treatment of pji - pro-implant foundation · 2018-06-25 · treatment of pji andrej trampuz...

Treatment of PJI

Andrej Trampuz

Charité – University Medicine Berlin

Germany

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Implants improved life quality

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Treatment

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Treatment concept

To achieve high treatment success, a concerted

surgical and antimicrobial concept is needed

Cure rate >90%

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Acute PJI

- Good bone/soft

tissue?

- Stable prosthesis?

- No DTT (if known)?

Prosthesis exchange

Chronic PJI

Débridement & retention,

exchange of mobile

parts

Eradication of infection

not possible

- DTT (if known)?

- Bad bone/soft tissue?

- Fistula?

- Multiple revisions?

One-stage exchange

Long-term suppressive

antibiotic therapy, permanent

arthrodesis/girdlestone

Three-stage exchange

Unsatisfactory

course?

Yes

No

No

- DTT-organism?

- Bad bone/soft tissue?

Short interval

(2-3 weeks)

YesNo

Yes

Treatment algorithm

Two-stage exchange

Long interval

(6-8 weeks)

DTT = difficult-to-treat infections caused by

pathogens resistant to biofilm-active

antimicrobials

- Rifampin-resistant staphylococci

- Ciprofloxacin-resistant gram-negative bacteria

- Fungi (Candida)

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Acute infection

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Prolonged discharge: early postoperative PJI?

• C-reactive protein (CRP) should decrease after

surgery!

• Exclude other reasons of prolonged discharge

(coagulopathy, hematoma, albumin deficiency)

→ revision surgery if

prolonged discharge

(>7-10 days)

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Acute pain & fever, 10 y after implantation

The solution to pollution is dilution

0

1

2

3

4

5

6

7

8

9

10

Bacte

rial

co

un

t (l

og

)Systemic

antibiotic

No surgery

Resistant strains

Insufficient debridement,

Sufficient debridement, change of mobile parts

Time

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Johnson et al. J Bone Joint Surg Br 1986; Bengtson et al. Acta Orhop Scand 1991

Cure rate 8% Cure rate 9%

Antibiotics without surgery

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Always (!): Change of mobile parts

Debridement &

retention

Changing of

mobile parts

Not changing

mobile parts4/52 (7%)

50/55 (91%)

Clinical successAcute hip and

knee

infection

Intervention

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Zimmerli W et al. N Engl J Med 2004:351:1645–1654

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2004

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Chronic infection

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

• 78-y-o female

• Primary hip prosthesis 4 months ago

• Since implantation pain, walking distance

now 20 m

• CRP normal, no loosening on x-ray

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High leukocyte count in

joint aspirate (59,000/µl)

Aspiration 4 months after implantation

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Delayed (low-grade) infection

Joint aspiration:

•Culture: Staphylococcus epidermidis

•Cell count: 59.000/µl leukocytes, 90% PMN

•CRP normal, no prosthesis loosening

Prosthesis exchange:

•1-stage exchange OR

•2-stage exchange with short interval (2 weeks)

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Prosthesis exchange

Chronic PJI

- DTT (if known)?

- Bad bone/soft tissue?

- Fistula?

- Multiple revisions?

One-stage exchange Three-stage exchange

Unsatisfactory

course?

No

- DTT-organism?

- Bad bone/soft tissue?

Short interval

(2-3 weeks)

YesNo

Yes

Two-stage exchange

Long interval

(6-8 weeks)

Treatment algorithm: chronic infection

DTT = difficult-to-treat infections caused by

pathogens resistant to biofilm-active antimicrobials

- Rifampin-resistant staphylococci

- Ciprofloxacin-resistant gram-negative bacteria

- Fungi (Candida)

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Aim of PJI-algorithm

To select the

• least invasive treatment option depending

on the present features

• with the best functional result

• without compromising the cure rate!

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Retention of fixed prosthetic

components

One-stage exchange

Two-stage exchange(short interval)

Two-stage exchange (long interval)

Three-stage exchange

2 weeks 10 weeks

Explantation & implantation

Explantation Implantation

Explantation Implantation

Débridement & biopsies

4 weeks 1 week 5 weeks 2 weeks

i.v. antibiotics withoutantibiofilm activity

p.o. antibiotics without antibiofilm activity

Ex- and reimplantation of prosthesis

Type of surgery Intervention Antibiotics (total 12 weeks)

Explantation Implantation

1 week 5 weeks 3 weeks 3 weeks

1 week p.o. antibiotics withantibiofilm activity

2 weeks 10 weeks

Change of mobile parts

9 weeks 2 we.

