Transcript Background

Resistant Organisms and Nosocomial
Infections: MRSA and CRBSI
Jim Pile, MD, FACP
Divisions of Hospital Medicine and
Infectious Diseases
CWRU/MetroHealth Medical Center
Disclosures
 Advisory Boards:
-- Baxter
-- Ortho-McNeil
-- Pfizer
What We'll Cover
 MRSA
- Epidemiology
- Clinical aspects
- Controversies surrounding vancomycin
- Alternative agents
 Catheter-related bloodstream infection (CRBSI)
- Diagnosis
- Prevention
- Treatment
A 35 Year Old Man . . . .
 Is admitted with a several day history of a "boil"
on his right upper arm. The area has become
increasingly tender, and "feels like it has pus in
it." He noted chills and subjective fever last
night, and states he has had 2 similar episodes
in the past 6 months. On exam, he has a T of
38.0º C, with BP of 138/84, HR 94. A 6 cm
abscess is present on the lateral aspect of his R
upper arm, with modest surrounding cellulitis.
Exam is o/w normal.
A 35 Year Old Man . . . .
He reports throat swelling with vancomycin, and
hives with sulfa drugs
 Does he need antibiotic therapy, or will drainage
suffice?
 If "yes," which antibiotic will you choose?
 Should he be cultured for MRSA colonization,
and if + should decolonization be attempted?
MRSA
 Arose from single clone
 Carry mecA gene, located on SCC
 5 types of SCCmec, which code for antibiotic
resistance
 Spread of SCCmec from MRSA to MSSA isolates
well-documented
 > 50% of Staph aureus isolates from U.S.
hospitals
The Emergence of CA-MRSA
Community-Associated MRSA
(CA-MRSA)
 Most U.S. isolates are SCCmec-IV
 Majority stem from single clone: USA300 strain
 Almost all have Panton-Valentine leukocidin
(PVL)
- Purulent SSTIs
- Necrotizing fasciitis
- Necrotizing pneumonia
Extent of the Problem: 8/04
 422 patients with acute,
purulent SSTIs
 Antibiotic
Sensitivities:
 MRSA in 59% (range, 1574%)
 TMP/SMX: 100%
 97% of MRSA USA300
 100/175 antibiotic
courses were 'wrong'
 Rifampin: 100%
 Clindamycin: 95%
 Tetracycline: 92%
 Quinolones: 60%
 Erythomycin: 6%
Moran, NEJM 2006;355:666
Moran et al, NEJM 2006;355:666
Changing Epidemiology of
Nosocomial MRSA Infection
 Harbor-UCLA study found
CA-MRSA made up
increasing proportion of
nosocomial MRSA infxs
 Stroger/Cook County: %
of nosocomial MRSA BSI
due to CA-MRSA rose
from 24% in 2000-03 to
49% in 2003-06
Maree, EID 2007;13:236
Popovich, CID 2008;46:787
Multi-Drug Resistant CA-MRSA:
More Bad News
 Retrospective study of
CA-MRSA from SF
hospitals, SF/Boston
clinics
 MDR CA-MRSA highly
associated with MSM
 Raises ? of epidemic of
difficult-to-treat CAMRSA
Diep, Ann Intern Med 2008;148:249
MRSA vs MSSA Bacteremia:
Does it Matter?
 2003 meta-analysis
suggested worse
outcome for MRSA
 Pooled hazard ratio of
1.93 for MRSA
 Appeared to hold up even
when co-morbidities and
severity of underlying
illness controlled for
Cosgrove, CID 2003;36:53
CA-MRSA vs CA-MSSA: Not
So Much?
 Single-center Taiwanese study examined
outcome in pts admitted with CA-MRSA vs CAMSSA bacteremia 2001-2006
 More SSTI and pneumonia in MRSA group, more
endovascular infection in MSSA
 30-day survival: 90% (MRSA) vs 87% (MSSA);
p=0.62
Wang, CID 2008;46:799
Does Our Patient Require
Antibiotic Therapy?
 Several studies have suggested that CA-MRSA
skin infections may not require abts after
adequate drainage (all small/flawed)
 492 patients, 531 episodes of CA-MRSA SSTIs
 41% received inactive antibiotics
 8.5% treatment failure: 5% with active abt, 13%
with inactive (OR 2.80, p=.001)
Ruhe, CID 2007;44:777
MRSA Colonization
 Colonization typically precedes infection
 Is eradication of colonization possible?
