Invasive Staphylococcal Infections Henry F. Chambers, M.D. - - PDF document

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Invasive Staphylococcal Infections Henry F. Chambers, M.D. - - PDF document

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Invasive Staphylococcal Infections Henry F. Chambers, M.D. Professor of Medicine, UCSF San Francisco General Hospital Disclosures AstraZeneca advisory board Cubist research grant, advisory panel Genentech advisory board

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SLIDE 1

Invasive Staphylococcal Infections

Henry F. Chambers, M.D.

Professor of Medicine, UCSF San Francisco General Hospital

Disclosures

  • AstraZeneca – advisory board
  • Cubist – research grant, advisory panel
  • Genentech – advisory board
  • Merck – stock
  • Theravance – advisory board
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SLIDE 2

Case 1

  • 45 year old man with cirrhosis due to alcohol

presents with one week of fever, malaise, diffuse arthralgias and shortness of breath

  • T=39.1 C, P=128, BP=115/65, RR=20
  • New 3/6 holosystolic murmur at the Lt. sternal

border, radiating to axilla

  • TTE: 1 x 1.5 cm mitral valve vegetation
  • 2 of 2 blood cultures growing latex-

agglutination test coagulase positive but tube coagulase negative staphylococci

Which one of the following organism is most likely causing endocarditis in this patient?

  • 1. Micrococcus luteus
  • 2. Staphylococcus aureus
  • 3. Staphylococcus epidermidis
  • 4. Staphylococcus lugdunensis
  • 5. None of the above, the blood cultures are

contaminated

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SLIDE 3

Staphylococcus lugdunensis

  • Coagulase negative….

– The tube “free” coagulase test is negative – The latex “bound” coagulase (i.e., clumping factor) test may be falsely positive and confuse physicians

  • Spectrum of disease: virulent, aggressive, similar

to S. aureus.

– Bacteremia, NV and PV endocarditis – Bone and joint infection – Pacemaker, other device-related infections

  • Susceptible to many antibiotics (only rarely mecA

positive)

Coagulase-negative staphylococci

  • Commensals, not invasive, rarely disseminate,

relatively benign clinical course

  • Spectrum of disease

– Vascular catheter-associated bacteremia – Prosthetic device (joint, valve), pacemaker, device-related infections – Neonatal sepsis – Peritoneal dialysis catheter infections

  • Virulence factors: biofilm formation
  • Multiple drug resistant (reservoir for S. aureus)
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SLIDE 4

Coagulase-negative staphylococci

  • Therapy is NOT required if:

– Positive intravascular catheter tip culture without signs of infection – Positive intravenous catheter culture with negative peripheral cultures

  • Catheter salvage may be an option
  • Removal of prosthetic device generally

required for cure

CoNS Prosthetic Valve Endocarditis

  • Prosthetic valve

– TEE to assess valve ring abscess; abscess is an indication for surgery – MS CoNS: Nafcillin 2 gm q4h x 6 wks + Rifampin 300 mg q8h x 6 wks + Gentamicin 1 mg/kg q8h x 2 wks – MR CoNS: Vancomycin 30-60 mg/kg 3 divided dose instead of Nafcillin

  • Endocarditis with implantable cardiac devices

– Device removal associated with improved 1-year survival, especially if valve is also infected – Therapy as above

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SLIDE 5

Case 2 Catheter-Associated Bacteremia

38 y/o man, new CHF, alcoholic cardiomyopathy, Hct = 13. He is transfused and on hospital day 3 an upper + lower endoscopy performed. Post- procedure T = 38oC. The site of the previous IV, d/ c’d post-procedure is tender and red. Two peripheral blood cultures are drawn. The next day he is afebrile and 1 blood culture is growing GPC in

  • clusters. Cultures are repeated and vancomycin is
  • administered. The following day the organism is

identified as MSSA and repeat blood cultures show no growth to date.

Case 2: Catheter-Associated Bacteremia

Which of the following has been shown to improve

  • utcome of S. aureus bacteremia?
  • 1. Treatment with daptomycin instead of

vancomycin for MRSA.

  • 2. Echocardiography to rule out endocarditis.
  • 3. Infectious diseases consultation.
  • 4. Gentamicin combination therapy instead of

single drug therapy with vancomcyin or nafcillin.

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SLIDE 6

Get an Infectious Disease Consult!!