Surgical procedures

Biofilm treatment

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Retention of fixed prosthetic

components

One-stage exchange

Two-stage exchange(short interval)

Two-stage exchange (long interval)

Three-stage exchange

2 weeks 10 weeks

Explantation & implantation

Explantation Implantation

Explantation Implantation

Débridement & biopsies

4 weeks 1 week 5 weeks 2 weeks

i.v. antibiotics withoutantibiofilm activity

p.o. antibiotics without antibiofilm activity

Ex- and reimplantation of prosthesis

Type of surgery Intervention Antibiotics (total 12 weeks)

Explantation Implantation

1 week 5 weeks 3 weeks 3 weeks

1 week p.o. antibiotics withantibiofilm activity

2 weeks 10 weeks

Change of mobile parts

9 weeks 2 we.

Surgical procedures

Osteomyelitis

treatment

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Explantation Implantation

4 W 1 W 5 W2 W

Explantation Implantation

1 W 5 W 3 W 3 W

Explantation Implantation

1 W 9 W 2 W

Spacerwechsel

Strategy: long interval (6 weeks)

Osteomyelitis

therapy

=

Suppression

Biofilm-active

therapy

=

Eradication

No prosthesis Prosthesis

No rifampin

during interval!rifampin

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Retention of fixed prosthetic

components

One-stage exchange

Two-stage exchange(short interval)

Two-stage exchange (long interval)

Three-stage exchange

2 weeks 10 weeks

Explantation & implantation

Explantation Implantation

Explantation Implantation

Débridement & biopsies

4 weeks 1 week 5 weeks 2 weeks

i.v. antibiotics withoutantibiofilm activity

p.o. antibiotics without antibiofilm activity

Ex- and reimplantation of prosthesis

Type of surgery Intervention Antibiotics (total 12 weeks)

Explantation Implantation

1 week 5 weeks 3 weeks 3 weeks

1 week p.o. antibiotics withantibiofilm activity

2 weeks 10 weeks

Change of mobile parts

9 weeks 2 we.

Surgical proceduresNo drug holidays before reimplantation

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Two stage

(short interval)

Two stage

(long interval)

Explantation Implantation

3 weeks

i.v.

Explantation Implantation

4 weeks

i.v.

8 weeks

p.o.

4 weeks

p.o.1 week

i.v.

4 weeks

p.o.

“Fast-track”-study: Short vs. long interval in two-

stage prosthesis exchange

3 we

7 weeks

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

9599

105

90

110

80

7175

66

43

32

21 19

0

20

40

60

80

100

120

Med

ian

(d

ays)

Year

Interval from explantation until

reimplantation (hip & knee PJI)

Cure rate >90%

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

• Acute infections (<3

weeks of symptoms)

• Stable prosthesis

• Good soft tissue

• No difficult to treat

organism (see below)

Yes

No

Difficult-to-treat organism?

• Rifampin-R staphylococcus

• Ciprofloxacin-R Gram- rods

• Fungi

No

Yes

2 weeks

i.v.

10 weeks

p.o.

Debridement

Debridement

and retention

One stage

Two stage

(short interval)

Two stage

(long interval)

6 weeks

i.v.

Explantation Implantation

or

Explantation and implantation

Explantation Implantation

“Biofilm treatment”

(with rifampin if

applicable)

“Osteomyelitis

treatment” (no

rifampin)

2 weeksNo treatment

2-3

weeks

i.v.

Only if good

soft tissue

Treatment concept of PJI: 1998-2009

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

2 stage exchange: removal of all foreign

material

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

No drug holidays

• No need: does not change the further treatment

• Not sensitive (local antibiotics if spacer in situ)

• Misleading (if false positive/contamination)

• Additional intervention - additional risk of infection

• Prolonged treatment (longer exposure to antibiotics

and spacer, longer period of immobility)