 Does eradication of colonized state prevent
infection?
 Mupirocin + chlorhexidine + rifampin +
doxycycline vs no treatment
-74% vs 32% MRSA-free at 3 months
-54% MRSA-free at 8 months
Simor, CID 2007;44:178
Should Decolonization be
Attempted in Our Patient?
 Criteria for attempting decolonization not well
defined
 Importance of CA-MRSA at extranasal sites
 If attempted:
-Consider multi-modality therapy
-Be cognizant of AEs
-Remember decay of results
Whither Vancomycin (Wither
Vancomycin)?
Vancomycin: A Short History
 Isolated in early 1950s,
from S. orientalis
 Early preparations
markedly impure
 Little used, due to
A. advent of antistaph Blactams
B. oto, nephrotoxicity
 Dosing/monitoring issues
Vancomycin Use, 1975-1996 (Levine,
CID 2006;42:S5)
Vancomycin: A Suboptimal
Agent for Staph aureus
 Recent case-control study of MSSA bacteremia:
mortality 37% with vanco, 11% with B-lactams (p<0.01)
 54 cases of MSSA bacteremic pneumonia treated with
vancomycin or cloxacillin: mortality 47% vs 0%
 123 ESRD pts with MSSA bacteremia treated with vanco
or cefazolin: 31% vs 13% failed treatment, OR 3.5
Kim, AAC 2008;52:192; Gonzalez CID 1999;29:1171; Stryjewski, CID
2007;44:190
Time-Kill Curves for MSSA (from
Stevens, CID 2006;42:S51)
Mounting Concerns Over
Vancomycin Effectiveness
 Growing sense that efficacy against MRSA may
be lessening
 Emergence of VISA, VRSA
--VISA: MIC 4-8 mcg/ml; VRSA: ≥ 16 mcg/ml
 Phenomenon of heteroresistance (hVISA) a
much bigger problem at present
--Heterogeneous population of MRSA, with a
sub-population unresponsive to vancomycin despite
reported sensitivity
MIC Uncertainties
 Based on mounting data, MRSA susceptibility
breakpoint for vanco changed from ≤ 4 mcg/ml
to ≤ 2 mcg/ml in 2006
 Many labs have difficulty with MRSA MICs
 ≤ 2 mcg/ml, however, still does not confirm true
susceptibility
 15% of strains with very low MIC by reliable
testing still vanco tolerant!
MRSA MIC vs Vancomycin
Failure Rate (Stevens, CID 2006;42:S51)
agr Polymorphism: Still More
Trouble?
 agr gene cluster
regulates a variety of key
virulence and metabolic
pathways
 Down-regulated function
appears to confer
tolerance to vancomycin;
MIC may still be very low
 Have low vanco levels in
past driven emergence?
Sakoulas, CID 2006;42:S40
MRSA Pneumonia Issues
 Evidence suggests that a vancomycin trough of
4-5X the MIC may be optimal for serious MRSA
infections
 Penetration of vancomycin into lung only 2030% of that achieved in serum
 It may be difficult to achieve adequate
concentrations of vancomycin in the lung,
particularly if the MIC of the organism is
relatively higher
Will High-dose Vancomycin
Overcome These Concerns?
 95 pts with nosocomial MRSA infections (low vs
high MIC: ie, ≤ 1 mcg/ml or > 1 mcg/ml)
 Study targeted aggressive vancomycin trough
levels
 Even with achievement of high trough levels,
outcome worse in high MIC group: 62% vs 85%
response (p=.02)
 Uncertain whether benefit associated with high
troughs
Hidayat, Arch Intern Med 2006;166:2138
"There is an antibiotic called mud
That's proving to be quite a dud.
