der infektiologe stamm- oder ersatzspieler?. dr. a. tramp… · dalbavancin lipoglycopeptide...
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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
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