Der Infektiologe –

Stamm- oder Ersatzspieler?

Charité – Universitätsmedizin Berlin

Interdisziplinary septic surgery unit

Andrej Trampuz

Key to success

How would you call two surgeons

reading a microbiology result?

How would you call two Infectious

Diseases physicians reading surgical

report?

How would you call two microbiologists

discussing about the type of implant?

=> A double blind study

=> A randomized study

=> Expert opinion conference

Concept based on:

1. Teamwork

2. Understanding biofilm

3. Definition & classification

4. Diagnosis

5. Treatment: first treatment attempt!

Infection is the best possible complication

Infectious Diseases specialist’s dogma

Implant infections can be treated with antibiotics ONLY

Mechanical reduction of bacterial load

0

1

2

3

4

5

6

7

8

9

10

Bacte

rial

co

un

t (l

og

)

Antibiotic

No surgery

Resistant strains

Insufficient debridement

Extensive debridement (+/- local antibiotics)

Time

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

0

50

100

150

200

250

Johnson, 1986 Bengtson, 1991

Patients treated withantibiotics only

Cured

Cure rate 8% Cure rate 9%

Error: antibiotic treatment without

surgery

Surgeon’s dogma

Implant infections can ONLY be cured with device removal

Implant Implant

Antibiotic

Immune system

Bacteriostatic Bactericidal

TETRACYCLINE

Tigecycline

Minocycline

Azithromycin

Doxycycline

Fusidic acid

OTHER

Oxytetracycline Streptomycin

Gentamicin

Amikacin

Rifampin

Mupirocin

Methicillin Nafcillin

Cephaloridine

Ceftobiprole

Ampicillin

Oxacillin

Cefazolin

Amoxicillin

Ciprofloxacin

Moxifloxacin

Telavancin

Dalbavancin

LIPOGLYCOPEPTIDE

BETA-LACTAMS Daptomycin

AMINOGLYCOSIDE

OTHER

Antibiotics today

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

35-y-old policewoman

• 2/11 Crucial ligament repair left knee

• Infection with 24 surgical interventions

(Staphylococcus aureus & S. epidermidis)

• 2/12 Arthrodesis

Persistent pain, no sinus tract

Subfebrile temperatures, night sweet

CRP <5

Admission August 28, 2013

X-ray at admission

CT at admission

MRI at admission

August 30, 2013

• Open debridement of the knee with reaming of

femoral & tibial medullary canal, removal of

genatmicin beads & anterior crucial ligament

• Temporary arthrodesis with vancomycin cement

• Antibiotic treatment with flucloxacillin i.v.

Histology periprosthetic tissue:

Chronic inflammation

Microbiology: no growth

September 13, 2013 (2 weeks later)

• TEP-implantation of cemented varus-

valgus-stabilised knee

• Postoperative: oral levofloxacin +

rifampicin for 10 weeks

At discharge

(September 29)

6 weeks after

implantation (45°)

12 weeks after

implantation (60°)

Goal

Functional and pain-free implant

Highly efficient concept (90% cure)

Least invasive (retention, whenever possible)

Eradication of infection

Combination of surgery + antibiotics (bundle)

Not antibiotic suppression (whenever possible)

Scientific evidence

In vitro

Animal models

Clinical studies } What do we know?

Definition

Sinus tract (fistula)

Visible purulence1

Wound discharge, abscess

Acute inflammation in tissue histology

≥1 to ≥10 neutrophils/high-power field

Leukocytes in synovial fluid2

Knee: ≥1.7 x 109/l leukocytes, ≥65% neutrophils

Hip: ≥4.2 x 109/l leukocytes, ≥70% neutrophils

Microbial growth

Synovial fluid

≥3 periprosthetic tissue (for low-virulent organisms >1 positive)

Sonication fluid (>50 CFU/ml)

1 Pseudopus: metal-on-metal prostheses 2 Excluded: Early postoperative (3 months) and inflammatory joint diseases

Diagnosis

Biomarkers: dynamic

Multiplex PCR (SeptiFast)

in sonication fluid

Portillo ME et al. J Clin Microbiol 2012 (in press)

86 explanted

prostheses:

56 knee

25 hip

3 elbow

2 shoulder

16%

69%

0–3 months 3–24 (36) months Any time

Early

postoperative

Delayed

(low grade)

Late

S. aureus

Streptococci

Enterococci

Coagulase-negative

staphylococci

P. acnes

S. aureus

E. coli

Perioperative Haematogenous

Time after

implantation

Type of

infection

Route

Pathogen

Signs Chronic: Persistent

pain, loosening,

fistula

Acute: fever,

effusion, warmth,

dehiscence

Acute or

subacute

Classification

Dogmas, personal opinions and

misleading information

AAOS Clinical Practice Guidelines

Diagnosis of PJI (2012)

www.aaos.org/research

Painful prosthetic joint:

Effusion => joint aspiration

Synovial fluid for:

- culture (native)

- leukocyte count (with

anticoagulants, analysis

within 24 h)

Inoculation in blood culture

bottles improves sensitivity

Risk for iatrogenic infection

under aseptic conditions

extremely low (>0.01%)

Ostriches: bury their heads

in the sand to avoid danger

(legend).

The ostrich effect

In humans: Avoid an

apparently risky situation

by pretending it doesn’t

exist (not legend).

Trampuz A. Am J Med 2004; 117: 556

94%

97%

Aspiration of prosthetic knee joints, underlying inflammatory disorders excluded

Trampuz A. Am J Med 2004; 117: 556

94%

Joint aspiration: leukocyte count

Dinneen A et al. B Joint J

2013;95-B:554-557

Intraoperative tissue culture

Obtain 3 tissue specimens

- No swabs, no sinus tract cultures!

