S. aureus

The Skin Microbiome -
Clinical Laboratory Impact on
Hospital Acquired Infections Affecting
Patient Outcomes
ASM, New Orleans
May 22, 2011
Lance R. Peterson, MD
Director of Microbiology and
Infectious Disease Research
Epidemiologist, NorthShore University HealthSystem
Clinical Professor
University of Chicago, Chicago, IL USA

• Research Grants
Potential COI
– Bayer, Cepheid, NorthShore, GeneOhm, GSK, Johnson and
Johnson, Merck, MicroPhage, Nanogen, Nanosphere,
NIAID, Roche, 3M, Washington Square Health Foundation,
Wyeth (Pfizer), AHRQ
• Consultations (in conjunction with research projects
and new diagnostics)
– Cepheid, GeneOhm, GSK, MicroPhage, Nanogen,
Nanosphere, Roche, 3M, Wyeth (Pfizer)
• Industry support for this presentation
– None

Objectives
• Review the relevance of the skin Microbiome to
infections impacted by the clinical laboratory
• Discuss the application of MRSA surveillance
• Summarize the literature on pre-surgical testing
for S. aureus to lower surgical site infection

Skin Ecology
• Hairy, moist underarms lie a short distance
from smooth dry forearms
– “These two niches are as ecologically dissimilar as
rainforests are to deserts”
• Molecular approaches (as opposed to
traditional culture) have revealed a greater
diversity of skin microbiota within and
between distinct topographical regions
• Methicillin-resistant S. aureus acquired genes
that promote growth on skin from the symbiont
S. epidermidis
EA Grice et al. Science 324:1190-2, 2009
EA Grice et al. Nature Rev Microbiol: 9:244-253, 2011

Skin Ecology - Dominance
• Propionibacteria and Staphylococcus species
predominate in sebaceous sites
• Corynebacteria spp. predominate in moist
sites, although staphylococci also are present
• A mixed population of bacteria reside in dry
sites, with a greater prevalence of
β-Proteobacteria and Flavobacteriales
• Unique microenvironment of the anterior
nares consists of moist, epithelia contiguous
with noncornified nasal mucosa and drier
keratinized skin EA Grice et al. Science 324:1190-2, 2009
EA Grice et al. Nature Rev Microbiol: 9:244-253, 2011

Microbiome of the Nose
• Studied 5 healthy carriers and 42 hospital patients
– Culture-independent analysis of 16S rRNA
• Healthy nares had only two bacterial phyla
– Actinobacteria (i.e., High-G+C Gram positive organisms
such as corynebacteria - 68% of sequences)
– Firmicutes (i.e., Low-G+C Gram positive organisms such
as staphylococci - 27% of sequences)
– S. aureus found in the nares (of 2/5 individuals)
– Nares samples similar mostly to each other (p

Microbiome of the Nose
• S. aureus was most abundant in patients classified
as S. aureus-carriers by femA PCR
– Confirms the diagnostic utility of the femA PCR assay
used to classify patients with staphylococcal species
DN Frank et al. PLoS ONE 5(5):
e10598. doi:10.1371, 2010

What Does this Suggest for the
Clinical Laboratory?

Risk for S. aureus Infection
• Systematic review (10 studies) to estimate of
the risk of infection following colonization with
MRSA compared with colonization by MSSA
• Random effects model was used to obtain
pooled odds ratio estimates
• Overall, colonization by MRSA was
associated with a 4-fold increase in the risk of
infection (odds ratio 4.08, 95% confidence
interval, 2.10-7.44) N Safdar et al. Am J Med 121:310-15, 2008

Risk for S. aureus Infection
• Measured 1-year risk of MRSA infection
following detection of nasal colonization
– 4 hospitals over 4.5 years with 211,339 episodes
• 1-year risk of MRSA infection was 11.8% for
nasally colonized persons
• 1-year risk of MRSA infection was 0.7% for
non-colonized persons
D Ridgway et al. IDSA meeting, 2011
• Suggests 1-year risk of MSSA infection is
2.9% for nasally colonized persons

Review of Mupirocin
Decolonization
• Nasal carriage of S. aureus is a defined risk
factor for subsequent infection in patients
• 8 studies compared mupirocin with placebo
or with no treatment: Statistically significant
reduction in the rate of S. aureus infection
associated with intranasal mupirocin (RR
0.55, 95% CI = 0.43 to 0.70)
M van Rijen et al. Cochrane Database of Systematic Reviews 2008,
Issue 4. Art.No.:CD006216.

