Where Do We Stand On

Periprosthetic Joint Infection

• Professor of Orthopaedic Surgery
• Vice chairman for Research
• The Rothman Institute at Thomas
Jefferson University
• Interest:
• Regenerative Medicine
•Tissue engineering
•Outcome Research
•Design: Self Protective Smart Implants

• Enjoys Biking, Hiking, Travel, Reading

Javad Parvizi , MD, FRCS and Opera
• Contact: www.neareastspine.org
Where Do We Stand On Periprosthetic
Joint Infection

Javad Parvizi MD
Professor

Rothman Institute at Thomas Jefferson

University, Philadelphia

SPINE Meeting, Beirut June 24-26, 2010

 Conflict of Interest
 Research support:
• NIH
• OREF  Consultant for:
• DOD • Stryker Orthopaedics
• Aircast
• MTF
• Stryker Orthopaedics  Intellectual Property:
• Pfizer
• Smartech
• The Knee Society
• Kimberly Clark • Smith and Nephew
• Ortho McNeill • Stryker Orthopeadics
• Adolor • CyruMed
• Cubist
• 3M
• KCI
• Zimmer
• Biomet
 Periprosthetic Joint Infection

Prevention
Diagnosis
Treatment
 Recent Literature

There has been rise in the

incidence of PJI caused by
resistant organisms

Parvizi J, et al Instr Course Lecture 2008

 Periprosthetic Infection

Major reason for

failure of TKA
Berry et al CORR 2006
 Periprosthetic Infection

Second most
common reason
for failure of THA
Bozic et al AAHKS 2008
 Infection

Incidence 1-4% of primary

• May
loweroccur in up to 30%
limb arthroplasties
after revision arthroplasty
THA Infection: Medicare Data
TKA Infection: Medicare Data
 Infected Revisions: 1990-2003

6,000
Infected THA
5,000 Infected TKA
No. of Infected Revisions

4,000

3,000

2,000

1,000

0
1990 1992 1994 1996 1998 2000 2002 2004

Kurtz, S, Parvizi J JOA 2008

 Two Stage Exchange

 Success variable
 On decline
• Elderly
• Sick
• Immunocompromised
• Surgeon volume
 (rule of 80/20)
Deep Infection Rate

1 %
 Cost

$100,000 per
infected joint
Annual Cost

$800 Million
 But
MRSA MRSE
1999 15% 8%
Incidence of
29% 32%
MRSA and 2006

other resistant
organisms on 50

45

the rise 40

35
Sensitive Resistant

30
Percentage
25

20

15

Parvizi J, et al Instr Course Lect 2008 10

0
1999 2000 2001 2002 2003 2004 2005 2006
Media Rubbish
 Survey of 326 Staphylococcus
aureus clinical isolates
Genotyping, strain identification
 Isolates obtained from:
Extremely
virulent type
USA400 USA100
• Centers for Disease Control
• Johns Hopkins University
• University of Arizona
USA200/1100 USA300
The precise value of minimal inhibitory concentration
(MIC) impacts on the efficacy of vancomycin

> 50% of the

MRSA
strains
MIC
0.25 0.5 1 2
 Predictors of Failure

Surgical factors P-value

TKA <0.0001
MRSA/MRSE <0.0003
Longer hospital stay <0.0001
Longer operative time <0.0001

Pulido L, et al Clin Orthop 2008

C. Salgado
Higher Risk of Failure of Methicillin-resistant Staphylococcus aureus
Prosthetic Joint Infections.
Clinical Orthopaedics and Related Research 2007; 461: 48–53

MRSA infections 9.2

times (Odds ratio)
more likely to fail
Fehring T, Parvizi J, Barrack R, Hanssen AD
Fate of methicillin resistant infections
Clinical Orthopaedics and Related Research 2009

MRSA infections–
higher failure
70% failure for I&D
 New
Antibiotics
• New Glucopeptides: dalbavancin,
telavancin, oritavancin
• New betalactam: ceftobiprole
• New rifamycin: AB-0043
• New inhibitor of DHFR: iclaprim
 DAPTOMYCIN
 Cyclic lipopeptide
 3D structure and Mechanism of
actoion is unknown
 Gm (+)
• MRSA
• VRSA
• VRE
• Synergy with Rifampicin and b-lactams
Rand Antim. Agent. Chem. 2004
 TIGECYCLINE