- Culture sensitivity: 60-80%

- Prolonged culture incubation 7-14 d (anaerobes)

- Stop antibiotics 2 weeks before

- Delay surgical prophylaxis

Sonication for diagnosis of

biofilm infections

Trampuz A et al. N Engl J Med 2007;357:654–663

Vortex, 30 s Sonication, 1 min, 40 kHz

Sonicate

Standard method

(3 tissue biopsies)

Tissue

Removed implants

May 2005–Feb 2007

Sonication studies with implants

Shoulder prosthesis (Piper KE et al. JCM 2009)

Breast implants (Del Pozo JL et al. JCM 2009)

Breast implants (Rieger UM et al. Aesth Plast Surg 2009)

Pacemakers and ICDs (Rohacek M et al. Circulation 2010)

Spine implants (Sampedro M et al. Spine 2010)

Ureteric catheters (Bonkat G et al. W J Urol 2010)

Multiplex PCR in sonication fluid (Achermann Y et al. JCM 2010)

Pacemakers (Mason PK et al. Pacing Clin Electrophysiol 2011)

Joint prostheses (Sierra JM et al. Arch Orthop Trauma Surg 2011)

Joint prostheses (Holinka J et al. J Orthop Res 2011)

Joint prostheses (Bjerkan G et al. J Med Microbiol 2012)

Joint prostheses (Portillo ME et al. J Infection 2012)

Joint prostheses (Larsen LH et al. J Med Microbiol 2012)

Multiplex PCR (SeptiFast)

in sonication fluid of PJI

Achermann Y et al. J Clin Microbiol 2010

Therapy

Debridement

and retention

One stage

Two stage

(short interval)

Two stage

(long interval)

Surgical and antibiotic

treatment concepts

Onset of

infection 2–4 weeks

i.v.

8–10 weeks

p.o.

Explantation and implantation

Explantation Implantation

6 weeks

i.v.

Zimmerli W et al. N Engl J Med 2004 Borens O et al. Rev Med Suisse 2009

Explantation Implantation

(2 weeks)

“Biofilm

treatment”

(with rifampin)

“Osteomyelitis

treatment” (no

rifampin)

Debridement

Debridement & retention

1. Stable prosthesis (no loosening)

2. Short duration of infection (<3 weeks)

3. Good soft tissues

4. No “difficult-to-treat” organism:

Rifampin-resistant staphylococci

Quinolone-resistant Gram-negative bacilli

Enterococci

Fungi

Modern surgical / antibiotic concepts

Rapid & sufficient debridement (no fear)

Wound closure (no repeated washout)

Soft tissue couverage (no VAC)

Dead space management

No antibiotics before proper surgical

intervention and with open wound.

Winkler T et al. Der Orthopäde 2014

Winkler T et al. Der Orthopäde 2014

Antibiotics with antibiofilm activity

1. Staphylococci: Rifampin (in combination)

2. Streptococci: Penicillin, ceftriaxon

3. Enterococci: None (fosfomycin?)

4. Gram-negative bacilli: Ciprofloxacin

5. Candida: echinocandins (caspofungin)

Staphylococcal PJI

El Helou et al. EJCMID 2010

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

4 most common mistakes

1. Use of oral drugs with low bioavailability: beta-lactams

(penicillins, cefalosporins)

2. Use of bacteriostatic antibiotics: linezolid, clindamycin

3. Wrong interpretation of in vitro susceptibility:

quinolones against staphylococci or enterococci

4. Rifampin: use in draining wounds, without implant (in

prosthesis-free interval)

Unacid i.v. versus p.o.

Unacid i.v. 3 x 3 g = 9 g

Unacid p.o. 2 x 750 mg = 1.5 g

= oral max. 17% der i.v.-Dosis

Penetration in Knochen 15-20%

= Konzentration im Knochen unter der MHK

Risik factors for rifampin resistance

Achermann Y et al. Infection. 2013;41:431-437

95 99

105

90

110

80

71 75

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%

Results VI: Microbiology

48% 93% 90% 90% 88% 66%

90% 70% 77% 86% 76% 58%

1st: Definition of PJI

Sinus tract

Visible purulence1

Wound discharge, abscess

Acute inflammation in tissue histology

≥1 to ≥10 neutrophils/high-power field

Leukocytes in synovial fluid2

Knee: ≥1.7 x 109/l leukocytes, ≥65% neutrophils

Hip: ≥4.2 x 109/l leukocytes, ≥70% neutrophils

Microbial growth

Synovial fluid

Periprosthetic tissue (for low-virulent organisms >1 samples positive)

Sonication fluid (>50 CFU/ml)

1 Pseudopus: metal-on-metal prostheses 2 Excluded: Early postoperative (3 months) and inflammatory joint diseases

0–3 months 3–24 (36) months Any time

Early

postoperative

Delayed

(low grade)

Late

S. aureus

Streptococci

Enterococci

Coagulase-negative

staphylococci

P. acnes

S. aureus

E. coli

Perioperative Haematogenous

Time after

implantation

Type of

infection

Route

Pathogen

Signs Chronic: Persistent

pain, loosening,

sinus tract

Acute: fever,

effusion, warmth,

dehiscence

Acute or

subacute

2nd: Correct classification

3rd: Mechanical reduction of bacteria

0

1

2

3

4

5

6

7

8

9

10

Bacte

rial

co

un

t (l

og

)

Antibiotic

No surgery

Resistant strains

Insufficient debridement

Extensive debridement (+/- local antibiotics)

Time

Bacteriostatic Bactericidal

TETRACYCLINE

Tigecycline

Minocycline

Azithromycin

Doxycycline

Fusidic acid

OTHER

Oxytetracycline Streptomycin

Gentamicin

Amikacin

Rifampin

Mupirocin

Methicillin Nafcillin

Cephaloridine

Ceftobiprole

Ampicillin

Oxacillin

Cefazolin

Amoxicillin

Ciprofloxacin

Moxifloxacin

Telavancin

Dalbavancin

LIPOGLYCOPEPTIDE

BETA-LACTAMS Daptomycin

AMINOGLYCOSIDE

OTHER

4th: Antibiotics against biofilms

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

Summary

1. Implant can be retained, if: Stable (no loosening)

Short duration of symptoms (<3 weeks)

