Diabetic foot infection diagnosis and treatment workshop

Subjects
Diabetic foot infection
diagnosis and treatment
workshop
• Introduction / case
• Diagnosis
Nashwan Al Naiemi
Medical Microbiologist, ZGT, Almelo
– Infection
Edgar J.G. Peters
Internist, VU Univ Med Cent, Amsterdam
– Osteomyelitis
• Pathogens
• Treatment (what, how and how long)
Credits to Prof. Schaper, Maastricht MUMC+
Mr H, 60 years: infection?
Epidemiology foot infections in diabetes
Past: DM2, neuropathy, BDRP
• Incidence / prevalence:
Present: 4 months skin defect tip hallux after infected toe. Used
– Risk: 4 % lifetime - 9% in 3 years
– 50% of foot ulcers infected at presentation
penicillin for 10 days. Gets tired legs easily
– 18% osteomyelitis at presentation of ulcer in Eurodiale
study
Med: Glimepiride / metformin / ARB
• Amputation:
Exam: Crusta tip hallux, some hyperaemia and swelling, no
palpable periph puls.
– Expensive
Lab: Hba1c 63 mmol/mol (7.9%), CRP 5 mg/L, Leuco 5,8 x
109/L, Creat 130 ug/L
P – Perfusion
•
E – Extent
•
D – Depth
•
I – Infection
•
S – Sensibility
– If osteomyelitis: amputation in 69% of cases (= OR 16)
Verhoeven 1991; Armstrong 2002; Pecoraro 1991; McMahon 1995; Lavery 2006; Prompers 2008; Eurodiale data
IWDGF/ IDSA classification
Diabetic foot ulcer classification
•
– ≥ 60% 2nd to infected ulcer
• Grade 1: no signs or symptoms
• Grade 2: mild
≥ 2 signs of local inflammation, erythema ≤ 2 cm
• Grade 3: moderate
erythema ≥ 2 cm, lymphangitis, deeper than skin:
abscess, arthritis, osteomyelitis
• Grade 4: severe
SIRS: systemic toxicity or metabolic decompensation
Schaper 2004
Schaper 2004, Lipsky 2004, Lipsky 2012
IWDGF/IDSA classification predicts outcome
Diagnosis of infection
1666 patients in a prospective study
Hospitalisation
p <0.0001
90%
Amputation
p < 0.0001
89%
• Infection = clinical diagnosis
78%
80%
• Symptoms and signs often mild despite serious infection
70%
• Limited usefulness of laboratory variables:
60%
54%
46%
50%
50% of inflammatory parameters normal in foot abscess
40%
30%
• Chronic wound become colonised:
20%
10%
10%
6%
3%
3%
None
Mild
Mild
cultures not useful for diagnosis
0%
No infection
None
Mild
Moderate Severe
Severe
Mild
Moderate
No infection
Moderate
Severe
Moderate
Severe
Lipsky 2004, Peters 2012
Lavery, Clin Infect Dis, 2007
Mr H: osteomyelitis ?
Your antibiotic advice?
•
•
•
•
•
Clindamycin
Flucloxacillin
Ciprofloxacin
Clindamycin and ciprofloxacin
Meropenem
• S. aureus
– clinda R, fluclox S, cipro R, rif S, cotrim S
•
Coag. Neg. Staphylococcus
Exam: Crusta tip hallux, erythema and edema hallux, absent
pulsations
Lab: Hba1c 63, CRP 5, Leuco 5,8, Creat 130
What next?
Removal of crusta: some yellow debris, deep defect.
Probe-to-bone test: +
– clinda R, fluclox R, cipro S, rif R, cotrim S
•
E. cloacae
•
E. coli
– cipro S, cotrim R, mero S
– cipro S, cotrim R, mero S
Clinical clues for osteomyelitis
• Deep and large ulcers
• Chronic ulcers
Accuracy of tests for osteomyelitis
• Clinical impression
– Likelihood ratio negative (LR-): 0.54
– Likelihood ratio positive (LR+): 5.5
• "Sausage toe"
• Visible bone
• Palpable bone
• Leukocytosis
• Elevated ESR/CRP
Berendt 2008; Butalia 2008; Dinh 2008
Mr H: yes / no osteomyelitis ?
