Antibiotic Selection in the Management of the Diabetic Foot

Dr Jim Greig Consultant Medical Microbiologist 24 th June 2009

Antimicrobial consumption PHNT Sep 07-

1200 1000 800 600 400 WHO DDD 200 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 PHNT Days of therapy

What do we want from antibiotics?

 Prevent systemic sepsis  Retain useful functioning limb  Prevent the induction and proliferation of antimicrobial resistance  Avoid drug side effects and antibiotic associated diarrhoea  Affordable costs ie cheap

Initial management of the infected foot

Assess extent of the infection Probe the base of the ulcer looking for collections and sinus tracts Can the bone can be painlessly probed Toilet and debride the wound, tissues and bone biopsies preferable to swabs Transport the samples to the laboratory in a timely manner, anaerobes are fragile

Typical infecting pathogens

Cellulitis on intact skin

S.aureus, haemolytic streptococci (A,B,C,G)

Infected ulcer

 Early ‘antibiotic naïve’ S.aureus, haemolytic streptococci (A,B,C,G)  Late ‘antibiotic experienced’ Staphs, streps, coliforms, pseudomonas and diphtheroids

Fetid gangrenous

As above and anaerobes

Colonising bacteria

No ulcer bed is sterile (nor do you want it to be) Antibiotic exposure creates an ecological niche for MDR bacteria Status of enterococci, pseudomonas, CoNS etc very difficult to asses Target the main pathogens and see If antibiotic experienced or treatment fails consider better sampling or broader spectrum

Infecting flora of ulcer wounds

Typically in pre treated complex ulcers on average 3-5 bacteria will be isolated Only a minority of bacteria isolated from polymicrobial wounds are identifiable by standard techniques and this is likely to be the same with diabetic foot infections Need for better microbiological studies into the infecting flora

50 40 30 20 10 0

Isolated bacteria (% of all bacteria isolated) SIDESTEP study 2005

Sampling of the wounds

Superficial samples yield more strains of bacteria and correlate poorly with deeper specimens though needle aspirates of soft tissue samples have a greater diagnostic precision Bone biopsies are the gold standard for osteomyelitis The correlation with superficial samples is poor, both for sensitivity and specificity Suggested that there are better clinical outcomes when treatment is directed by bone biopsy

Superficial wound swab Deep ulcer wound aspirate Bone biopsy (though intact skin) N=31 Culture positive 30 (97%) 18 (58%) 21 (68%) Strains 2.5

1.3

1.4

Using bone biopsy as the gold standard the sensitivity and specificity of superficial wound cultures was 85% and 0%!

Superficial wounds may be used to exclude MDR pathogens but cannot be used to definitively identify the likely pathogens Ref: Clin Infect Dis 2009; 48: 888-893

50 40 30 20 10 0

Isolated bacteria (proportion of positive bone biopsies) Senneville et al 2006

50 40 30 20 10 0

Isolated bacteria (% of all bacteria isolated) SIDESTEP study 2005

Determining the severity of the infection

Application of simple clasification allows one to select the narrowest spectrum antibiotics Degree of tissue involvement Extent of exposure to MDR flora

Infectious Diseases Society of America classification



Involvement of skin and soft tissue only/MILD

Wound inflammation, cellulitis or erythema do not extend beyond 2cm, no systemic manifestations of infection 

Involvement of deep tissues/stable patient/MODERATE

local inflammation with spreading cellullits/ lymphangitis or spread deep to the fascia/abscess 

Osteomyelitis/MODERATE

Involvement of deep contiguous bony structures 

Diabetic foot infection leading to systemic toxicity/SEVERE

Commonly used antibiotics

Flucloxacillin

S. aureus and haemolytic streptococci

Pen V Amoxil Clindamycin Co-amoxiclav Levofloxacin Avoid poor absorption, streps only

Streps and coliforms

(if confirmed sensitive)

Staphs and streps and anaerobes

Well absorbed and good tissue penetration

Staphs, streps, coliforms and anaerobes

good for soft tissues and bone Less reliable oral bioavaliability Similar to co-amoxiclav if combined with clindamycin, well absorbed good bone penetration

Antibiotic associated diarrhoea

Antibiotic associated diarrhoea 20->50% of AAD due to Clostridium difficile 2-10% of community diarrhoea due to C. difficile often with no recent hospitalisation Usually a mild nuisance disease but can be fatal Antibiotics to worry about: Clindamycin Cephalosporins esp 2/3 gen Quinolones Co-amoxiclav

Principles of antibiotic choice

Likely infecting flora, depends to a great degree on how extensive the infection is, duration or the infection and previous exposure to antibiotics Route of the antibiotic and likely drug penetration What is the local resistance flora Where are you going to go when it is time for orals?