  • Amer J Med 123:631, 2010
  • J Infect 59:232, 2009
  • Emerg Infect Dis 18:1072, 2012
  • Infect Dis Clin Pract 20:261, 2012
  • Clin Infect Dis 46:1000, 2008
  • Clin Microbiol Infect 16:1783, 2010

Case 2 Catheter-Associated Bacteremia

You would

  • 1. Continue vancomycin pending blood culture

results, d/c if those are negative.

  • 2. Switch from vancomycin to cefazolin pending

blood culture results, d/c if those are negative.

  • 3. Continue vancomycin pending blood culture

results, plan to treat for at least 14 days if those are negative.

  • 4. Switch from vancomycin to cefazolin pending

blood culture results, plan to treat for at least 14 days.

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SLIDE 7

Predictors of Complicated Staphylococcus aureus Bacteremia

  • Community-onset
  • Septic shock
  • Persistent or secondary focus of infection
  • Prolonged bacteremia on therapy (>48-72h)
  • Fever > 3 days on therapy
  • Elderly patient (age > 60 years)
  • MRSA
  • Use of vancomycin instead of a β-lactam
  • Duration of treatment < 10-14 days

Nafcillin vs. Other β-lactmas for MSSA

  • Cefazolin similarly efficacious and better tolerated

than nafcillin/oxacillin

– Antimicrob Agents Chemother 55:5122, 2011 – Clinical Infectious Diseases 59:369, 2014 – Antimicrob Agents Chemother 58:5117, 2014 – Clin Microbiol Infect 17:1581, 2011

  • Ceftriaxone, other β-lactams may be less

efficacious

– Clin Microbiol Infect 17:1581, 2011 – Int J Antmicrob Agents 44:235, 2014

– (But see Int J Clin Pharm 36:1282, 2014)

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SLIDE 8

Duration of Therapy:

  • S. aureus Bacteremia

Duration Indications

14 days

  • Fever resolves by day 3
  • Sterile blood culture after 2-3 days
  • Easily removed focus of infection
  • No metastatic infection (e.g., osteo)
  • Negative echo, no evidence of endocarditis
  • No predisposing valvular abnormalities
  • No implanted prosthetic devices
  • (No DM, immunosuppression)

4-6 weeks

  • Failure to meet one or more of above criteria
  • Osteomyelitis, endocarditis, epidural

abscess, septic arthritis (3 wk), pneumonia (3-4 wk), complicated UTI

Clin Infect Dis 49:1, 2009; Clin Infect Dis 52:285, 2011

Case 1: Catheter-Associated Bacteremia

You would

  • 1. Continue vancomycin pending blood culture

results, d/c if those are negative.

  • 2. Switch from vancomycin to cefazolin pending

blood culture results, d/c if those are negative.

  • 3. Continue vancomycin pending blood culture

results, plan to treat for at least 14 days if those are negative.

  • 4. Switch from vancomycin to cefazolin pending

blood culture results, plan to treat for at least 14 days.

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SLIDE 9

Case 1: Catheter-Associated Bacteremia And if those blood cultures turn positive…

– Obtain an ECHO – Search for secondary or metastatic focus – Treat for a minimum of 4-6 weeks

What about Echocardiography?

  • Consider obtaining TTE is all cases of
  • S. aureus bacteremia and especially for

the following

– Positive blood cultures for 3 or more days – Intracardiac device (pacer, valve) – Secondary/metastatic focus of infection – Relapse or recurrence – Suspected endocarditis on other grounds – Some say community-onset, HD, h/o IVDU but data less convincing

Circulation.132:1435-86, 2015.

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SLIDE 10

The Facts about Echocardiography?

  • TEE is more sensitive than TTE
  • TEE can visualize smaller vegetations: 5 mm
  • TEE is better than TTE for prosthetic valve

endocarditis

  • Few data that it improves outcome
  • Compliance is poor

– 379 ECHOS in 877 SAB cases (43%) in one Michigan hospital*

*Medicine 92:182, 2013; Lancet Infect Dis 11:208, 2001

Case 3

  • 66 yo M with 4 days prior to admission
  • Admission exam (day 1)

– VS: T 39.5C, HR 128, BP 110/60, RR 22 – 3/6 systolic murmur L sternal border – Vasculitic lesions

  • Labs

– Admission blood cultures: MRSA, vancomycin MIC = 2 µg/ml – 2/2 blood cultures from day 3: Gram-positive cocci in clusters – Creatinine 1.2 mg/dl on admission, now 1.8 – Vancomycin trough: 17.5 µg/ml