Good soft tissues (no fistula)

No difficult-to-treat organisms

2. In all other situations, implant must be removed Short interval until re-implantation (2-4 weeks)

3. Antibiotics against biofilm: Eradication (oral long-term treatment): rifampin for

staphylococci, ciprofloxacin for gram-negative rods

Important to lower bacterial density

Loose implant cannot be retained

Collaborative Centres & Observerships

Charité Berlin: Focus on implant-associated infections

Microbiology: New methods for biofilm detection

Infectious diseases: Current concepts and controversies

Charité - University Medicine 50 registered centres

www.escmid.ch/ecc

Research team Infectious Diseases

Ulrika

Furustrand

Stéphane

Corvec Bertrand

Bétrisey

Cyrine

Belkhoja

Elena

Maiolo

Laura

Rio

Laura Sessa

Inês da Fonesca

Christen Ravn

Alessandra Oliva

Thank you!

andrej.trampuz@charite.de

Werner Zimmerli Olivier Borens Carsten Perka

85-y-old biologist. Knee implantation 5 years ago, no

complains until 2 weeks ago. Suddenly fever & joint

swelling. Prosthesis is radiological stable. Which

procedure would you suggest?

a) Joint puncture and antibiotic therapy

b) Arthroscopic lavage

c) Open revision with change of mobile parts

d) Prosthesis removal, reimplantation after 2 weeks

e) Leg amputation & new job search

Question No. 3

85-y-old biologist. Knee implantation 5 years ago, no

complains until 2 weeks ago. Suddenly fever & joint

swelling. Prosthesis is radiological stable. Which

procedure would you suggest?

a) Joint puncture and antibiotic therapy

b) Arthroscopic lavage

c) Open revision with change of mobile parts

d) Prosthesis removal, reimplantation after 2 weeks

e) Leg amputation & new job search

Question No. 3

Activity of fosfomycin and rifampin

against MRSA in the guinea pig model

Mihailescu R et al. ECCMID 2012 (P 2062, Monday, April 2, 13.30-14:30)

Highest cure rate with

FOS+RIF (83%), which

was superior to other

RIF-combinations.

No in vivo emergence

of FOS resistance was

observed in mono- or

combination therapy.

Treatment of E. faecalis biofilms in

the guinea pig foreign-body model

Furustrand Tafin U et al. Antimicrob Agents Chemother 2011

Low inoculum: 104 cfu/cage

Duration of infection: 3 h

Activity against ESBL-producing E. coli

in the guinea pig model

Antibiotic MIC MBClog MBCstat

Tigecycline 0.25 32 32

Colistin 0.25 0.5 2

Fosfomycin 0.12 0.12 8

Gentamicin 2 8 16

Corvec S et al. ICAAC 2011 (manuscrupt submitted)

*p<0.05, **p<0.001

Activity against planktonic Candida albicans

in the guinea pig model

Maiolo EM et al. AAC 2014 (in press)

*p<0.05, **p<0.001

Activity against biofilm Candida albicans in

the guinea pig model

Maiolo EM et al. AAC 2014 (in press)

*p<0.05, **p<0.001

Long-term treatment toxicity

Quinolones: tendinopathy, long QT syndrome

Rifampin: hepatotoxicity, GI-intolerance, rash, polyarthralgia

Betalactams: myelosuppression, interstial nephritis

Cotrimoxazole: rash Steven Johnson, renal insufficiency,

hyperkaliemia

Doxycycline: phototoxicity

Daptomycin: eosiophilic pneumonia, rhabdomyolisis

Linezolid: myelosuppression, neuropathy

All: rash, drug fever, C. difficile colitis (except rifampin)

Error: use of oral drugs with poor

bioavailability

Drug Oral bioavailability Bone penetration

Amoxicillin/clavulanic acid

or ampicillin/sulbactam

15% (AUC 6x lower

with PO dose)

7%

Cefuroxim, cefadroxil 10% (AUC 10x lower

with PO dose)

12%

Ciprofloxacin 70% 48%

Levofloxacin 100% 77%

Rifampin 80% 51%

Co-trimoxazole 85% 55%

Clindamycin 90% 45%

Sanford Guide to Antimicrobial Therapy 2013. 43nd ed.

Lorian. Antibiotics in Laboratory Medicine. 5th ed.

Common reasons for failure

Surgical

No (late) surgery

Arthroscopic instead open surgery (change of mobile parts)

Retention attempt of loose prosthesis

Prosthesis removal in early and hematogenous infection

Antimicrobial

No highly-active bactericidal antibiotic (initial i.v.)

Short duration (total 3 months)

No rifampin for staphylococcal biofilms

Rifampin with open wound, fistula or VAC

120 111 110

100

122

89 80 83

71

44 35

25 25

0

20

40

60

80

100

120

140

Med

ian

(d

ays)

Year

Duration of hospital stay

(patients with hip & knee PJI)

Cure rate >90%

Debridement

and retention

Two stage

(short interval)

High-dose daptomycin for PJI:

ongoing phase II study

Onset of

infection

2 weeks i.v.

daptomycin* 10

mg/kg +

rifampin p.o.

10 weeks p.o.

antibiotics

Explantation Implantation

2 weeks i.v.

daptomycin* 10

mg/kg

(no rifampicin)

Stable

Loose

Prosthesis

Levofloxacin 2 x 500 mg

Co-trimoxazole 3 x 1 DS

Doxycycline 2 x 100 mg

Fusidic acid 3 x 500 mg

+ rifampin

*Daptomycin is not licensed for the treatment of PJI

• Acute infections (<3

weeks of symptoms)

• Stable prosthesis

• Good soft tissue

• No difficult to treat

organism (see below)

Yes

No

One of difficult-to-treat

organisms?

• Rifampin-R staphyloco

• FQ-R Gram- rods

• Enterococci

• Fungi

No

Yes

2 weeks

i.v.

