Treatment of MRSA: IDSA Treatment Guidelines and Beyond - Vance G. Fowler, Jr., MD, MHS
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Treatment of MRSA:
IDSA Treatment Guidelines and Beyond
Vance G. Fowler, Jr., MD, MHS
Disclosures
Will discuss commercial products and/or
services
Will discuss off-label or investigative product
use
Disclosures
Nature of Relevant Financial
Commercial Interest
Relationship
Astellas, Cubist, Merck, Theravance, Cerexa, Pfizer,
Grant or research support Novartis, Advanced Liquid Logics, National
Institutes of Health
Astellas, Cubist, Inhibitex, Merck, Johnson &
Johnson, Leo Pharmaceuticals, NovaDigm, The
Paid consultant
Medicines Company, Baxter Pharmaceuticals,
Biosynexus, MedImmune, Galderma, Inimex
Speaker’s Bureau Cubist
Employment Duke University
Arpida, Astellas, Cubist, Inhibitex, Merck, Pfizer,
Honoraria Targanta, Theravance, Wyeth, Ortho-McNeil,
Novartis, Vertex Pharmaceuticals
Membership on advisory committees or Cubist – advisory committee
review panels, board membership,
etc.
Ownership Interest (e.g., stocks, stock NONE
options or other interests
Other relevant financial interests NONE
Approved Treatment Options 2012
Bacteremia: Vancomycin
Daptomycin
Pneumonia: Vancomycin
Linezolid
Soft Tissue Infection: Vancomycin
Linezolid
Daptomycin
Ceftaroline
Tigecycline
Telavancin
Do Guidelines for MRSA Matter?
Brindle et al J Antimicrob Chemotherap 2009; 64: 1111–3
Multisite retrospective
comparison of 28-day
all cause mortality in P = 0.73
1675 patients with
MRSA bacteremia
before and after
UK National MRSA
Treatment GuidelinesDoes Expertise Matter? ID Consultants Improve Outcome of S. aureus Bacteremia Fowler Clin Infect Dis 1998; 27(3):478-86. Prospective cohort of 244 patients Compliance with IDC associated with less Recurrent SAB (P
The Most Important Aspect of MRSA Treatment is to Make the Right Diagnosis
Points of this Talk Make the Right Diagnosis Bacteremia & Endocarditis Pneumonia Soft Tissue Infection
Points of this Talk Make the Right Diagnosis Bacteremia & Endocarditis Pneumonia Soft Tissue Infection
S. aureus Bacteremia Key Issue: Complicated or Uncomplicated?
Uncomplicated MRSA 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)
TAKE HOME PAY:
Uncomplicated MRSA Bacteremia
Not common
Not benign
If you think someone has it and treat
someone for it, be sure you are right.Complicated MRSA Bacteremia
Complicated SAB is Common
Frequency in 724 Duke
patients
43%
Fowler, et al. Arch Intern Med. 2003;163:2066-2072.Complicated SAB is Complicated
Infective endocarditis
Septic arthritis
12% Deep-tissue abscess
Vertebral osteomyelitis
Epidural abscess
Septic thrombophlebitis
Patients (%)*
7.4% Psoas abscess
Meningitis
5.7% Other complications
3%
2.5% 2.4% 2.4%
2.2% 1.7%
n=89 n=54 n=41 n=22 n=18 n=17 n=13 n=12 n=16
Fowler, et al. Arch Intern Med. 2003;163:2066-2072.Identifying Complicated S. aureus Infection
Identifying Complicated SAB
Scoring Systems Matter
100 90
80
Probability, %
80 70
60
40
40 30
20 15
0
0 1 2 3 4 5
Score
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.Identifying Complicated SAB
Clinical Context Matters
SAB + Median Sternotomy = Trouble
Blood culture Postoperative Postoperative LR+ (95%CI)
results Mediastinitis Mediastinitis
Present (n=98) Absent
(n=757)
S. aureus 46 14 25
(14.7-44.4)
Other 15 111 1.0
Pathogen (0.64-1.71)
No Growth 37 632 0.46
(0.36-0.58)
Fowler, Circulation 2003; 108: 73-78Identifying Complicated SAB
Devices Clinical Context Matters Matter
S. aureus Bacteremia + Prosthesis = Trouble
SAB + Arthroplasty = 28% Joint Infection
Murdoch et al Clin Infect Dis 2001; 32:647-9.