Probe to bone
Exam: Crusta tip hallux, erythema and edema hallux, absent
• Neg predictive value up to 98%
pulsations.
• Positive LR: 4.3–9.4
Removal of crusta: some yellow debris, deep skin defect.
Probe-to-bone test: +
• Negative LR: 0.15 tot 0.68
Lab: Hba1c 63, CRP 5, Leuco 5,8, Creat 130
What next?
X-foot: bone destruction
Grayson 1995,Shone 2006, Lavery 2007
Plain radiography (in DFO)
• Summary positive LR 2.3
• Summary negative LR 0.63
• Diagnostic OR 2.84
– Sensitivity 28% to 75%
MRI (in DFO)
Objectives
Microbiology
Pathogenesis
Principles
• Only marginally predictive if positive
• Negative result even less predictive
• No studies to follow up X-rays
Lavery Peters Bush, High risk diabetic foot, New York, 2010
• Summary positive LR 3.8
• Summary negative LR 0.14
• Diagnostic OR of 42 (CI, 15–120)
– Sensitivity 77% to 100%
– Specificity 40% to 100%
Objectives
Microbiology
Pathogenesis
Principles
Specials
Specials
Conclusions
Conclusions
Lavery Peters Bush, High risk diabetic foot, New York, 2010
Mr H: yes / no osteomyelitis ?
Xray of mr H
Exam: Crusta tip hallux, erythema and edema hallux, absent
pulsations.
Removal of crusta: some yellow debris, deep skin defect.
Probe-to-bone test: +
Lab: Hba1c 63, CRP 5, Leuco 5,8, Creat 130
X-foot: bone destruction
What next?
Bone biopsy: Path: histological evidence of infection
Culture: S. aureus and E. coli
Bot biopsy
Comparison of culture results
Gold standard in osteomyelitis
1. Pathology
2. Microbiology
Senneville, Clin Infect Dis 2006
Culture method
Culture results
90
35
80
30
70
25
60
50
Superficial swab
Deep swab
Tissue biopsy
40
30
Number of bacteria
per sample
MDRO
20
15
10
20
5
10
0
0
2003
2005
2003
2007
De Sotto, Diabetologia 2010
2005
2007
De Sotto, Diabetologia 2010
Outcome with bone biopsy
Senneville CID 2008
Bacterial culture the “GOLD” STANDARD?
Bacterial culture the “GOLD”
STANDARD?
EXAM PLES OF LOW-LEVEL M UTATIONS I N TUM OR CLI NICAL SAM PLES, PREVI OUSLY
‘I NVISI BLE’ VI A SANGER SEQUENCI NG, THAT BECOM E DETECTABLE VI A COLD PCR
Sanger-di-deoxy-sequencing of CLI NI CAL tumor samples for p53 exon 8 mutations
Reasons of undiagnosed clinical sample
REGULAR PCR
(94oC denaturation)
167 bp p53 exon 8 sequence
COLD PCR
(denaturation at Tc=86.5oC)
Lung tumor 64
Lung tumor 64
•Focussing on the wrong sample
reverse seq.
NO mutation visible
reverse seq.
G>A mutation VI SIBLE
•Detection of non viable bacteria because of antibiotic
treatment
forward seq.
NO mutation visible
I NDEPENDENT VERI FI CATI ON via RFLP
G>A mutation verified
•Inappropiate transport conditions; not strictly anaerobic
26
Sequencing
Two different
genes
Naiemi, JCM 2006
Next Generation Sequencing (NGS)
Next Generation Sequencing (NGS)
16S PCR of patient X gave a strong signal in real-time 16S
PCR. The bacterial population of a pus sample has been
determined with deep sequencing (NGS).
species
Fusobacterium nucleatum
Prevotella species
Filifactor alocis
Dialister invisus
Bacteroides species
Campylobacter gracilis
Porphyromonas endodontalis
percentage
67
22
3
3
2
2
0.5
Microbiology
• Most diabetic foot infections are polymicrobial, with up to five
to seven different specific organisms
• Superficial diabetic foot infections are likely due to aerobic
gram-positive cocci (including S. aureus, S. agalactiae, S.
pyogenes, and coagulase-negative staphylococci).