8 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 weeks No treatment

2-3

weeks

i.v.

Only if good

soft tissue

Treatment concept of PJI

Landersdorfer CB. Clin Pharmacokinet 2009

Bone penetration

Débridement with retention of knee PJI

Debridement

& Retention

Changing of

mobile parts

(n=11)

No changing of

mobile parts

(n=14)

1/14 (7%)

10/11 (91%)

2 years

16%

69%

Kaplan-Meier Analyse

von 112 Prosthesen

Portillo ME et al. CORR 2013

Outlook

Foreign-body infection (FBI) model

4 Teflon cages implanted subcutaneously in guinea pigs

Aspiration of cage fluid (planktonic bacteria)

Cages removed 5 days after treatment (eradication)

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

Efficacy in the guinea pig

infection model (MRSA)

0 10 20 30 40 50 60 70 80

DAP 40 + RIF

DAP 40

DAP 30 + RIF

DAP (30)

DAP (20) + RIF

DAP (20)

LIN (50) + RIF

LIN (50)

LEV (10) + RIF

LEV (10)

VAN (15) + RIF

VAN (15)

RIF (12.5)

NaCl 0%

0%

0%

0%

67%

8%

33%

58%

Cure rate, %

0%

25%

0%

0%

25%

0%

0%

17%

17%

58%

Rifampin resistance rate

John AK et al. Antimicrob Agents Chemother 2009 & unpublished data

0%

0%

History of rifampicin

Inhibits DNA-dependent RNA

polymerase.

1957: A new substance was

discovered in Milan from the soil

of French Riviera, produced by

Streptomyces mediterranei (now

Amycolatopsis rifamycinica).

1959: A new semi-synthetic

molecule was produced (today

"rifampicin“ = “rifampin”).

Definition & classification

Study Group on Implant-Associated Infections

ESGIAI Business Meeting

(Monday, April 2, 2012, 9:00-11:00, room 13 + 14)

1. European implant cohort study

- Web-based case report form

2. Educational activity

- Educational Workshops (ECCMID 2013, Berlin)

3. Guidelines

- Prevention, diagnosis and treatment of implant-associated infections

4. Multicenter studies and collaborative projects

- Collaboration with other ESCMID Study Groups and societies

www.implantinfections.com

Results: Debridement and Retention

Survival of Debridement and Retention:Survival proportions

0

10

20

30

40

50

60

70

80

90

100

No. at risk

According the algorithm

Not according the algorithm

p=0.0007

According the algorithm 54 38 28 21 17

Not according the algorithm 76 41 34 31 23

Years 0.5 1 1.5 2

Perc

en

t su

rviv

al

Of 76 cases not treated according the algorithm:

• 30 cases mobile parts were not changed during surgery

• 38 cases soft tissue was not good

• 8 cases symptoms lasted >21 days

Observational descriptive

study

All patients with orthopedic

device-related infection due

to quinolone-susceptible

staphylococci

June 2006 to April 2009

Results

Discussion: authors Efficacies of moxifloxacin treatment:

- 80% for patients with at least 2 years of follow-up

- 71% for patients managed with implant retention

Quinolones:

Good in vitro

antistaphylococcal activity

in biofilms

Increased treatment

compliance by a single

dose

Low rate of side effects

(4,2%)

Low rate of interaction with

other drugs

Rifampin: Not needed to treat

staphylococcal OA infections

Protective effect on the emergence of quinolone-resistant staphylococci not necessary when more active antistaphylococal quinolones administred

Increased risk of adverse effect and pharmacological interactions

Conclusion: reviewers

71% cure rate (with debridement and implant

retention) does not reflect the better activity of

moxifloxacin (compared to ciprofloxacin)

No good effect on biofilm for Staphylococcus

Suppression instead of eradication?

Short-time follow-up

Osteomyelitis treatment in 56,2%

With rifampin, the cure rate would be probably close

to 100%

Randomized study needed before to change practice

Imaging studies

Plain radiographs

Helpful to detect infection when studied serially over time

after implantation

New subperiosteal bone growth and transcortical sinus tracts are specific for infection

Cave: Migration of implant and periprosthetic osteolysis can also occur without infection

Bone scintigraphy with technetium-99m or labeled leucocytes has high sensitivity, but it lacks specificity for infection

Smith S, et al. Clin Radiol 2001

Controversies

Stable implant

No sinus tract

Short symptom

duration (<3 weeks)

Median follow up

of 3.7 years

(1.8–4.7 years)

Orthopedic devices (n = 24)

Trebse R et al. J Bone Joint Surg Br 2005;87:249–256

Estimate of survival with debridement and retention (1999-2002)*

1.0

0.8

0.6

0.4

0.2

0.0 0 1 2 3

24 23 22 20 19 19

Time after study inclusion, years

Su

rviv

al

pro

bab

ilit

y w

ith

ou

t

treatm

en

t fa

ilu

re

Number

at risk

95% CI

Kaplan–Meier estimate

*Infections included hip prostheses (n=14), knee prostheses (n=5), internal fixation (n=4) and an ankle prosthesis (n=1)

Period,

years

Infection

free, %

1 96

2 92

3 86

Fernandes P. Nature Biotechnology 2006;24:1497–1503

Timeline of antibiotic discovery

Natural origin

Synthetic origin

Ampicillin, penicillin analogues

Tetracycline analogues

Gentamicin

Tobramycin

Amikacin

Cephalosporins

Methicillin

Clavulanic acid

Linezolid

Daptomycin

Genomics, chemical library screening

Antibiotic

analogues

Natural product screening 1940 1960

2000 1980

Genomics, screening,

crystallography,

de novo design,

natural product template

Oritavancin

Telavancin

1.Type of infection => Surgery

- Acute (early & hematogenous(

- Delayed (low-grade)

2. Type of microorganism

- Antibiotic against biofilm?