  • Hospital course (day 4)

– On vancomycin + gentamicin (low dose)

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SLIDE 11

Case 3

You are asked to see the patient for treatment

  • recommendations. You would
  • 1. Continue vancomycin + gentamicin
  • 2. Continue vancomycin + gentamicin and add rifampin
  • 3. D/c gentamicin, continue vancomycin
  • 4. Switch to daptomycin
  • 5. Switch to ceftaroline

FDA Approved Agents for MRSA Infections Other than ABSSSI

Agent Dose Indications

Daptomycin IV 6 mg/kg q24h Bacteremia, R-sided endocarditis* Linezolid PO/IV 600 mg q12h MRSA pneumonia (Also a 1st Line agent) Vancomycin 15-20 mg/kg q8-12h Serious MRSA Infections Telavancin IV 10 mg/kg q24h HAP/VAP *DO NOT USE DAPTOMYCIN FOR PRIMARY PNEUMONIA!

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SLIDE 12

First Line Choices for MRSA Bacteramia

  • Vancomycin
  • Daptomycin

See, Holland et al: JAMA 312:1330, 2014

Recommended Vancomycin Dosing

  • For serious infections (pneumonia, bacteremia)

– 15-20 mg/kg IV q8-12h (loading dose of 25-30 mg/kg) – Target trough concentrations of 15-20 µg/ml; target AUC24/MIC = 400 (or > 211?*) – Adjust for renal function, actual body weight

  • For less serious infections (SSTI):

– 15 mg/kg q12h (1 gm q12h) – Routine measurement of trough not necessary

Clin Infect Dis 52:285, 2011, *Antimicrob Agents Chemother 56:634, 2012

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SLIDE 13

Vancomycin Target Attainment

AUC/MIC = 400 vs AUC/MIC = 200

Patel, Clin Infect Dis 52:969, 2011 0" 20" 40" 60" 80" 100" 120" 0.25" 0.5" 1" 2" 4" 200"@"15"q12h" 200"@"30"q12h" 400"@"15"q12h" 400"@"30"q12h"

**"Clinical,""""" micro"" response" §"Mortality,"" bacteremia" and"endocardiBs"

** Moise-Broader, Clin Pharmacokinet 43:925, 2004 (LRTI) § Brown, Antimicrob Agents Chemother 56:634, 2012 (Bacteremia)

Vancomycin MICs by Method

Hsu, Int J Antimicro Agent 32:378, 2008

*

* MIC 4-8 µg/ml = VISA, MIC > 16 µg/ml = VRSA

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SLIDE 14

MIC Method Matters

  • 182 patient cohort with S. aureus bacteremia

– End-point: 30d all-cause mortality – Troughs, media µg/ml (IQR): 19.5 (15-24) – AUC/MIC calculated based on vanco dose

  • AUC/MIC, median (IQR)

– BMD: 436 (309-650) versus E-test: 272 (189-378)

  • AUC/MIC mortality breakpoint

– BMD: 373 versus E-test: 130

  • Other findings

– No difference for Etest MIC < 1.5 µg/ml vs > 1.5 µg/ml. – 90% of survival difference due to variables other than AUC/MIC

Holmes, Antimicrob Agents Chemother 57:1654, 2013

Duration of Staph. Aureus Bacteremia

SFGH Data

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SLIDE 15
  • Meta-analysis, 38 studies, 8291 episodes
  • MIC < 1.5 µg/mL (low) versus MIC > 1.5 µg/

mL (high)

  • Mortality low = 25.8%, high = 26.8%
  • Adjusted risk difference = 1.6% (-2.3 to

5.6%), p = 0.43

Kalil, JAMA 312:1552, 2014.