• Ulcers that are deep, chronically infected, and/or previously
treated with antibiotics are more likely to be polymicrobial,
above organisms in addition to enterococci,
Enterobacteriaceae, Pseudomonas aeruginosa, and
anaerobes.
• Wounds with extensive local inflammation, necrosis,
gangrene should be presumed to have anaerobic organisms
in addition to the above pathogens, include anaerobic
streptococci, Bacteroides species, and Clostridium species
E. coli (ESBL)
amoxicilline
augmentin
cefazolin
cefuroxim
cefotaxime
ceftazidime
Piperacilline/tazobactam
imipenem
meropenem
trimetroprim/sul
ciprofloxacin
gentamincine
R
S
R
R
R
R
S/R
S
S
S/R
S/R
S/R
ESBLs in The Netherlands
• Community aquired ESBLs in The Netherlands is
3%-8,6%
• Prevalance of ESBLs in The Netherlands is 5,5%
Paltansing, EID 2013; Reuland, ECCMID 2013; www.isis-web.nl
Carbapenemase positive
K. pneumoniae
amoxicilline
augmentin
Piperacilline/tazobactam
cefazolin
cefuroxim
cefotaxime
ceftazidime
cefepime
imipenem
meropenem
trimetroprim/sul
ciprofloxacin
gentamincine
colistin
tigecycline
R
R
R
R
R
R
R
R
R
R
S/R
S/R
S/R
S/R
S/R
Occurrence of carbapenemase-producing
Enterobacteriaceae in 38 European countries
Microbiology
Microbiologie
Zijn alle diabetische voet infecties polymicrobieel ?
• Staphylococcus aureus
…. Waarschijnlijk niet !
• ß-haemolytic streptococci
• Aerobic Gram-negative rods, e.g. E. coli
• Coagulase-negative staphylococci
Linezolid vs ampicillin/sulbactam trial:
• Other organisms
geen verschil in cure rates
Lipsky, CID, 2004
Wat is uw locale resistentie?
S. aureus
Treatment
MUMC+ op 20-4-2012
n
% sens
Flucloxacilline
985
99%
Clindamycine
981
90%
Ciprofloxacine
965
93%
A Oude Lasthof
What is your local resistance pattern?
Systematic review antibiotische behandeling
UMC Utrecht diabetic foot infection n=110
n
S. aureus
% sens
44
• 29 trials
• 12 studies over antibiotica
Flucloxacillin
100%
Clindamycin
83%
– 7 in osteomyelitis
• 1 bone biopsie versus empirische therapie
• 2 vroege chirurgische interventie
Gram negative rods
Ciprofloxacin
29
78%
Results systematic review IWGDF
Antibiotics: how and how long?
Infection severity
• No differences among antibiotic regimes
• Bone biopsy + rifampicine (retrosp trial): better outcome
• Early surgery: decrease in major amputation (2 retrosp
studies)
Class 2: mild
Class 3: moderate / severe
Route
Duration
oral
1-2 weeks
oral/initially iv
2-4 weeks
Bone/joint:
• Healing percentages
Resected
oral/initially iv
2-5 days
– Soft tissue 48 - 90%
Debrided (soft tissue infection)
oral/initially iv
4-6 weeks
– Soft tissue and osteomyelitis 61- 94%
No surgery or dead bone
oral/initially iv
> 3 months
– Osteomyelitis treated conservatively with 3 - 6 months of
antibiotics: 65 - 80%
Flucloxacillin
Peters DMMR 2012
Which antibiotic?