- Difficult to treat

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

PK of daptomycin in sterile cage fluids after administration of single

intraperitoneal doses of daptomycin

Daptomycin PK study in a guinea pig

implant model

Cmax > MBCstat

AUC0–24 dose-dependent

~4, 6 and 8 mg/kg doses in humans

Dose

(mg/kg)

Cmax

(µg/ml)

Cmin

(µg/ml)

Tmax

(h)

20 23.1 ± 7.0 1.5 ± 1.1 6.0 ± 2.0

30 46.3 ± 8.8 9.8 ± 2.9 4.7 ± 1.2

40 53.7 ± 1.3 4.1 ± 2.3 6.0 ± 0.0 40 mg/kg

20 mg/kg

30 mg/kg

MBCstat

Time, h

Co

ncen

trati

on

of

dap

tom

yc

in,

µg

/ml

(mean

± S

D)

0

10

20

30

40

50

60

70

0 4 8 12 16 20 24

John AK et al. Antimicrob Agents Chemother 2009;53:2719–2724

Daptomycin activity against high-inoculum,

stationary-phase MRSA in vitro

Lo

g10 C

FU

/ml

0

1

2

3

4

5

6

7

8

0 4 8 12 16 20 24 Time, h

0 × MIC 4 × MIC (2.5 µg/ml)

8 × MIC (5 µg/ml) 16 × MIC (10 µg/ml)

32 × MIC (20 µg/ml)

64 × MIC (40 µg/ml)

128 × MIC (80 µg/ml)

3 log reduction

Time–kill assay of daptomycin against high-inoculum*

MRSA (ATCC 43300) in stationary phase (mean ± SD, n=3)

*5 × 106 CFU/ml

John AK et al. Antimicrob Agents Chemother 2009;53:2719–2724

OPAT in bone and joint infection

Osteomyelitis & implant infections

Whenever possible => switch to oral (2 + 10 = 12 weeks)

Multiresistant organisms => difficult to treat (6 weeks)

Often no oral alternatives

Possibilities for gram-positive cocci

Vancomycin (TDM, BID)

Teicoplanin (loading dose 800 mg OD, then 400 mg OD)

Daptomycin (high-dose: 10 mg/kg OD)

Investigational: lipoglycopeptides (oritavancin, telavancin)

Outline

Biofilm and implants

Diagnosis

Preoperative

Intraoperative

Management

Surgical options

Antibiotics (local and systemic)

Outlook

Controversies

Vitamin B12 - Imaging

Essencial growth factor

Produced by 0.001% of living organisms,

consumed by 99.999%:

• Low uptake: Differentiated somatic cells

• High uptake: Microorganisms, tumor cells

Complex chemical structure (mammals & most

bacteria unable to synthesize) → have efficient

uptake systems

Can radiolabeled vitamin B12 be used for imaging

infections?

Specimen

Calorimeter Thermostat 37°C

∆T <10-6°C

Detection limit ± 20 nW

≈ 2000 bacterial cells

Reference

Ampoule

Lifter

Equilibration

Zone

Heat detector

(thermoelectric

modules)

Cylinder

Microcalorimetry of sonicate

Trampuz A et al. RMS 2010 (in press)

Quantitative assessment of DNA

Achermann Y et al. J Clin Microbiol 2010

Daptomycin

Cycle

x M

IC

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

0

10

20

30

40

50

500

1000

Linezolid

Cycle

x M

IC

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

0

10

20

30

40

50

Vancomycin

Cycle

x M

IC

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

0

10

20

30

40

50

108CFU

106CFU

104CFU

PJI (n = 118)

Treatment

Debridement and retention 75/81 (93%)

One-stage exchange 13/14 (93%)

Two-stage exchange 15/15 (100%)

Prosthesis removal 5/5 (100%)

No surgery 2/3 (67%)

Time after study inclusion, years

Infe

cti

on

-fre

e s

urv

iva

l

Number

at risk 102 99 81 70 64 56 118

Treatment outcome in 118 PJIs (1994–2006)*

*Infections included hip (n=78), knee (n=22), ankle (n=10) and shoulder (n=8)

0.8

0.9

1.0

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0 0 1 2 3

95% CI

Kaplan–Meier

estimate

Hip (n = 78)

Knee (n = 22)

Ankle (n = 10)

Shoulder (n = 8)

Hip and knee PJI (n = 68)

Betsch BY et al. Clin Infect Dis 2008;46:1221–1226

Time after PJI diagnosis, months

Failu

re-f

ree s

urv

iva

l

1.0

0.8

0.6

0.4

0.2

0.0

0 5 10 15 20 25

Estimate of survival without treatment failure

in 68 infections (1995–2004)

Inadequate treatment

Partially adequate treatment

Adequate treatment

58%

100%

n=12

n=15

33%

Elbow PJI (n = 27)

Achermann Y et al. Clin Microbiol Infect 2010

According to algorithm

Pro

bab

ilit

y o

f re

lap

se

-fre

e s

urv

iva

l 1.0

0.8

0.6

0.4

0.2

0.0

0 1 2 3

Not according to algorithm

Time after diagnosis of infection, years

Giulieri S. Infection 2004

Hip PJI (n = 63), 1985-2001

According to algorithm

Not according to algorithm

Controversies in management of PJI

between North America and Europe

North America

Standard: 2-stage exchange with long interval (6–8 weeks)

No rifampin – dogma that infection is not possible to

eradicate without implant removal

Retention: life-long suppression of infection

Europe

4 surgical approaches according to situation (algorithm)

Early and aggressive revision to make salvage of the

implant possible

Highest success with lowest invasiveness

Low cure of debridement & retention

Marculescu CE et al. Clin Infect Dis 2006;42:471–478

60% cure rate at 2 years1

Berbari EF et al. Clin Infect Dis 2006;42:216–223

32% cure rate at 2 years2

Chiu FY, Chen CM. Clin Orthop Relat Res 2007;461:

130–135

30% cure rate, minimum 3-years follow up3

1. Improper patient selection

2. Insufficient surgical debridement

3. No rifampin use for biofilms

Staphylococcal PJI

(Mayo Clinic, Rochester, MN)

Organism Parenteral therapy Oral therapy initiated following

Recommended Alternative the end of parenteral therapy

Oxacillin- Vancomycin 15 mg/kg iv Linezolid b 600 mg po/iv Levofloxacin 750 mg daily + rifampin 900 mg daily

c

resistant Q12hrs + Q12hrs + rifampin followed by suppressive therapyd with

rifampin 900 mg dailya

900 mg dailyb

trimethoprim /sulfamethoxazole PO DS Q12hrs

for 4 weeks or minocycline 100 mg po Q12hrs

Oxacillin- Cefazolin 1–2 g iv Q8hrs Vancomycin 15 mg/kg iv Levofloxacin 750 mg daily + rifampin 900 mg dailyc

sensitive + rifampin 900 mg dailya

Q12hrs + rifampin followed by suppressive therapyd

for 4 weeks 900 mg dailya

with cephalexin 500 PO Q6hrs or Q8hrs

or cefadroxil 500 mg Q12hrs

a Rifampin 900 mg BID or TID (300 mg BID in case of GI intolerance) b Daptomycin or Synercid can substitute linezolid (if contraindicated) c Given for a total of 6 months for TKA and 3 months for THA d Suppressive therapy for the life of the total joint arthroplasty

El Helou et al. EJCMID 2010

P. acnes in the guinea pig model

Pathogenesis of infection

P. acnes

switches from

planktonic to

biofilm form

and persists

with high

inoculum on

cages for ≥50

days.

Furustrand Tafin U et al. Antimicrob Agents Chemother 2012

Daptomycin indications in Europe

Daptomycin is approved for treatment of:1

Complicated skin and soft tissue infection (cSSTI)

Right-sided infective endocarditis (RIE) due to Staphylococcus aureus

S. aureus bacteraemia (SAB) when associated with RIE or cSSTI

Creatinine

clearance

Dosing

frequency Approved doses

≥30 ml/min q24h cSSTI:

4 mg/kg

RIE or cSSTI

associated with SAB:

6 mg/kg <30 ml/min* q48h

Dosing recommendations for daptomycin

*With or without dialysis. The same dose adjustments are recommended for patients on haemodialysis or continuous

ambulatory peritoneal dialysis. Whenever possible, daptomycin should be administered following the completion of

dialysis on dialysis days

1. Novartis Europharm Ltd. Cubicin Summary of Product Characteristics. 2011

High-dose daptomycin for PJI:

phase II study

Background:

High-dose daptomycin is active against biofilm staphylococci

Rifampin can (in combination) eradicate staphylococcal biofilms

Long treatment for eradication of biofilms (3 months)

Inclusion criteria

Type of prosthesis: Hip, knee, shoulder

Pathogen: Staphylococcus aureus or coagulase-negative

staphylococci (susceptible to daptomycin, rifampin)

Other: 18-80 years old

Non-comparative evaluation of daptomycin plus rifampin for PJI

Primary endpoint: cure rate

Secondary endpoint: safety

Rieger U et al. Br J Surg 2013

Association of capsular contracture and

biofilm on breast implants

108 www.bactosonic.info

Sonication

Mechanical vibrations >20 kHz

Microbubbles (cavitation)

0

10

20

30

40

50

60

70

80

90

100

No

. re

vis

ion

s

Year

Knee

Hip

Hip & knee revisions for PJI

Cure rate >90%

Spacer and local antibiotics?

Temporary foreign body (spacer)

Local elution of high antibiotic concentration

Impregnated with antibiotics (vancomycin, gentamicin

/ tobramycin, clindamycin, daptomycin?)

No rifampicin is needed in the interval before

implantation (emergence of resistance)

Permanent fixation (cement)

In revision knee surgery (vancomycin + gentamicin)

Modified biomechanical properties

Debridement

and retention

One stage

Two stage

(short interval)

Two stage

(long interval)

Treatment algorithm

Onset of

infection 2–4 weeks

i.v.

8–10 weeks

p.o.

Explantation and implantation

Explantation Implantation

6 weeks

i.v.

Zimmerli W et al. N Engl J Med 2004 Borens O et al. Rev Med Suisse 2009

Explantation Implantation

(2 weeks)

“Biofilm

treatment”

(with rifampin)

“Osteomyelitis

treatment” (no

rifampin)

Debridement

Chocolate consumption vs.

Number of Nobel laureates

Multiplex PCR (SeptiFast)

in sonication fluid of PJI and AF

Portillo ME et al. J Clin Microbiol 2012 (accepted)

Type of diagnostic techniques Prosthetic joint infection

(n = 24)

Aseptic failure

(n = 62)

Periprosthetic tissue culture

1 sample positive 2 (8%)a 7 (11%)b

≥2 samples positive 17 (71%) 0

Sonication culture

<50 CFU/ml 1 (4%)c 5 (8%)d

≥50 CFU/ml 16 (67%) 1 (2%)e

Multiplex-PCR of sonication fluid 23 (96%) 0

Basic questions

1. Do we want to diagnose PJI?

“If you don’t measure fever, you can’t have fever”

2. Do we believe that we can cure PJI?

“If you don’t believe, you will do everything to proof

that another concept doesn’t work”

3. Do we have the courage to consider another

concept?

“Or do we want to invent a wheel?”