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 Catheter = 71% Thrombophlebitis
Crowley Crit Care Med 2008;36:385-90
.Identifying Complicated SAB:
How You Look Matters
Rate of IE Diagnosed by TEE
IE Diagnosed by TEE 30
25
20
15
10
5
0
Fowler (n=103) Rasmussen (n=244)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
Post-operative State
Things to Fear:
Pain
ProsthesesPoints of this Talk Make the Right Diagnosis Bacteremia & Endocarditis Pneumonia Soft Tissue Infection
TREATMENT
MRSA Bacteremia & Endocarditis
Uncomplicated MRSAB: Vanco or Dapto
“at least 2 weeks”
Complicated MRSAB: 4-6wks
Endocarditis: Vanco or Dapto x 6 wks
“Some experts recommend higher dosages of daptomycin at 8-
10mg/kg IV once daily”
“Addition of gentamicin to vancomycin is not recommended for
bacteremia or native valve endocarditis”
“Addition of rifampin to vancomycin is not recommended for
bacteremia or native valve endocarditis”MRSA Prosthetic Valve IE
Methicillin-Resistant:
- Vancomycin x 6-8wks
- Rifampin 900mg/d x 6-8wks
- Gent 3mg/kg daily x 2 wks
Baddour Circulation 2005;111:e394-e434.When? Who?
Valve Surgery: Randomized Trial?
Inclusion Criteria
1) Periannular Complications
2) New Onset Atrio-ventricular
Block
3) New Severe Valvular
Insufficiency
4) Early Onset Prosthetic IE
5) S. aureus IEEarly Surgery Improves Survival for Native Valve
IE
Lalani et al Circulation 2010; 121:1005-13Early Surgery Improves Survival in Propensity-
Matched Patients with Heart Failure
Keifer et al JAMA 2011; 306(20):2239-2247Linezolid for Persistent MRSA Bacteremia
Jang Clin Infect Dis 2009; 49:395-401.
Observational study comparing patients with PMRSAB
(>7d) salvaged with Linezolid or Vanco
Linezolid-treated patients had higher rates of:
- Early microbiological response: 75% vs. 17%; p=0.006
- LONGER duration of Bacteremia 26.4 + 38.8d vs. 11.8 + 3.9d
- Salvage Response: 88% vs. 0%; pTreatment: MRSA Osteomyelitis
Surgical debridement “whenever feasible”
Antibiotics: IV: vancomycin, daptomycin
PO: TMP-SMX + Rif
Linezolid
clindamycin
Optimal duration: Unknown but at least 8wksTreatment: Device-Related Osteoarticular Infection Early onset (
Vancomycin
Response: Increased Vancomycin
Dosing
Troughs of 15-20 mcg/mL for severe infections1
– Trough > 10 mcg/mL for all MRSA infections due to
association with hVISA
– 15-20 mcg/mL improved outcomes2
Loading dose of 25-30 mg/kg in severe infections
– Risk of overshooting target
Consider lower loading dose in older patients or those with
potential occult renal issues: consider 20-25 mg/kg
– Difficult in larger patients
1. Rybak M et al. Am J Health-Syst Pharm. 2009;66:82-98.
2. Kullar R et al. Clin Infect Dis. 2011;52:975-81.Higher Vancomycin Dosing and
Troughs May Cause Nephrotoxicity
Predictors of vancomycin nephrotoxicity
Characteristic Odds Ratio (95% CI) P value
Vancomycin serum trough > 14 3.18 (2.31-4.37) < 0.001
mg/L
Vancomycin therapy duration > 7 1.89 (1.39-2.56) < 0.001
days
Baseline Cr > 1.7 3.00 (2.16-4.18) < 0.001
Pritchard L et al. Am J Medicine 2010; 123: 1143-1149 38IDSA GUIDELINES POSITION: How should results of vancomycin susceptibility be used to guide therapy? “For isolates with a vancomycin MIC < 2ug/ml…, the patient’s clinical response should determine the continued use of vancomycin, independent of the MIC.”