• Holidays for patient = holidays for

bacteria→implantation of a new prosthesis when

bacteria are recovered

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Antibiotics

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Properties of antibiotics

•Knochenpenetration Activity against biofilms

Good oral bioavailabilityBactericidal activity

Good bone penetration

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Bacteriostatic Bactericidal

TETRACYCLINE

Tigecycline

Minocycline

Azithromycin

Doxycycline

Fusidic acid

OTHER

OxytetracyclineStreptomycin

Gentamicin

Amikacin

Rifampin

Fosfomycin

MethicillinNafcillin

Cephaloridine

Ceftaroline

Ampicillin

Oxacillin

Cefazolin

Amoxicillin

Ciprofloxacin

Moxifloxacin

Telavancin

Dalbavancin

LIPOGLYCOPEPTIDE

BETA-LACTAMSDaptomycin

AMINOGLYCOSIDE

OTHER

Bactericidal activity

OXAZOLIDINONE

Clindamycin

Teicoplanin

Linezolid

GLYCOPEPTIDE

Co-amoxiclav

Flucloxacillin

LIPOPEPTIDE

QUINOLONES

Nalidixic

acid

Vancomycin

Levofloxacin

Penicillin

Rolinson GN. Int J Antimicrob Agents 2007;29:3–8

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

How much ends up in the bone?

Drug Oral bioavailability Bone penetration

Ampicillin/Sulbactam 50% 7%

Cefuroxim, cefadroxil 50% 12%

Levofloxacin 100% 77%

Rifampin 80% 51%

Cotrimoxazole 85% 55%

Clindamycin 90% 45%

Linezolid 100% 85%

Sanford Guide to Antimicrobial Therapy 2015. 45nd ed.

Lorian. Antibiotics in Laboratory Medicine. 5th ed.

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Antibiotics with biofilm-activity

• Staphylococci: rifampin (in combination)

• Gram-negative rods: ciprofloxacin

• Streptococci: penicillin G (amoxicillin p.o.)

• Enterococci: ampicillin + gentamicin

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Foreign body infection (FBI) model in guinea pigs

• Subcutaneous implantation of 4 Teflon “cages”

• Infection of cages with different inocula

• Systemic treatment of infection

• Aspiration of cage-fluid (planctonic bacteria?)

• Removal of cages after 5 days and sonication of cages

Zimmerli W et al. J Clin Invest 1984;73:1191–1200

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Staphylococcal PJI

El Helou et al. EJCMID 2010

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Targeted therapy

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Empiric treatment

No specific exposure:

→ Ampicillin/Sulbactam

Fistula, VAC, multiple revisions etc:

→Piperacillin/Tazobactam

Several previous interventions, MRSA-carrier:

→normal renal function (eGFR > 60ml/min): add

Vancomycin

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Switch to oral treatment after surgery

When...

... CRP is nearly normalized

... wound is closed and dry

... organism and its susceptibility is known

→ usually after 2 weeks

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Rifampin – precious but delicate

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Rifampin

• Check interactions (CYP450-induction;

anticoagulants, antiepileptics, antihypertensive

agents, immunmodulators etc)

• Monitor liver enzymes (toxic hepatitis)

• Inform patient about red coloration of body

fluids (urine, tears)

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Rifampin: Quick emergence of resistance

Do not use:

• Before surgery

• In the interval before re-implantation of prosthesis

• In open wounds

• As single antibiotic (monotherapy)

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Therapy during interval: suppression

➢ Aim: suppression of the infection (no eradication)

➢ used substances:

➢Seamless intake until implantation (no

drug holidays)

Organism substance

Staphylococci Cotrimoxazol, Doxycyclin, Clindamycin

Streptococci Amoxicillin, Clindamycin, Levofloxacin

Enterococci Amoxicillin, (Linezolid)

Anaerobes Clindamycin, Amoxicillin, Metronidazole

Gram negative organisms Ciprofloxacin, Cotrimoxazol

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Suppression with antibiotic

cycling• Longterm antibiotic therapy is splitted in treatment phases with

different antibiotics instead of a single drug

• Changement of substance every 2-4 weeks

• Indications:

– No anti-biofilm-active agent available

– Intolerance of antibiotics/side effects

• Benefits:

– Bacteria are getting confused→prevention ofemergence of resistance

– Antibiotic tolerance is better, adverse effects are less

4 weekscotrimoxazol

4 weeksdoxycyclin

4 weeksclindamycin

4 weeks drugholidays

✓ adäquate Penetration in Haut/Weichteil, Knochen und Biofilm

Warum Fosfomycin?Anforderung an ein Antibiotikum zur Therapie von Periprothetischen Infektionen (PPI)

