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
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