Take Home Pay:
Vancomycin
New uses favor higher troughs, probably at
the expense of adverse events
Association between Vancomycin MIC of S.
aureus & Clinical Outcome is Present but
Complex
Remains standard treatment for MRSA IEPoints of this Talk Make the Right Diagnosis Bacteremia & Endocarditis Pneumonia Soft Tissue Infection
MRSA Pneumonia - Community Acquired - Healthcare-Associated
Community-acquired pneumonia
“For hospitalized patients with severe
community-acquired pneumonia defined
by any of the following: (1) a requirement
for intensive care unit (ICU) admission, (2)
necrotizing or cavitary infiltrates, or (3)
empyema, empirical therapy for MRSA is
recommended…”Healthcare-Associated MRSA
Pneumonia
“…IV Vancomycin (A-II) or linezolid 600mg
po BID (A-II) or clindamycin 600mg PO/IV
TID (B-III), if the strain is susceptible, is
recommended for 7-21 days, depending on
the extent of infection.”Linezolid: Pros and Cons
Pros Cons
– Excellent Oral – FDA Black box warning for
increased mortality concerns in
Bioavailability
catheter-BSI trial*
– Pneumonia – Myelosuppression – duration
dependent >2wks
– Novel mechanism
– Serotonin syndrome esp with SSRI,
– Resistance low MAO-inhibitors, ca
(will likely change – Optic neuritis
after 2015)
– Lactic acidosis
Stevens DL, et al. Expert Rev Anti Infect Ther. 2004;2(1):51-59
Aneziokoro CO, et al. J Chemother. 2005;17(6):643-650.
Rao N, et al. Diagn Microbiol Infect Dis. 2007;59(2):173-179.
Bernstein WB, et al. Ann Pharmacother. 2003;37(4):517-520.
Waldrep TW, et al. Pharmacotherapy. 2002;22(1):109-112.
*FDA. Available at: http://www.fda.gov/cder/drug/infopage/linezolid/default.htm.Linezolid & S. aureus Pneumonia Wunderink Chest 2003; 124(5):1789-97
Randomized, Double-Blind Controlled Multicenter trial of
Linezolid IV or Vanco for MRSA healthcare-associated or
hospital-acquired pneumonia
Non-inferiority with superiority (Efficacy)
Primary Endpoint: Clinical Cure at End of Study in evaluable
Per Protocol patients
Clinical Cure: -resolved signs/symptoms pneumonia
-stable/improved chest imaging
-no additional antibiotics
Per Protocol: all mITT patients meeting study criteria,
received adequate antibiotic therapy, and had outcome 1225 pts enrolled from 150 sites in 4 continents
Efficacy Outcomes
Outcomes: No Difference in Mortality in Linezolid vs. Vancomycin-Treated Patients
Safety Outcomes
CONCLUSIONS
Cure rates in PP and mITT patients with MRSA HAP
were higher in patients treated with LNZ vs. VAN
(58% v. 47%; p=0.42)
Significance lost in HCAP, HAP, & VAP subgroups*
Nephrotox higher in VAN (18.2%) vs. LNZ (8.4%)
No difference in mortality
MY TAKE: LNZ probably does have clinical
advantages for MRSA HAP, but not sure if it is worth
the cost (resistance, $)
GAME-CHANGER?: Patent Expiration 2015
*Torres Clin Infect Dis 2012;54(5):630–2Points of this Talk Make the Right Diagnosis Bacteremia & Endocarditis Pneumonia Soft Tissue Infection
Most CA-MRSA Infections
are Skin Infections
Fridkin et al NEJM 2005;352:1436-44Skin and Soft Tissue Infections
– Incision & Drainage
Essential and Sometimes Sufficient
– Antibiotics indicated for:
severe/multiple disease
multiple sites of infection,
rapid progression,
systemic illness;
comorbidity or immunosuppression,
face, hand, or genitalia,
associated phlebitis,
lack of response to I& DSkin and Soft Tissue Infections (2) Purulent Cellulitis: “…empirical therapy for CA-MRSA is recommended pending culture results. Empirical therapy for infection due to β-hemolytic streptococci is likely to be unnecessary (A-II). Five to 10 days of therapy is recommended but should be individualized…” Non-Purulent Cellulitis: “…empirical therapy for infection due to β-hemolytic streptococci is recommended (A-II). Empirical coverage for CA-MRSA is recommended in patients who do not respond to β-lactam therapy and may be considered in those with systemic toxicity.”
