what an internist needs to know. and also maybe some ... head sab talk.pdf · clinical identifiers...

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