Critical Review of MRSA
Screening by Rapid Methods
• Review and meta-analysis of randomized, nonrandomized,
and observational studies
– Random-effect model was used
– Ten studies (nine interventional studies and one
unblinded, cluster-randomized, crossover trial) reviewed
• Between wards applying rapid screening tests and
those without screening, noted a significantly
decreased risk for MRSA bloodstream infections
• Overall, concluded that active screening for MRSA
is more important than the type of test used
E Tacconelli et al. Lancet Infect Dis 9: 546–54, 2009

CDC Surveillance (2005)
• Prospective study on MRSA risk
• Nearly 9,000 cases from 9 sites (ABC surveillance)
– 77% of HAI* were blood infections (2-fold rise in 6 years)
– 31.8 invasive infections/100,000 persons
– Nationally translates to 94,360 cases of invasive disease
– 18,650 annual US deaths (greater than HIV-AIDS)
• No longer well defined risk groups
• 85% healthcare associated
– “It is a major health problem primarily related to health care
but no longer confined to intensive care units . . ”
* HAI = Healthcare Associated Infection
- RM Klevens, JAMA 298:1763-71, 2007

Comparative Mortality of MSSA
and MRSA Bacteremia
• Meta-analysis of 31 reports from 1980-2000
– 3963 MSSA and 2603 MRSA cases
– Significant increase in mortality noted for MRSA
» OR 1.93; 95%
CI = 1.54-2.42,
p

US Infection Mortality 2005
FR DeLeo &
HF Chambers
JCI 119:2464, 2009

Do Colonized Patients Spread MRSA?
• Compared 58 patients with MRSA disease to
57 with nasal colonization to determine risk for
skin and environmental contamination
– Skin and environment contaminated 50 vs 47%
– Various skin sites 38-66% vs 30-63%
– Various environment sites 27-60% vs 21-63%
• Glove acquisition from skin 14-45% vs 16-38%
• “Strategies to limit transmission must address
colonized patients”
S Chang et al, CID 48: 1423-8, 2009

Percent Positive on Admission
25.0
20.0
15.0
10.0
5.0
0.0
MRSA Prevalence by Age
n=18,898
Disease risk* = 3.7%/year Disease risk = 8.2%/year; P=0.067
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
*Risk of invasive disease if MRSA colonized; N=993
A Robicsek et al, ICHE 30:623-32, 2009
Age
CMS Recipients

MRSA Screening Program
• Intervention: Admission MRSA screening and
isolation to assure new admissions we are doing
our best so they will not get MRSA from
NorthShore
– Start with >90% compliance
• Admission order set for PCTs and nursing
– Admission MRSA Screen
– Choice for response either yes or refused
• Treatment order package (nasal mupirocin twice
daily for 5 days with chlorhexidine bathing)
– Type in MRSA, and order MRSA Decolonization Panel
LR Peterson et al, Jt Com J Qual Pt Safety, 33:732-8, 2007

NorthShore MRSA Program
Began on August 1, 2005
• Observational study in a 3-hospital, 850-bed
organization with 40,000 annual admissions
comparing rates of MRSA clinical disease
during and 30 days after hospital admission
• Real-time PCR-based nasal surveillance for
MRSA followed by topical decolonization
therapy and contact isolation of patients who
tested positive for MRSA

Prevalence Density
(Cases/10,000 patient-days)
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
P = 0.15
Total MRSA Healthcare Infections
8/03 - 7/04 9/04 - 7/05 9/05 - 7/06 8/06 - 7/07 8/07 - 7/08 8/08 - 7/09
ICU surveillance Universal surveillance
P ≤ 0.001
Years
A Robicsek et al, Ann Int Med 148:409-18, 2008
70% reduction in
total MRSA disease
during hospitalization
and 30 days post-discharge
2 BSI in 3 hospitals
LR Peterson et al, Decennial Meeting on
Nosocomial Infections, Atlanta, 2010
Total

Includes all admissions (Community and Hospital onset)
Data generated solely by capturing
positive clinical cultures from LIS:
Chart review (n=1,194) of all positive
cultures found that 77.1% represented
actual infection
Universal surveillance begins
P

How Much Does MRSA HAI Cost?
No MRSA HAI
(n=5796)
LOS ≥8d
MRSA HAI
(n=178)
Mean Total
Cost
$50,013 $42,363,
$57,662
$73,795 $63,743,
$83,847
Excess $23,783 $16,771,
$30,794
95% CI Mean Profit/Loss 95% CI
-$25,000 -$28,883,
-$21,116
-$35,479 -$42,034,
-$28,923
-$10,479 -$16,110,
-$4,848
LR Peterson et al, Jt Com J Qual Pt Safety, 33:732-8, 2007

Medical and Economic Outcome
• Excess expense of MRSA infection
(compared to no infection) = $24,000
– Actual cost data from 178 cases/5,796 controls
• During first four years of NorthShore MRSA
containment program avoided 406 infections
– Net expense reduction = $8.8 million
– Number of deaths avoided = 72
LR Peterson, JCM 48:683-9, 2010
LR Peterson et al, Jt Comm J Qual Patient Saf 33:732-8, 2007
RM Klevens et al, JAMA 298:1763-71, 2007

