Treating skin and soft tissue and bone and
joint infections in acute and OPAT settings
Andrew Seaton
Infectious Diseases Consultant and Lead Doctor
Antimicrobial Management Team,
Brownlee Centre
Gartnavel General Hospital
NES Training Day to support Antimicrobial
Pharmacists
Friday 30 August 2013
Cellulitis
• Cellulitis vs Erysipelas
• Risk factors: Previous cellulitis, lymphoedema,
DM, Obesity, varicose excema, insect bites
(summer), tinea pedis….
• Usually caused by:
– Beta haemolytic Streptococci Gp A>> Gps B, C, G
– Staphylcoccous aureus
– Rarely Gram negatives (immunocompromised)
Cellulitis: First line antibiotic
management
• Flucloxacillin (vs MSSA, BHS (most))
– Oral 7 days if mild
– IV-IVOST if moderately severe 7-10 days total
– IVOST when significant reduction in heat, erythema and
swelling
• Should Ben Pen be added?
• Penicillin allergic
– Clarithromycin or Clindamycin (PO)
– Vancomycin (IV)
How is severity assessed?
• Extent, speed of progression and
presence of systemic inflammatory
response
• Abrupt onset fever, rigors and
confusion ++
• Rapidly progressive Cellulitis of leg
• BP 80 systolic, HR 140,Temp 39.80C
• Abrupt onset fever, rigors and
confusion ++
• Rapidly progressive Cellulitis
of leg
• BP 80 systolic, HR 140,Temp
39.80C
Severe GAS Sepsis
• “Eagle effect”
– Static growth phase
– Failure to produce PBPs
– Exotoxin: STSP
28 day Mortality & Sepsis Severity
Patients suspected of bacteraemia
60
50
40
30
20
10
0
SIRS 0
SIRS 2
SIRS 3
SIRS 4
SEVERE SHOCK
INFECTION SEVERITY
Jones & Lowes, QJM 1996
Mortality Risk and time to initiation of effective therapy
Necrotising Fasciitis
• Usually caused by:
– Beta haemolytic Streptococci Gp A>> Gps B, C, G
– Staphylcoccous aureus
– Rarely Gram negative organisms
• Pain out with appearance
• Masked by NSAIDs
• Rapidly progressive with multiorgan failure
Management of severe/ rapidly
progressive SSTIs
• SEPSIS 6, Fluid resuscitation and inotropes
• HDU setting
• Antibiotic considerations:
– Cover: BHS, Anaerobes, Staph aureus and Gram –ves
– Cidality: Beta lactam based regimen
– Toxin production/ EAGLE effect: Clindamycin
• Immunoglobulin (GAS)
• SURGERY
MRSA carrier.
not getting better on
VANCOMYCIN
Why not?
Surgical Site Infections
Diabetic with forefoot
cellulitis
Not getting better on
FLUCLOXACILLIN
Why not?
Drug users:
MSSA and GAS most
usually
Cellulitis, deep SSTIs,
Abscesses,
Vascular infections,
DVTs and bacteraemia
OPAT and SSTIs
OPAT Evidence in SSTI
• 2 RCTs of OPAT: 1999 (n=100, variety)
and 2004 (n=200, SSTI).
– Mainly Cefazolin BD
• RCTs of new antimicrobials includes
OPAT Rx pts
Corwin et al BMJ doi 10.1136/bmj.38309.447975.EB;
Board et al Aust N Z J Public Health 2000; 24:305
When to consider OPAT
• Non-life-threatening SSTI amenable for home
care and requiring i.v. therapy
• Admission avoidance or early discharge
• Exclusions:
– The system
• Lack of facility/ system for FU/ emergency cover
– The infection
• Sepsis syndrome
• Rapidly progressive/ progression not clear
– The patient
• Unstable co-morbidity
• Psycho-social
Good Practice
Recommendations
4.1 Patients with superficial skin and soft
tissue infection should be reviewed daily
by the OPAT team to optimize speed of
intravenous to oral switch.
Patient group direction for
SSTIs
• ‘Patient group’: non-lifethreatening cellulitis amenable for
home care and requiring i.v.
therapy
• Uniform therapeutic management
• Suitable protocol in place
–
–
–
–
Exclusions
Prior physician review
Indications for specialist review
Indications for IVOST
• Trained, experienced staff
• Approved by ADTC
IVOST, i.v. antibiotic – oral switch therapy
Seaton RA et al. J Antimicrob Chemother 2005;55:764–767
OPAT treatment pathway for
SSTIs: empiric antibiotic choice
History of MRSA
or Beta-lactam allergy?