Konzentrationsprofil nach Gabe von 100 mg/kg

Fosfomycin

Nach 3 h Knochenspiegel

= Serum-

/Weichgewebespiegel

Fosfomycin Vancomycin

Schintler

2009

Prosthetic Joint Infection Outcome with

Fosfomycin

The PROOF-study

Andrej Trampuz, MD • Head of Septic Surgery Unit • Center for

Musculoskeletal Surgery • Charité – University Medicine Berlin

Allergy Drug feverToxic

hepatitisToxic nephritis

Psychologic

disturbances

Eosinophilic

pneumonia

Diarrhea

C. difficile

infection

Myelosuppression

Electrolyte imbalanceAdverse effects

Achilles tendinopathy

Monitoring und dose adjustment

Monitoring

Through level: Vancomycin

2x/week

Blood count, creatinin,

electrolytes 1x/week

Liver enzymes (Rifampin)

every 2-4 weeks

Dose adjustment

Kidney function (eGFR <60 or

50ml/min)

• Age: reduce dose in patients

>75 Jahre

• Weight (>100kg and <40kg)

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Pathogenesis

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Pathogenesis of PJI

Peri- /post-

interventional

colonisation

Hematogenous

spread from a

distant focus

through blood

75%

20%

5%

Contiguous spread from

adjacent infected tissue

PJIs treated at Charité, 01/2017-01/2018

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Diagnostic tests

Positive test All episodes (n = 106)

Increased serum CRP (>10 mg/l) 96/104 (92)

Pathological WBC (>10 G/l or <4G/l) 61/104 (59)

Elevated synovial fluid leukocyte count 64/64(100)

Peri-implant tissue histopathology 86/95 (91)

Culture (synovial fluid, tissue or sonication fluid) 99/106 (93)

Blood culture 43/70 (61)

→ PJI is easy to diagnose

Rakow A, Renz N (own data)

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Pathogens

• Highly virulent, i.e. S. aureus, gram-negative bacilli, Streptococcus

spp.

Rodriguez D, CMI 2010; Uckay I, CMI 2009; Tande AJ, Clin Microbiol Rev 2014

• Predominantly monobacterial infections

Staphylococcus

aureus,

43

Streptococcus spp.,

32

Enterococcus

faecalis,

13

Gram-negative

bacteria, 9

Clostridium innocuum, 1

Culture-negative, 1Coagulase-negative

staphylococci, 8

• 104 monobacterial

• 1 polymicrobial

• 1 culture-negative

Rakow A, Renz N (own data)

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Primary foci: cohort of 106 episodes

• 1 (+3?) colon adenoma

• 1 GI bleeding

• 2 GI infections

• 14 endocarditis

• 5 infected CIED

• 3 catheter infections

• 9 skin erosion (pedicure, skin

disease, chronic ulcers)

• 7 skin and soft tissue infections

• 7 dental treatments

• 5 dental infections

• 2 manipulations

• 10 infections

• 1 contralat. PJI

• 1 pneumonia

• 1 epidural abscess

Rakow A, Renz N (own data)

Cardiovascular

system, 22

Skin and

soft tissue, 16

Others, 3

Oral cavity, 12

Unknown, 34

Urogenital tract, 12

Gastrointestinal tract, 7

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Investigation of causePathogen Source Diagnostics

Staphylococci Blood cultures

Echocardiography (TEE)

Skin examination

Streptococci

• S. oralis/mitis

• S. agalactiae

• S. dysgalactiae

• S.

bovis/gallolyticus

Orthopantomogram (OPTG),

dentist, TEE

Urinanalysis, imaging abdomen,

skin examination, OPTG

Colonoscopy

Enterococci Urinanalysis, TEE

Enterobacteriaceae Urinanalysis, CT Abdomen

Renz N., Chirurg, 2017

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Reality

• Studies not usable (wrong

design)

• Significant bacteremia

after dental interventions

• Prophylaxis reduces

bacteremia

• Clinical practice:

association exsists

• Prospective studies

neededLockhart PB. Circulation. 2008

Bacteremia after tooth brushing and dental

extraction

0 min 1.5min 5min 20min 40min 60min

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Workshops: www.pro-implant-foundation.org

Pocket Guide: www.pro-implant-foundation.org

Consultation service: www.pro-implant-foundation.org

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Thank you

andrej.trampuz@charite.de

Focus on implant, bone and joint-associated infections:

• Surgery: New concepts (retention, 1-stage, 2-stage short interval)

• Diagnosis: Fast innovative methods

• Antibiotics: Active against biofilms

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Thank you!

Consultation service Pocket Guide Workshops

andrej.trampuz@charite.de

www.pro-implant-foundation.org