65-y-old surgeon. Progressive hip pain since

implantation 1 year ago. 1 month ago fistula

occurred with growth of S. epidermidis in fistula

swab. What would you suggest?

a) Ciprofloxacin + rifampicin p.o.

b) Debridement and retention

c) 1-stage exchange

d) 2-stage exchange: short interval (2 weeks)

e) 2-stage exchange: long interval (6-8 weeks)

Question No. 4

65-y-old surgeon. Progressive hip pain since

implantation 1 year ago. 1 month ago fistula

occurred with growth of S. epidermidis in fistula

swab. What would you suggest?

a) Ciprofloxacin + rifampicin p.o.

b) Debridement and retention

c) 1-stage exchange

d) 2-stage exchange: short interval (2weeks)

e) 2-stage exchange: long interval (6-8 weeks)

Question No. 4

Future development - Diagnosis

• Molecular diagnosis (PCR)

• Leukocyte esterase stick (synovial fluid)

• Microcalorimetry heat detection of bacteria)

• Mass spectrometry (MALDI-TOF)

• Fluorescence in situ hydridization (FISH)

Leukocyte esterase

Parvizi et al. JBJS 2011

Vitamin B12 for tumor diagnosis

In-111Adenosylcobalamin 650 μCi (2.2 μg) i.v.

Accumulation in liver, spleen, salivary glands

Solution: Tumor-selective derivatives (not binding to transcobalamin II = TCII)

Collins et al. Mayo Clin Proc 2000;75:568

SPECT 4 h

Prostata

carcinoma

Septic arthritis of the wrist

(incidental finding)

European Implant Cohort Study

(EICS)

Heidelberg, Germany

• To evaluate and improve the treatment concept

of prosthetic joint infections (PJI) • Standardized surgical and antimicrobial treatment

algorithm

• To determine factors associated with: • Infection outcome (infection-free interval)

• Joint function (range of motion, mobility, pain)

• To perform research projects • Clinical (outcome, definition, diagnostic)

• Laboratory (microbiology, PK/PD, genetic)

Acute or fatigue implant

fracture, oxidative

degredation, corrosion

ARTIFICIAL JOINT

FAILURE: loosening, dislocation, neurovascular

deficits, tendon lesions, limb lenght

discrepancy, poor range of motion,

pain, sounds

Wear

particles Infection

Excessive

micromotion Stress shielding,

week bone

Effective joint

space fluid

pressure

Unnatural force transfer

Artifical joint

material failure

Bone to implant

interface failure

Acute mechanical overload

Chronic mechanical overload

Poor surgical

technique

Osteolysis

Bone to implant

toughness mismatch

MOP, MOM,

COC bearing

couples

Preoperative

diagnosis

Implant positioning,

poor approach

Periprosthetic

fracture

Production errors,

improper materials or

design

Excessive

rigidity

Metal ion

release

Hypersensitivity,

mutagenicity?

Aggresive

activity - sports

Sistemic

alterations

complication

rate poor

education,

low

surgical

volume

Preoperative

Prabhu RM. Mayo Clinic 2002

Hematology L, ESR, CRP, PCT

Imaging X-ray, US

MRI, PET, CT

Scintigraphy

Synovial fluid

Leukocyte count

Gram / Culture

Tissue specimens Histopathology

Gram / Culture

New methods Sonication

Bead beating

PCR

Microcalorimetry

Mass spectrometry

Intraoperative

Diagnosis

Microbiology

Microorganism Frequency

Coagulase-negative staphylococci

(e.g. Staphylococcus epidermidis)

30%

Staphylococcus aureus 20%

Streptococci & enetrococci 10%

Gram-negative bacilli (e.g. Escherichia coli) 10%

Anaerobes (e.g. Propionibacterium acnes) 5-10%

Mixed infections 10-20%

Fungi (e.g. Candida albicans)1 1-3%

Culture negative 10-20%

1 Often after VAC-therapy or fistula (with antibiotic therapy).

Treatment against adherent

P. acnes in the guinea pig model

• No spontaneus cure

• Emergence of

rifampin-resistance

not observed

• None of the cure

rates exceeded 50%

• Daptomycin +

rifampin showed

highest cure (42%)

DAP = daptomycin, RIF = rifampicin.

Number in brackets: No cages cleared from adherent bacteria/total number

High inoculum: 109 cfu/cage

Duration of infection: 3 days

Shark Bay, West-Australia: 2.5 bilion years ago

Cyanobacteria biofilms allowed development of higher

forms of life through O2-production

Air for breathing

Stomatholiths Cyanobacteria

Future development - Therapy

New / old systemic antibiotics

• Daptomycin (against MRSA)

• Fosfomycin (against gram-positive/-negative bacteria)

• Oritavancin (against staphylococci, only 1 dose weekly)

Local antibiotics

• For spacers (PMMA), chemical cement modification for

improved or controlled antibiotic release

• For fixation in revision surgery (vancomycin or

daptomycin +/- gentamicin)

• For bone substitutes (calcium sulfates / phosphates)

Evolution of life

100 years = 1 second

Organism Date Time

Bacteria January 1 00:00

Fungi June 18 04:48

Mammals December 24 12:00

Homo sapiens December 31 23:56

Antibiotics December 31 23:59

(last 5 sec)

Route of implant infection

Time, years

Incid

en

ce o

f in

fecti

on

, %

Intraoperatively: ≥100 bacteria sufficient

Postoperatively: risk <48 hours

1

2

2 1

Distant urinary, skin and

respiratory infections

Perioperative

Hematogenous

Patient 1, m., 41, Libyer

Diagnose:

Z.n. Schussverletzung Oberschenkel rechts mit mehrfacher auswärtiger Vor-OP

und

Z.n. Plattenosteosynthese mit ca. 15cm ossärer Defektzone im Z.n.

