; 56:527-35. in 342 Finnish patients with
MSSA bacteremia (all MRSA patients excluded…. N=5).
– 72% formal IDC, 18% phone, 10% no consultation
– Deep focus of infection identified in 78% formal, 53% phone, 29% no consult cases
– In regression analysis, factors independently associated with death were PNA, steroid
use, ICU care, no ID consult, and phone consultation (OR 2.31, 95% CI 1.22-4.38)
– From the accompanying editorial:
“Most ID clinicians lack sufficient time or motivation to provide comprehensive
advice when they receive an unsolicited call from another physician who intends
to manage a problem as complex as SAB without a formal bedside consultation.
Such calls are not rare even in tertiary care centers.”
Of course, consults to hospitalists are no different…
• Burden J Hosp Med 2013; (8)1:31-35. Prospective study of 47 patients who
received phone consultation followed by bedside consultation (by a different
hospitalist)
– 24/47 (51%) of curbside consults had inaccurate or incomplete information
– 28/47 (60%) had different advice after formal consultation
– Of the 24 with inaccurate/incomplete curbside info, 22 had different advice after formal
consultation
How does IDC help?
• Across these studies, patients with IDC are more likely to
have the following:
– removal of IV catheters
– obtaining follow-up blood cultures
– Get an echo
– using β-lactam for MSSA
– Drain abscesses and remove prosthetic material
– appropriate (longer) duration of therapy for complicated infection
Case resolution
• The patient is transferred to our facility. TEE shows multiple mobile
echodensities on PM lead, including a 1.4 x 0.7cm vegetation
adherent to the RV lead as it traverses the tricuspid valve.
• Foot is debrided, cuboid bone resected
• PM removed, residual vegetation on TV
• Requires temp PM for 2 weeks while TV IE is treated
• Treated with vancomycin for 6 weeks from date of device removal
(last source control procedure)
S aureus bacteremia treatment pearls
• Identify complicated infection
• Remove infected foci
• Treat for at least 2 weeks for uncomplicated infection, 4-6 weeks for
complicated infection
• Use beta lactams for MSSA – probably cefazolin for most patients
• Only vancomycin and daptomycin are FDA approved for MRSAB
• Where available, involve your ID consultant