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

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

• 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




• TEE or no TEE



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




• TEE or no TEE



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




• TEE or no TEE



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




• TEE or no TEE



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


If no history of anaphylaxis, cefazolin is

clearly better


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




• TEE or no TEE



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

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