Management of Persistent MRSA Bacteremia on Vancomycin Therapy

  • Median time to clearance of MRSA bacteremia is 7-9 days
  • Persistent bacteremia around day 7 of therapy should

prompt assessment to determine if a change in therapy is indicated:

– Search for and remove other foci of infection (source control!) – Evaluate clinical response – Assess micro data (vanco MIC, results of f/u bld cx)

Day of vancomycin therapy

1 2 3 4 5 6 7 8 9 10 11 12 13 Consider change if: 1) Unsatisfactory clinical response, regardless of MIC

  • r

2) Vanco MIC = 2

No change if: 1) Clinically responding and 2) Vanco MIC < 2

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SLIDE 16

Case 4: Persistent Bacteremia

  • Mr. Q is a 53 year old diabetic. He was hospitalized four weeks ago for

hyperosmolar coma and was readmitted a week ago for fevers to 39oC. A CT scan showed findings consistent with a 4 cm psoas abscess. Three blood cultures were drawn and empirical therapy begun with vancomycin and piperacillin-tazobactam. All three blood cultures grew MRSA with a vancomycin MIC of 2 by microbroth dilution. TEE is

  • negative. Treatment was de-escalated to vancomycin alone with

documented trough concentration of 15 µg/ml. One of two blood cultures obtained on day 5 of therapy now is reported as positive for Gram-positive cocci in clusters. Which of the following is the most likely explanation for the persistently positive blood culture?

  • 1. Vancomycin resistance MRSA strain
  • 2. Treatment failure due to the MIC = 2
  • 3. Undrained psoas abscess
  • 4. Subtherapeutic levels of vancomycin
  • 5. Contamination of the blood culture with coag-neg staph

Case 5: Vancomycin Treatment Failure

  • 38 y/o woman, injection drug user with TCV endocarditis
  • Presented with pleural effusion (exudate, sterile), multiple

septic pulmonary emboli, 2/2 blood cultures positive for MRSA (vanco MIC < 0.5 µg/ml, dapto MIC < 1)

  • TTE: 2 x 2.4 cm TCV vegetation
  • Vancomycin 1.25 g q8h (troughs 15-23 µg/ml)
  • Blood cultures:

– Vanco day 2: 2/2 MRSA – Vanco day 3: 2/2 MRSA – Vanco day 4: 1/2 MRSA (MIC = 1) – Vanco day 5: 2/2 NG – Vanco day 9: 2/2 NG

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SLIDE 17

Case 5: Vancomycin Treatment Failure

  • Vanco days 11-18

– Afebrile – Slowly declining WBC, – Serum creatinine 1.53, GFR ~38 ml/min

  • Antibiotic day 18

– Vancomycin discontinued – Daptomycin 500 mg (10 mg/kg) q24 hours started

  • Day 19 (dapto day 2)

– Fever spike to 39C – 2 blood cultures drawn, eventually grow MRSA (vancomycin MIC=1, dapto MIC = 1)

Persistent S. aureus Bacteremia/Treatment Failure Risk Factors

  • Definitions vary: >3d or >5d or >7d
  • What factors are consistently identified as being

correlated?

– Endocarditis, endovascular source – Metastatic infection – Retained catheter or foreign body – Use of vancomycin instead of β-lactam for MSSA

  • Controversy over vancomycin MIC > 1 µg/ml (E-test)

Scand J Infect Dis 38:7, 2006; Arch Intern Med 167:1861, 2007; Diag Microbiol Infect Dis 67:228, 2010; J Antimicrob Chemother 65:1015, 2010; Clin Infect Dis 52:975, 2011

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SLIDE 18

What to do when vancomycin is not working?

  • 1. Source control!!!
  • 2. Get and ID consult
  • 3. Abandon vancomycin

– Do not add rifampin – Do not add gentamicin

  • 4. Switch to another agent(s)

– Which?

Daptomycin

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SLIDE 19

Daptomycin Endocarditis Trial

  • Non-inferior to comparator overall

– Cure rate MSSA: 44.6 v 48.6% – Cure rate MRSA: 44.4 v 31.8% – Duration of bacteremia: no difference v comparator

  • Microbiologic failure:

– 19/120 daptomycin vs. 11/115 comparator (9/53 vancomycin, 2/62 nafcillin)

  • Rising MICs

– 6/19 isolates from daptomycin failures (5 MRSA) (often mprF mutants) – 1/9 (4/9 if local results used) from vancomycin failures

Fowler, et al, NEJM 355:653, 2006

Do we have the right dose for daptomcyin?

  • Dose was chosen based on concerns for

toxicity, not guarantee of efficacy

  • Daptomycin has concentration dependent killing
  • Higher dose may provide protection against

emergence of resistance

  • IDSA guidelines committee recommends

that if daptomycin is used for treatment failure, it be used at a dose of 10 mg/kg/d

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SLIDE 20

Daptomycin MIC Distribution for Vancomycin Susceptible and Non-Susceptible Strains

Percent of Strains Daptomycin MIC, µg/ml

Data on file. Cubist Pharmaceuticals; Sader, Antimicrob Agents Chemother. 2006;50:2330.