Summary: S. aureus Skin & Subcutaneous Abscesses Incision and Drainage most important Purulent cellulitis - Empirical therapy for CA-MRSA pending culture. - Empirical therapy for strep unnecessary. Non-Purulent cellulitis - Empirical therapy for strep recommended - MRSA role unknown Coverage of both strep + MRSA: - Clindamycin - TMP-SMX/Tetracycline + β-lactam - Linezolid
Skin and Soft Tissue Infections (3):
Empiric MRSA Coverage
Outpatients Inpatients
clindamycin Vancomycin (IV)
TMP-SMX Linezolid
daptomycin
Doxycycline/Minocycline
telavancin
Linezolid clindamycin
ceftaroline*Points of this Talk Make the Right Diagnosis Bacteremia & Endocarditis Pneumonia Soft Tissue Infection
Extra Slides
TMP-SMX-DS vs. CA-MRSA
PRO CON
Poor vs. S. pyogenes
CA-MRSA
susceptible Photosensitivity
Rash – Stevens-Johnson
Dose? K+ & creatinine
Aseptic meningitis
Cheap
G6PD deficiency - hemolysisReduced Efficacy of TMP-SMZ
1) Resistance: Altered target enzymes*
2) Exogenous thymidine from pus
DH folate*
reductase TMP
PABA folic acid folinic
= acid
SMX dihydro-
pteroate synthetase*
Pus: exogenous thymidine,
thymidine purine, DNA
Proctor Clin Infect Dis 2008; 46: 584-93.Doxycycline/Minocycline vs CA-MRSA
PRO CON
+/- vs. S. pyogenes
MostMRSA
susceptible Photosensitivity
Resistance on therapy
(Efflux pump)
BID
PediatricDoxycycline, but Not Minocycline,
Induces its Own Resistance in USA 300
tet(k) encodes drug-inducible efflux pump
conferring resistance to tetracycline & doxycycline
but not minocycline
Subinhibitory Doxy induced resistance to doxy but
not mino in tet(K) +/ tet(M) – USA300 MRSA
Schwartz Clin Infect Dis 2009; 48:1483–4.Clindamycin vs. CA-MRSA
PRO CON
80 % or more C. difficile
susceptible in vitro Inducible resistance due
Covers Strep. to MLSB
pyogenes (Macrolide/Lincosamide/
Inhibits toxin Streptogramin)
synthesisTelavancin
Once-daily glycopeptide
Activity against MRSA, VISA, VRSA
FDA-approved (2009) for Complicated Skin & Skin
Structure Infections
Side effects: Nephrotoxicity, Taste Disturbances, Avoid
In PregnancyD-zone test for Inducible Clindamycin
Resistance due to MLSB
E CC
-Perform on all erythro-R, clinda- S S. aureus isolates
-Treatment failures have occurred
- Found on same S. aureus gene as mec A; high % of
MRSA resistant to erythromycinCeftaroline: “Pros” and “Cons”
Pros Cons
Anti-MRSA Cephalosporin No Activity vs. Pseudomonas,
ESBL, Acinetobacter
Bactericidal vs. Gram Pos
(MRSA, VISA, S. pyogenes)
& Gram Neg bacteria
Twice daily dosing
Non-Inferior to comparator in
cSSSI & Pneumonia
Kanafani. Future Microbiol 2009; 4; 25-33.“Add-omycins” (Gentamicin, Rifampin)
Add Gentamicin?
In vitro synergy BUT
– No data that impacts mortality
– Associated with nephrotoxicity in daptomycin
study when combined with either ASP or
vancomycin
Median duration: 4 days
Clinically significant decrease in CrCl occurred in
8% of dapto-treated pts vs. 22% of comparator
patients
Korzeniowski & Sande. Ann Intern Med. 1982;97:496; Cosgrove SE et al. Clin Infect Dis. 2009;48:713-21.Add Gentamicin?
Low Dose, Short Course Gent for SAB is
Nephrotoxic
…we recommend
against the use of
initial low-dose
gentamicin in the
management of most
cases of S. aureus
bacteremia and
native valve
endocarditis …
Cosgrove Clin Infect Dis. 2009; 48: 713-721.Addition Rifampin?
No evidence for better outcomes
Significant evidence for ↑↑ resistance & ↑↑ side
effects
Rifampin No Rifampin P-Value
Emergence of Resistance* 21%* 0% < 0.001
Increased LFTs** 23% 2% 0.014
Drug Interactions*** 52% 0% < 0.001
* All had been started on rifampin before blood cultures had cleared
** All had concomitant HCV
Levine D et al. Ann Intern Med. 1991;115:674.