1stGlycylcycline
• Minocycline derivative
Structural modifications
Broad-spectrum
 TIGECYCLINE

 Labthavikul Antim. Agent. Chem. 2003

• 4x better than Vanc against S. epi biofilm
 Yin J. Antim. Chemotherap. 2005
• Rabbit MRSA Osteomyelitis
• Tigecycline + Rifampicin = 100%
• Tigecyline alone = 90%
• Untreated control = 26%
 Minimum data in implant associated infections
Sarah Gander
Telavancin: in vitro activity against staphylococci in a
biofilm model
J Antimicrobial Chemother 2005; 56: 337–343

strain Log reduction strain Log reduction

R.O. Darouiche, et al
Dalbavancin compared with vancomycin for prevention of
Staphylococcus aureus colonization of devices in vivo
Journal of Infection 2005; 50:206–209

No. animals No. colonized % P

control 32 15 46.9
vancomycin 32 17 53.1
0.07
dalbavancin 32 9 28.1

(1) dalbavancin: single pre-operative dose of 10 mg/ Kg

(2) vancomycin: 1 pre-operative dose and 1 dose a day
after surgery of 20 mg/Kg/dose
(3) control group: sterile normal saline.
 Dorr MB et al.
Human pharmacokinetics and rationale for once-weekly dosing
of dalbavancin, a semi-synthetic glycopeptide
J Antimicrob Chemother 2005;55 (Suppl2):25-30

1000 mg • No adjustment in mild renal dysfunction

300
• Less-nephrotoxic
mg/L 250
• Well-tolerated
200
500 mg
150
Total
100

50
free
0

0 8 14 days
Ceftobiprole: the first betalactam with activity against MRSA
Ceftobiprole is a broad-spectrum antibiotic

MIC90 (mg/L)
Gram positive microorganisms
staphylococci
methicillin-susceptible 0.25 - 0.5
methicillin-resistant 2
group A streptococci 0.06
B-hemolytic streptococci ≤0.015
Gram negative microorganisms
Enterobacteriaceae spp 0.06 – 0.12
P. aeruginosa 8
PBP 1 2 3 4

JM
 Staphylococcus aureus (MSSA)

peptidoglucan

PBP 1 2 3 4

B-lactactam

JM
 Staphylococcus aureus (MSSA)

peptidoglucan

PBP 1 2 3 4

B-lactam

JM
 Staphylococcus aureus (MRSA)

peptidoglucan

PBP 1 2 2a 3 4

B-lactam
ceftobiprole
JM
 Staphylococcus aureus (MRSA)

PBP 1 2 2a 3 4

B-lactam
ceftobiprole
JM
Pierre Vaudaux, et al
Intensive Therapy with Ceftobiprole of Experimental
Foreign-Body Infection by MRSA
Antimicrob Agents and Chemother 2005; 49: 3789–3793
 ABI-0043: a new rifamycin

• Similar efficacy to rifampin in

an animal model of foreign-
body infection due to S. aureus

• No or minimal induction of
liver microsomal enzymes
(cytochrome P-450 system)
 Periprosthetic Joint Infection

Prevention
Diagnosis
Treatment
 Diagnosis of Periprosthetic Infection

1994 NIH Consensus

Diagnosis of periprosthetic
infection—challenging
Still true
 Experimental Investigations
Polymerase Chain Reaction

Target:
• Segment of the 16S
ribosomal RNA gene unique
to eubacteria

 Report:
• Sensitivity 100%
• Specificity 49%
(Mariani & Tuan 1985
Tuan et al JBJS 2008)
 Experimental Investigations
Microarray