Veterans Administration
Healthcare System (153 Hospitals)
• Reported 21-month results of all admission
screening for MRSA based on 1,312,840
admissions covering 8,318,675 patient days
• 45% reduction in MRSA disease in non-ICU
patients (P = 0.001) throughout the system
• 62% reduction in MRSA disease for ICU
patients (P < 0.001)
– 2 year baseline in ICU patients had no change in
disease
R Jain et al. NEJM 364:1419-30, 2011
• Testing primarily (92%) with rtPCR methods

Cluster Randomized Trial of ICU:
Demonstrated non-Utility of Culture
• Assessed VRE and MRSA surveillance plus
enhanced barrier precautions in the ICU
• 5,434 admissions to 10 intervention ICUs, and 3,705
to 8 control ICUs over 6 months
– Centralized, broth enriched culture used for testing
• Incidence of colonization or infection with MRSA or
VRE per 1000 patient-days at risk did not differ
significantly (P = 0.35)
• Mean (±SD) number of days from when surveillance
swab obtained until it was reported was 5.2±1.4
– 41% of patient days captured after reporting
WC Huskins et al. NEJM 364:1407-18, 2011

% of isolation days missed
50
45
40
35
30
25
20
15
10
5
0
Missed Isolation Day Percentage: Method Comparison
† = Failed Programs
* = Successful Program
†
Program † likely successful if capture
>80% of MRSA potential isolation days
*
*
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 84
Turnaround Time (hours)
Traditional or Chrom Agar
Enrichment + Chrom Agar
rtPCR
Ari Robicsek, ICAAC/IDSA 2008; A Robicsek et al, An Int Med, 48:409-18, 2008; D Jeyaratnam et al, BMJ ,
336;927-30, 2008; S Harbarth et al, Crit Care 10:R25, 2006; Ari Robicsek, ICAAC/IDSA 2008; K Hardy et al,
Clin Microbiol Infect 10.1111/j.1469-0691.2009; WA Bowler et al. ICHE 31:269-75, 2010; WC Huskins et al.
NEJM 364:1407-18, 2011
†
*
†
†

Changing Prevalence of
S. aureus in Surgery
• Percentage of S. aureus as a cause of
Surgical Site Infection in Coronary Artery
Bypass Grafting, Cholecystectomy,
Colectomy and Total Hip Arthroplasty rose
from 17% to 31% between 1992-2002
JA Jernigan, Maryland Patient Safety Center (NNIS), January 12, 2006

NorthShore Program for Detection of
Staphylococcus aureus Colonization:
Process Overview
• The patient is screened for S. aureus in the
nose 0-28 days prior to surgery
• If the test is positive, the physician will then
prescribe a 5-day course of mupirocin ointment
• The patient administers the nasal ointment
twice a day for the 5 days in the month prior to
surgery DM Hacek et al. Clin Orthop Relat Res 466:1349-55, 2008

Results of Preoperative Screening
for NorthShore Hip and Knee Surgery
Patients (n = 1,495)
• S. aureus SSI rate of decolonized S. aureus
carriers was reduced 3.8-fold (P≤0.05)
• Overall S. aureus infection rate in screened
versus unscreened group was 0.8% versus
1.7% DM Hacek et al, Clin Orthop Relat Res. 466:1349-55, 2008

Results of Preoperative Screening
for NorthShore Hip and Knee Surgery
Patients (n = 1,495)
• Mean readmission cost for 4 patients requiring
second hospitalization $17,122 (total=$68,500)
• 7 SSI from other pathogens (compared to 17 from
S. aureus)
– No change in rate from other bacteria over time
– All non-S. aureus considered superficial
– None required hospitalization
DM Hacek et al, Clin Orthop Relat Res. 466:1349-55, 2008

Prospective, Randomized Trial of
S. aureus decolonization
• Multicenter, prospective placebo controlled trial of
6,771 patients between 2005 and 2007
– Intervention was rtPCR screening with nasal
mupirocin/chlorhexidine bath for positive patients
• 808 positive patients had surgery
– 4 deep infections (0.9%) occurred in the treated group
– 16 infections (4.4%) occurred in the placebo group
» RR 0.21; 95% CI = 0.07-0.62
– LOS 1.8 days shorter in the treated group (p=0.04)
– Time to infection was shorter in the placebo group
(p=0.005) LGM Bode et al. NEJM 362: 9-17, 2010

Summary
• The nares is an essential site for
staphylococcal colonization
• Surveillance for S. aureus is helpful for
preventing infection in the pre-surgical setting
as well as for MRSA control
• The role of active surveillance is most
important when:
– Clinical disease is significant
– Colonization precedes clinical infection
– Clonal spread is important in disease escalation