Daptomycin Beta-Lactam Combination

  • Seven cases of relapse (n=2) and/or persistent

bacteremia (7-22d)

– 1 endocarditis, 1 cSSSI, 5 unknown

  • Prior regimens

– 7 vanco, 5 dapto, 5 dapto+gent

  • Dapto 8-10 mg/kg + Naf or Ox 12 g/day

– Negative BC @ 24-48h – 2 relapsed (1 death) – 3 rising dapto MIC (MIC > 1 in 2 cases)

Dhand, et al. Clin Infect Dis 53:158, 2011

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SLIDE 21

MprF Structure Ceftaroline

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SLIDE 22

Outcomes in S. aureus Bacteremia treated with Ceftaroline

Group Success Mortality

Endocarditis 23/33 (70%) 8/35 (23%) Pneumonia 21/29 (72%) 6/30 (20%) Micro evaluable 109/120 (91%) n/a Evaluable 101/129 (78%) n/a

Casapaso, et al. Antimicrob Agents Chenother, 2014

Duration of bacteremia: 6 days, 2.5 days after starting ceftaroline

Ceftaroline Salvage Therapy

MRSA Invasive Disease

  • 10 patients, case series, San Diego

– 5 endocarditis – 2 pneumonia (neg BC) – 3 bone and joint (1 bacteremia)

  • Duration of + BC pre-ceftaroline: 5-19
  • Vanco MICs (µg/ml): 0.5 (2); 1(4); 2 (4, 1 by E-test)
  • Dose 600 mg q8h
  • Time to BC clearance with ceftraoline: 2-7 days
  • Cures: 7/10 micro, 6/10 clinical

– Failures: AICD, PJI, pneumonia (comfort care)

Lin, et al, J Infect Chemother 19:42, 2013

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SLIDE 23

Ceftaroline Prospective Treatment Trial for S. aureus Bacteremia

  • Index blood culture positive within 24h (N=15)
  • Ceftaroline 600 mg q8h IV
  • MRSA 4/6 relapse-free success
  • MSSA 3/9 relapse-free success
  • Patient with +BC 3 h after first dose also failed
  • Time to clearance of bacteremia

– Median: 3 days – Range: 0 to 5 days

Fowler, et al. Abstract L-400, ICAAC 2014

Ceftaroline: Alone or in Combination for S. aureus bacteremia

  • 31 patients, 9 endocarditis
  • Days of +BC on ceftar: 3.4 (mean), 1-8 (range)
  • Ceftaroline alone (n=21)

– 8 failures

  • 3 toxicity (GI, rash)
  • 3 recurrence (catheter, endocarditis)
  • 2 deaths (osteo/epidural, pneumonia/comfort care)
  • Ceftaroline combos (n=10) (5 dapto/dapto+)

– 10 successes

Polenakovik & Pleiman. Int J Antimicrob Agents 42:450, 2013

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SLIDE 24
  • 26 patients, salvage regimens
  • Pre combo: 10 d median SAB (2-23 d)
  • Post combo: 2 d median SAB (1-6 d)

Clinical Therapeutics 36:1317, 2014

Telavancin

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SLIDE 25

Telavancin Salvage Therapy

MRSA Bactermia

  • 14 patients, case series

– 11 endocarditis: 2 R-sided, 7 L-sided, 2 MV PVE

  • Duration of + BC pre-telavancin: 4-31 d (median 13d)

– Duration of Vanco therapy: 3-26 days (n=14) – Duration of Telavnacin therapy: 3-17 (n=6)

  • Vanco MICs (µg/ml): 2
  • Dapto MICs(µg/ml): 0.125-1.5 (1 isolate >1 µg/ml)
  • Time to BC clearance with telavancin: 1-2 days
  • Discharged alive: 8 (57%)
  • Deaths: 6, all with L-sided endocaritis

Ruggero, et al, Infect Dis (Lond). 47(6):379, 2015

Treatment of Bacteremia and Other Serious Staph. aureus Infections

  • Source control is paramount
  • Prefer a β-lactam for MSSA infections
  • Vancomycin remains a drug of choice for MRSA but

has issues….

– High clinical and microbiological failure rate (25-50%) – Yet, no alternative agent(s) has been shown to be superior to vancomycin (they are non-inferior) – Switch to other agent(s) for treatment failure