 Gene signature
 Promising for future
 Numerous genes----
• Individual
• Time
• Disease
• Type of infection
 Ibis 5000: Step 1
Sample Prep and Broad Range PCR
 Ibis Process Part 2:
MS Analysis and Signal Processing
 Ibis Process Part 3: Triangulation Using
Multiple Primer Pairs
Primer #1 Mass Base Count
Primer Set Mass
BlueSet Mass 18234.970 Base GCount
A12Count
Primer Base 17C17T13
Blue
PrimerBlue
Set Mass 18234.970
17948.926 Base A G
ACount
12 C
G1417
17 CT1213T18
Blue 18234.970 A G 14C T
PrimerBlue
Set Mass
Blue 17948.926
18610.017 Base ACount
12
AC G14
17
GT17C12C13T
15T15
Blue 18234.970 A G 14 18
Blue 17948.926 A
12 G
17 11C
17 19
13T
Blue Blue 18610.017
Blue 18234.970
17936.912 A12 A11A17GT19
14 14
GC15
12
CT15T
18
Blue
Blue 17948.926
18610.017 AG GC
A17
14 GC1112
14 C13T1718
T 16 14
Blue Blue 17936.912
17948.926 A14 A11A12
11 G17
19 C16
15
C15T1514T13
Blue
Blue
Blue 18877.118
18610.017
17936.912 AG11GC
A14 G
19 C18TC
GT15
18
15 T
15
Blue Blue 18877.118
18610.017 A11AG19 AC181517
11 G15 C 14T
16
Blue
Blue 17936.912
18877.118 AG
11 G
17 CT16 CT14T15 13
15
Blue 17936.912 A11AG1718C 15T 15 13
Blue 18877.118 18G15C15T13
16 14
Blue 18877.118 A18G15C15T13
 Non-
specific

Infection

Pill S, Parvizi J, Zhuang H, Alavi A. Clin Orthop 2006

 Pregnancy Test for PJI
•Neutrophil enzymes
•Detected in joint aspirate
•1 minute for response

Protected by patent (METHODS AND DEVICES FOR DETECTING PERIPROSTHETIC JOINT INFECTION. Patent Number 29880)
 Multiplex ELISA

 Macroglobulin a-2
 Leucocyte esterase
 Leucocyte elastase
 IL-8
 CRP
Parvizi J, et al AAOS 2010
 Periprosthetic Joint Infection

Prevention
Diagnosis
Treatment
 Two Stage Exchange

COST
•Social
•Psychological
•Economic
 Results

“True” success rate (no

infection, no mechanical
failure, no reoperation)----

65%
Parvizi et al CORR 2009
RESISTANCE DEVELOPMENT
Parham Sendi, et al.
Staphylococcus aureus Small Colony Variants
in Prosthetic Joint Infection
Clin Infect Dis 2006; 43:961-7

Intracellular S. aureus in periprosthetic tissue

 Biofilm

 Natural barriers (opsonins)

 Immunization
• fragments of RNA to elicit cellular
immunity)
• Staph aureus vaccine (University of
Rochester)
 Periprosthetic Infection

 Systemic antibiotics
 Local Delivery

Coating
• Sol-gel (Duchane 2006) Permanent Binding
• Hydrogel • ATPS (Parvizi 2004)
• Chitosan (Hoggard) • Dansol (Jannsen 2006)
• Silver coating • Poly-ethyle glycol (Anseth
• Calcium sulfate (Jackson) CORR 2006)
• PMMA
 OUR SOLUTION
GRAFT ANTIBIOTICS TO TI ALLOY
 Implant: Ti90Al6V4
 Linking: APTS + AEEA
AEEA
 Antibiotic: Vancomycin
HO O Fmoc
O N
O H
Linker

O 2x
–APTS–AEEA–AEEA
O Si NH2 Deprotection
O Vancomycin
Passivation
Silanization
Ti-APTS

– OH
O
– OH O Si
NH2
– OH O

APTS
 Bactericidal Surface-pH Labile

pH

pH
Ti

pH

pH
Bactericidal Surface-Permanent

Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic
Vancomycin-Modified Ti6Al4V Inhibits
Biofilm Formation
 Investigations

 Does It Work
in-vivo?
Animal Experiments

SURGICAL X-RAYS
Animal Experiments: Radiographs

L R
Animal Model: micro-CT
 Animal Experiments: Micro CT

7L 7R

10D, 107 CFU INJECTED IN 150 MCL

Animal Model: Microbiology
Thank You