Riedel DJ et al. Antimicrob Agents Chemother. 2008;52:2463-7.Take Home Pay: Gentamicin / Rifampin for Native Valve Staph IE • No evidence for benefit • Significant evidence for ↑↑ resistance & ↑↑ side effects
Property Vancomycin Quinupristin Linezolid Daptomycin Tigecyclin Telavancin Ceftarolin
Generic / Pfizer Cubist e Theravanc e
dalfopristin Pfizer e/ Astellas Cerexa/
King Forest
Drug class Glycopeptide Streptogramin Oxazolidone Lipopeptide Glycylcyclin (Lipo)glyco- 5th gen.
First-in-class e peptide cephalospor
in
Mechanism Slowly Bacteriostatic Bacteriostatic Bactericidal Bacteriostat Bactericidal Bactericidal
of action bactericidal Cidal if MLS- ic (Multiple)
Resistance hVISA (?), Rare Rare 5%- SAB trial Rare Rare ?
VRSA, VISA Plasmid- Treatment-
Asstd, emergent
Treatment-
emergent
Cost ~ $15/day ~$300/d ~$150/d ~$130/d ~$200/d ~$150/d ?
Indication cSSSI cSSSI, VRE cSSSI cSSSI cSSSI cSSSI ABSSSI
HAP/CAP CAP HAP SAB / RIE Intra HAP CAP
Bacteremia abdom CAP
Osteomyelitis
Dosing IV BID Central IV BID IV IV, once daily IV, BID IV, Once IV BID
TID ORAL daily
Key issues Nephrotoxic Arthalgia SSRI Skeletal NICHE? NICHE? Safe
”Red man” Phlebitis Interaction Muscle Nausea
syndrome Central IV Myelosuppress Eosinophilic Not for
Poor clinical ion Pneumonia Bacteremia
effect Patent End Vanco-Dap Covers
2015 Resistance ESBLProperty Torezolid Delafloxacin Dalbavancin Oritavancin Ceftobiprole Amadacycline Iclaprim
Trius Rib-X Durata Medicines Co. J&J Novartis/Para Acino
tex
Development Phase III Phase II Phase III Phase III Approvable Phase II ?
stage Completed (SOLO I & II) letter Completed
?
Drug class 2nd Gen Fluoroquinolone 2nd gen Glycopeptide 4th gen. Tettacycline Diaminopyri-
Oxazolidone Glycopeptide cephalosporin midine
Mechanism of Bacteristatic Bactericidal Bactericidal Bactericidal Bactericidal Bactericidal Bactericidal
action
Spectrum Gram-Positive Gram + / G- G+ (No VRE) Gram-Positive G+/G- Gram + Rare
(no VRE) Pseudomonas
Indications ABSSSI ABSSSI ABSSSI ABSSSI ABSSSI ABSSSI ABSSSI
HAP CAP
Failed in VAP
Dosing PO, IV IV, BID IV, 2 Doses IV Single dose IV, TID PO/ IV IV, twice daily
Once Daily 1gm x 1; 500mg Once daily Oral in
x1 development
Key issues Once daily ? ? Safety Complicated Failed CSSSI
PO Safety Long Half Life syntheses FDA AB Board
Effective vs. Infusion Time May be
Linezolid- resubmitted
Resistant +/- 1 new trial
with new FDA
ABSSI
GuidanceFusidic Acid Resistance in S. aureus Causing Infections in Greek Children
Characteristics of 532 Patients with S. aureus Bacteremia (SAB) According to Antibiotic Treatment Received: A Prospective Cohort Study Performed in Australia Holmes NE et al. J Infect Dis. 2011;204:340–47.
Use of a Simple Criteria Set for Guiding
Echocardiography in Nosocomial S. aureus Bacteremia
Kaasch AJ, Fowler, VG, et al. Clin Infect Dis. 2011; 53:1–9
- Europe - USA
- Prolonged bacteremia >4 days
- Intracardiac devices (PV, ICD, PCM)
- Hemodialysis dependence
- Spinal infection/nonvertebral osteomyelitisRelative 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 Kaasch AJ, Fowler, VG, et al. Clin Infect Dis. 2011; 53:1–9
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