Its provenance is jungle
Its use is a bungle
It just won't get rid of your crud"
-Stan Deresinski, MD
CID 2007;44:1543
Trimethoprim/Sulfa and MRSA
 1992 study of 101 IVDU pts
with serious Staph aureus
infxs: 86% cured with
TMP/SMX, 98% (!) with
vancomycin
 No failures in either group with
MRSA (47%). Authors
concluded vanco superior, but
TMP/SMX a valuable
alternative
Markowitz, Ann Int Med 1992;117390; Proctor, CID 2008;46:584
Tetracycline and Clindamycin
Treatment of MRSA
 Retrospective study of 24
pts with MRSA infxs
treated with long-acting
tetracyclines: 83% cured
 Review of world
literature: 85% of 85 pts
treated with TCNs
responded well
Ruhe, CID 2005;40:1429
 Clindamycin: most MRSA
strains remain sensitive
 Some data suggest
efficacy in children with
serious MRSA infx
 Very limited data in adults
Daptomycin
 Cyclic lipopeptide, rapidly bactericidal against
S. aureus
 2006 study of daptomycin vs standard therapy
for MRSA, MSSA bacteremia
-Daptomycin "not inferior" to standard treatment
 2004 cSSTI trial, dapto vs standard tx:
-83% vs 84% cure
 Daptomycin NOT appropriate for pneumonia
Fowler, NEJM 2006;355:653
Arbeit, CID 2004;38:1673
Linezolid vs Vancomycin in
Nosocomial Pneumonia
 RCT comparing linezolid + aztreonam to vanco
+ aztreonam for nosocomial pneumonia
--204 evaluable pts: clinical cure (66%
linezolid, 68% vanco), mortality equivalent
 Continuation study: 345 patients evaluable,
clinical efficacy/mortality again equivalent (cure
in 68% vs 65%; mortality 20% both arms)
Rubinstein, CID 2001;32:402; Wunderink, Clin Ther 2003:25:980
Wunderink, RG. Linezolid vs vancomycin:
analysis of 2 double-blind studies of patients
with MRSA nosocomial pneumonia. Chest
2003;124:1789
Other Existing Agents
 Quinupristin/Dalfopristin
 Tigecycline
In the Pipeline
 Dalbavancin
 Ceftobiprole
 Iclaprim
 Oritavancin
 Telavancin
Summary
 The epidemiology of MRSA continues to evolve,
with CA-MRSA moving into the hospital
 Most CA-MRSA strains remain sensitive to
multiple antibiotics--for the moment
 Vancomycin MAY still be the drug of choice for
serious MRSA infections, but leaves much to be
desired
 Multiple alternatives exist, with more coming
CRBSI: Diagnosis, Prevention
and Management
A 54 Year Old Woman with an
Entero-cutaneous Fistula . . . .
After colo-rectal surgery and receiving TPN via
a Hickman catheter presents with 2 days of
fever to 102° F and no other symptoms. Her T
on presentation is 38.8° C, her BP/HR are
essentially normal, and her catheter exit site
and tunnel are not inflamed. The remainder of
her physical exam is unrevealing.
A 54 y.o. with an ECF . . . .
 Should the catheter be removed on arrival?
 If not, how will you decide whether it is the
culprit?
 If you decide the catheter is infected, will the
offending pathogen influence your decision to
remove it?
 If the catheter is retained, how will you treat the
infection?
Scope of the Problem
 > 5 million catheter-related infxs in US annually
 ? 200K infections
 80K CRBSI in U.S. ICUs, estimated 28,000
deaths
 CRBSI cost estimates/episode $3K-$50K
 ? > $2 billion per year
Raad, Lancet ID 2007;7:645; Pronovost, NEJM 2006;355:2725
Pathogenesis of CRBSI
 Non-tunneled CVCs:
1. Extraluminal colonization
2. Colonization of hub and catheter lumen
3. Hematogenous seeding of catheter
 Tunneled CVCS:
-Hub contamination/intraluminal colonization
Diagnosis of CRBSI
 Frequently not straightforward
 Exit site inflammation: relatively specific, but
very insensitive
 Catheters frequently not the culprit in pts with
unexplained fever (and may not be source of
bacteremia)
 How can non-infected CVCs be distinguished?