Antibiotic selections

Life threatening sepsis

Vancomycin (or other MRSA agent), Pip/Tazo and 1-3 days of gentamicin (step down therapy) Little time to play with Broad spectrum of likely pathogens MRSA and MDR coliforms possible Use step down therapy when cultures available IDSA Pip/tazo (confident no MRSA) Scottish Group Levofloxacin and clindamycin (confident no MRSA) Meropenem or vancomycin, ceftazidime and metronidazole Pip/tazo and vanc or ciprofloxacin and metronidazole

Mild (superficial wound infection)

Vast majority of pathogens gram positive Assess if MRSA likely or previously confirmed Flucloxacillin (at least 500mg QDS) or clarithromycin (at least 500mg BD) The laboratory can turn a result around in 24-48 hours Treat until resolved and if not resolved in 5-7 days review what is being treated IDSA Scottish Group Flucloxacillin, clindamycin, cepahlexin, septrin, co-amoxiclav, levofloxacin Flucloxacillin, doxycycline, clindamycin

Moderate disease (not involving bone)

The urgency of the correct choice increases The bacteriological causes for the infection may broaden but the majority are still gram positive Can I await Micro confirmation, can I use a step down approach?

Empirical option if treatment needed straight away is co amoxiclav or levofloxacin and clindamycin in the penicillin allergic IDSA clindamycin Co-amoxiclav, septrin, levofloxacin and metronidazole Scottish Group In antibiotic naïve treat for S aureus, if experienced co-amoxiclav, ciprofloxacin and metronidazole, gentamicin and metronidazole, ciprofloxacin and

Treatment of Osteomyelitis

Up to 80% of osteomyelitis can be treated medically providing:  Get the right pathogen  Get the right antibiotic at the right dose and the right route  Get the duration right Antibiotics are delayed in reaching site of infection due to need for new tissue growth Need to treat for 4-6 weeks to accommodate for this If site is removed then can effectively stop treatment if all infected tissues removed

Treatment of Osteomyelitis

Bone infections are problematic because:  Need protracted treatment courses with problems of side effects and compliance  Fewer objective signs of resolution  Spectre of amputation awaiting those who fail treatment  Greater need to use antibiotics one is confident of success with from initiation Options I favour are IV co-amoxiclav with preferred oral switch to quinolone and clindamycin

Mild

Durations of treatment

5-7 days usually oral (high dose)

Moderate soft tissue

2-4 weeks initially IV usually

Osteomyelitis

Amputate Viable infected bone Retained residual bone Stop within days 4-6 weeks route depends on drug ?? Greater than 3 months (IDSA REC)

MRSA

What is so special about MRSA?

Intrinsically resistant to commonly used antibiotics Ability to spread rapidly through hospitalised communities

MRSA bacteraemias Englans and Wales (Health Protection report 19th September 2008)

May be more virulent 2000 1500 1000 Treatment options are more 500 0 Q 2 20 06 Q 3 20 06 Q 4 20 06 Q 1 20 07 Q 2 20 07 Q 3 20 07 Q 4 20 07 Q 1 20 08 Q 2 20 08 Q 3 20 08 Q 4 20 08 Q 1 20 09 Q 2 20 09 limited than an MSSA but the M standards for methicillin not Multi!

MRSA

Is one adding the antibiotic or substituting?

Vancomycin and oral rifampicin Clindamycin if strain known sensitive (40%) Oral doxycycline and rifampicin Other options include, linezolid, daptomycin, trimethoprim In most cases the above antibiotics are a substitution for flucloxacillin/clarithromycin in mild disease and and addition in moderate and severe disease

Summary of Options

Numerically speaking there are numerous options In reality the nature of the infections and host attributes is stacked against you from the outset Prudent use of antibiotics and sensible use of the laboratory will assist you in management Antibiotic associated side effects are becoming more important and effective use of oral antibiotics will decrease hospitalisation