Knochenzementauffüllung und

Infektpseudarthrose i.S.e. Low-grade Infekts mit Nachweis von Pseudomonas

aeruginosa (multiresistent, 4MRGN) + Staphylococcus epidermidis

=> Vorstellung wegen persistierender Schmerzen mit Lockerung der

Femurplatte bei bestehender Fistel und Low-grade Infektion

Mibi.:

Pseudomonas aeruginosa (4MRGN) Femur

Staph. epidermidis (Oxa res, Rifa sen) Femur

Klebsiella pneumoniae (3MRGN) anal

Ext. Rö.-Bilder

von 12/ 2012:

CT vom 01/2013:

CT vom 08/2013

bei Aufnahme:

Procedere:

1. OP 19.08.2013:

Wundrevision, Entfernung des infizierten Implantats mit Resektion des

pseudarthrotischen Kallus-Chronos-Interponats mit radikalem Débridement,

Einlage armierter Zementspacer und Transfixation mit Fix. ext.

nachfolgend 4 wöchige Abx.-Therapie mit:

Colistin 160mg i.v. 1-1-1

Meropenem 2g i.v. 1-1-1

Vanco 1g i.v. 1-0-1

Fosfomycin 6g i.v. 1-1-1-1

Postop. Rö.-Kontr.

vom 26.08.2013:

Postop. CT.-Kontr.

vom 05.09.2013:

2. OP 16.09.2013:

Entnahme RIA kontralateral, autologe Fibulatransplantation mikrovaskulär

anastomosiert an R. descendens A. circumflexa femoris sowie

Plattenosteosynthese prox. Femur mit LCP

=> nachfolgend 6 wöchige Abx.-Therapie mit:

Colistin 160mg i.v. 1-1-1

Vanco 1g i.v. 1-0-1

Fosfomycin 6g i.v. 1-1-1-1

Rifa 450mg p.o. 1-0-1

Fibulaspan mikrovaskulär anastomosiert

am R.descendens A.circumflexa femoris:

gefäßgestielter

Fibulaspan:

Intraop. Rö.-Kontr.

vom 16.09.2013:

Postop. Rö-Kontrolle

Patient an UAGs mit 15 kg TB mobilisiert

Aktuelle Abx.-Therapie mit:

Colistin 160mg i.v. 1-1-1

Fosfomycin 6g i.v. 1-1-1-1

Cotrim 960 mg p.o. 1-1-1

Rifa 450mg p.o. 1-0-1

Ab 30.10. komplette Oralisierung für weitere 6 Wochen auf

Cotrim 960 mg p.o. 1-1-1

Ciprofloxacin 750 mg p.o. 1-0-1

Rifa 450mg p.o. 1-0-1

Risk of implant-associated infection

Device No. inserted in the US per year Rate of infection, %

Fracture fixation devices 2,000,000 5–10

Dental implants 1,000,000 5–10

Joint prostheses 600,000 1–3

Vascular grafts 450,000 1–5

Cardiac pacemakers 300,000 1–7

Mammary implants 130,000 1–2

Mechanical heart valves 85,000 1–3

Penile implants 15,000 1–3

Heart assist devices 700 25–50

Darouiche RO. Clin Infect Dis 2001;33:1567–1572

Hip and knee replacements in Europe

289 243 240

231 226

220 217

207 205

195 195

189 174

165 154 153

140 126

107 96 96

91 85

46 39

15

0 100 200 300

GermanyAustria

BelgiumNorway

SwitzerlandFrance

LuxembourgSweden

NetherlandsUnited Kingdom

FinlandSloveniaDenmark

IcelandItalyEU

GreeceIrelandLatviaSpain

HungaryEstonia

PortugalRomania

PolandCyprus

Per 100 000 population

206

187

184

179

168

155

146

119

119

114

110

107

106

106

97

79

61

54

47

46

45

5

0 100 200 300

Germany

Austria

Finland

Switzerland

Belgium

Luxembourg

United Kingdom

Netherlands

Iceland

France

Sweden

EU

Spain

Denmark

Italy

Slovenia

Latvia

Portugal

Hungary

Cyprus

Ireland

Romania

Per 100 000 population

Hip replacements in 2008 Knee replacements in 2008

Source: OECD Health Data 2010; Eurostat Statistics Database

Knee

Hip

Kurz et al. CORR 2009

Primary joint

replacement

Infection: What to do?

Stop performing implantations?

Multiple mutilating surgeries?

Aggressive tumor-like surgery?

Amputation?

Understanding biofilm

Evolution of life on Earth

2.5 billion

Cyanobacteria

form biofilms

4.6 billion

Development

of Earth

3.5 billion

First life

forms

Years ago

References Foreign Min. infectious dose Pathogen

(model) body (FB) no FB with FB

Elek 1957 Sutures 5 x 106 3 x 102 S. aureus

(human)

James 1961 Sutures 106 <103 S. aureus

(mice)

Zimmerli 1982 Cages >107 102 S. aureus

(guinea pigs)

Widmer 1988 Cages >107 103 S. epidermidis

(guinea pigs)

Pathogenesis of foreign-bodyinfection

An emeritus professor complains about hip pain,

prosthesis is radiologically loose.

During 1-stage exchange, a single tissue culture grew

coagulase-negative staphylococcus.

Which information helps to interpret this result?

a) CRP level

b) Bacterial species & susceptibility

c) Scintigraphy

d) Date of arthroplasty

e) Name of professor’s lawyer

Question No. 1

An emeritus professor complains about hip pain,

prosthesis is radiologically loose.

During 1-stage exchange, a single tissue culture grew

coagulase-negative staphylococcus.

Which information helps to interpret this result?

a)CRP level

b) Bacterial species & susceptibility

c) Scintigraphy

d) Date of arthroplasty: 12 years ago

e) Name of professor’s lawyer

Question No. 1

67-y: Increasing pain after knee implantation 1 year

ago. Which preoperative test most accurately detects

infection?

a) Serum C-reactive protein (CRP)

b) Synovial fluid Gram stain & culture

c) Synovial fluid leukocyte count & differentiation

d) Conventional x-ray

e) PET / CT scan

Question No. 2

67-y: Increasing pain after knee implantation 1 year

ago. Which preoperative test most accurately detects

infection?

a) Serum C-reactive protein (CRP)

b) Synovial fluid Gram stain & culture

c) Synovial fluid leukocyte count & differentiation

d) Conventional x-ray

e) PET / CT scan

Question No. 2

Sonication fluid Tissue biopsy

Better sensitivity (80-90%)

Quantitative (more specific)

Mixed infections (30%)

Faster, less expensive

Fluid for additional investigations