Quantitative Blood Cultures
 Blood Cxs drawn simultaneously from CVC and
peripherally
 ≥ 5-fold higher colony count from CVC considered
diagnostic of CRBSI
 Non-tunneled CVCs: sensitivity 82%, specificity 89%
 Tunneled (long-term) CVCs: S/S 83%/97%
 Both expensive and laborious
Safdar, Ann Intern Med 2005;142:451
Differential Time to Positivity
 Blood cultures obtained simultaneously from CVC and
peripherally
 CVC culture reported + at least 2 hours before
peripheral considered diagnostic for CRBSI
 Sens/specif 89%/87% for short-term catheters; 90%/72%
for tunneled catheters
 Simple and widely available
 More cost-effective than quantitative techniques
Mermel CID 2001;32:1249; Safdar Ann Intern Med 2005;142:451
CRBSI Prevention: Antiseptic
Practice
 Hand hygiene
 HCW education
 Removal of unnecessary
catheters
 Regular surveillance of
catheter site
 Don't routinely replace
non-tunneled CVCs
 Maximum sterile barriers
 Use subclavian vein
when possible
 2% chlorhexidine skin
prep
MMWR 2002;51/RR-10
MHA Keystone ICU Project
 103 ICUs in Michigan, 375K CVC days
 Comprehensive unit-based education, daily
goals sheet, and VAP intervention as well
 Included 5 key measures: hand hygiene, full
sterile barriers, chlorhexidine use, avoidance of
femoral site, removing unnecessary CVCs
 Central line carts created, nurses empowered,
checklists used to increase compliance
Pronovost NEJM 2006;355:2725
Keystone ICU Study
 Significant reduction in
rate of CRBSI in quarter
of implementation
 Results sustained over
duration of study
 CRBSI fell from mean of
7.7 to 1.4 infections per
catheter day
"The structure of the intervention involved daily
commitment to a culture of safety . . . . We can
no longer accept the variations in safety culture,
behavior, or systems of practice that have
plagued medical care for decades. Imagine the
effect if all 6000 acute care hospitals in the US
were to show a similar commitment and
discipline."
-Richard Wenzel, MD
Antimicrobial Catheters
 Silver-impregnated
catheters
 Antiseptic catheters
 Antibiotic-coated catheter
 CDC: "consider" use of
impregnated catheter
when expected to be in
place > 5 days
CRBSI Management: Key
Questions
 1. Is the catheter truly the culprit?
 2. Does the catheter need to be removed?
 3. What type of antibiotic therapy?
 4. How long should the infection be treated?
Deciding When to Remove the
Catheter
 Tunneled vs non-tunneled CVC
 Hemodynamic instability
 Identity of pathogen
 Complicated infection
 Tunnel/port pocket infections
Antibiotic Lock Therapy
 Failure appears to frequently relate to inability
to kill organisms in luminal biofilm
 Antibiotic concentration may need to be 1001000X greater to kill bacteria in biofilm
 ALT: 2-5 cc of antibiotic solution instilled into
lumen(s) and "locked"
 83% cure rate vs 67% with conventional therapy
only
Mermel CID 2001;32:1249
Coagulase Negative Staph
 Leading cause of CRBSI in most series
 Up to 80% of catheters salvageable
 If catheter retained: 7 days systemic therapy, 1014 days lock therapy (ALT)
 Catheter removed: 5-7 days systemic therapy
 Weekly dalbavancin therapy promising
Mermel CID 2001;32:1249; Raad CID 2005;40:374
Staph aureus
 Strong association with metastatic infection
 23% of S. aureus CRBSI had endocarditis in 1
study
 Faster sx resolution/less relapse with CVC
removal
 Uncomplicated infxs with catheter retention: 14
days systemic + abt lock therapy
Fowler JACC 1997;30:1072; Mermel CID 2001;32:1249
Gram Negative Bacilli
 Recent study reported cure in 13/15 HD catheter
infxs (87%) with systemic + lock tx
 "Tough" pathogens (S. maltophilia, B. cepacia,
Acinetobacter, non-aeruginosa Pseudomonas)
appear less likely to respond
 Catheter removed: 7-14 days systemic abts
 Catheter retained: 14 days systemic + ALT tx
Poole, Nephrol Dial Transplant 2004;19:1237; Raad Lancet ID 2007;7:645;
Mermel CID 2001;32:1249
Candida spp
 Multiple prospective studies support worse
outcome with attempted CVC salvage
 70% failure rate even with systemic + lock tx
 IDSA guidelines suggest amphotericin B for
unstable patients
 Echinocandin for C. glabrata or krusei
 Treat for 2 weeks after last + BCx
Summary
 Decision to attempt CVC salvage should be
made case-by-case, but many can be saved
 Many (most?) S. aureus and virtually all Candida
infections mandate CVC removal
 Antibiotic lock therapy is promising, and
probably still underutilized
 Revised guidelines in progress!