Which antibiotic?
Which antibiotic?
IDSA guidelines 2012
Infectie severity
Oral
Spectrum
Mild (2)
+
Gram +
Clindamycin
Mild (2)
+
Gram +
Cephalexin
Mild (2)
+
Gram +
Amox/clav
Severe (3+4)
+
Gram + / -
Pip/tazo
Severe (3+4)
-
Gram + / -
Moxifloxacin
Severe (3+4)
+
Gram + / -
Cipro/clinda
Severe (3+4)
+
Gram + / -
IDSA 2012
Clin Infect Dis
May 2012
Soort
infectie/wonden
Empirisch
gericht op
Empirische antibiotica
1e keus
Empirische
antibiotica 2 e
keus
Toedienings
Vorm
Duur behandeling
Klinisch niet
geïnfecteerd
Milde infectie:
oppervlakkige
infecties met
beperkte cellulitis
(<2cm erytheem)
Matig-ernstige
infectie:
uitgebreide
infecties zonder
septische shock
Geen
behandeling
S. aureus en
streptokokken
Flucloxacilline of
cefalexine
Clindamycine *
Oraal
1-2 weken
Clndamycine
+ chinolon*
Intraveneus **.
Per os bij goede
absorptie uit de
tractus
digestivus
(chinolonen,
clindamycine)
Intraveneus**
2-4 weken
Intraveneus.
Per os bij goede
absorptie uit de
tractus
digestivus
(chinolonen,
clindamycine
Na adequate amputatie: 2-5
dagen
Na operatie alleen infectie van
weke delen: 2-4 weken
Na operatie nog infectie van
restant vitaal bot: 4-6 weken
Geen operatie of na operatie
nog dood bot aanwezig: >3
maanden
Ernstige infecties
met septische
shock of hoog
risico op ESBL
Osteomyelitis
Gram-positieve Amoxicilline/clavulaanzuur
kokken,
of 2e /3 e generatie
Gramcefalosporine, eventueel
negatieve
gecombineerd met
staven,
anaerobe dekking
anaeroben
(clindamycine of
metronidazol)
Gram-positieve
Onbekend /
kokken,
Pseudomonas: zoals bij
Grammatig-ernstige infectie +
negatieve
gentamicine of chinolon
staven,
anaeroben,
ESBL:
pseudomonad
imipenem/cilastatine
en
meropenem
Zoals bij
matige ernstige
infectie
Onbekend/pse
udomonas:
Imipenem/cilas
tine
Meropenem
2-4 weken
ESBL:
Ertapenem
(indien
pseudomonas
uitgesloten)
Zoals bij matige ernstige
infectie
Ciprofloxacin
• Exposure to ciprofloxacin during the previous 30
days was an independent predictor of
resistance to ceftazidime, imipenem,
meropenem, piperacillin–tazobactam and
ciprofloxacin (p<0.001) (López-Dupla et al.,
2009)
• Lipman et al. (1998) suggest that to achieve
adequate serum ciprofloxacin levels in severe
sepsis, 400 mg i.v. 8-hourly should be used in
adults
Time = tissue
Step 1
Debridement (at bedside or in OR) to:
– Confirm diagnosis
– Drainage of pus / decompression of compartments
– Removal of dead tissue, including bone
– Material for Gram stain / culture
Start empirical antibiotic therapy
Assess vascular status
Improve metabolic condition
Time = tissue
Step 3
Step 2 (72 hours)
3-14 days
Adjust antibiotics
Antibiotics: stop or oral?
Repeat debridement?
Repeat debridement?
Start intensive wound care (e.g. VAC)
Reconstructive foot surgery?
Angiography followed by revascularisation?
Offloading
Developments in case Mr H.
Admitted for 1 week
Amoxicillin/clavulate 1,25 g iv qid
Toe pressure 28 mmHg, tcpO2 22 mmHg
MRA: all crural vessels obstructed
Endovascular procedure: proper flow to the forefoot
Distal toe amputation with planning of foot reconstruction