Yes
No
Teicoplanin
▼
Clindamycin*
Ceftriaxone
▼
Clindamycin
or
Flucloxacillin
*If Beta-lactam allergy or
sensitive MRSA
Nurse-led Mx for OPAT
SSTIs
Comparison of patients pre- and post-introduction of a nurse-led
management protocol
 Protocol management was associated with reduced duration of outpatient i.v.
therapy (from 4 to 3 days, P=0.02)
Seaton RA et al. J Antimicrob Chemother 2005;55:764–767
SSTI: Median duration of OPAT (days)
Nurse-led IVOST
14
13
Linear time trend in log (OPAT days)
Estmate 0.904 (0.886-0.922)
p<0.0001
12
Duration of OPAT (days)
11
10
9
8
7
6
5
4
3
2
1
0
2001
2002
2003
2004
2005
Year
2006
2007
2008
Seaton RA et al, IJAA, 2011
Common OPAT Antibiotics in SSTI
No.
Duration
(days)
Progression
(%)
Readmissio
n (%)
Significant
AE
OPAT
failure*
Ceftriaxone 811
3 (2-4)
2.6
5.3
5.5
10.5
Teicoplanin 144
8 (3-12)
4.2
10.4
14.6
25.7
*Switch of antibiotic, progression of infection or readmission
Seaton RA et al, IJAA 2011
Factors Associated with OPAT Failure*
in SSTI (n=963)
Multiple logistic Regression
Variable
OR (95% CI)
P value
Female
1.65 (1.10-2.47)
0.016
Diabetes
2.02 (1.12-3.67)
0.020
Teico vs Ceftriaxone
1.87 (1.05-3.33)
0.033
*Switch of antibiotic, progression of infection or readmission
Seaton RA et al, IJAA 2011
OPAT SSTI: Factors Associated with increase in
duration of OPAT
Multiple linear regression
Variable
Estimate* (95% CI)
P value
Age (per additional 10 years)
1.03 (1.01-1.05)
0.0097
MRSA
1.47 (1.17-1.84)
0.0010
Vascular disease
1.29 (1.01-1.64)
0.041
Teicoplanin vs Ceftriaxone
1.32 (1.16-1.50)
<0.0001
Referred from community
0.91 (0.84-0.99)
0.021
Managed via PGD
0.71 (0.65-0.77)
<0.0001
Bursitis vs cellulitis
1.81 (1.45-2.25)
<0.0001
Wound infection vs cellulitis
1.74 (1.31-2.3)
0.0001
Other infection vs cellulitis
1.25 (1.00, 1.56)
0.0049
Infection type
* Estimates: percentage change in number of days in OPAT: for example, an estimate
of 1.10 means that, on average, a variable is associated with a 10% increase in the
number of days of treatment.
Seaton RA et al, IJAA 2011
OPAT SSTI: Antibiotic therapy
• Nurse led IVOST effective and associated
with reduced duration of IV Rx
• OPAT failure and Teicoplanin
– confounded by another variable?
– Teicoplanin less effective / more adverse
events?
– Less subject to daily IVOST review therefore
longer therapy?
• Alternative therapies when ceftriaxone
contraindicated
65 yr old female diabetic
•
Bilateral amputee with recent admission with ?UTI
•
Readmitted 2/52 post discharge with fever, fatigue,
headache and confusion
–
Temp 39
–
HR 120
–
BP 134/90
–
WCC 16
–
Urinalysis; glycosuria
GAS, Pneumococcus,
Meningococcus, other Strep sp
MSSA
Gram negs
Gram positive cocci on blood culture
@ 24 hours
•
Continue empirical Rx until confirmed and
assuming clinical repsonse
•
S. aureus confirmed (MSSA)
•
Where is it coming from and what are the dangers?
Bone and joint Infection
Bone and joint Infection
• Diversity of presentations
• Managed by many specialties
• About 1m Implants/annum world wide
– 0.5% of THR
– 0.5-2% of other PJs
• BJI in Glasgow; >500 per year
Classification of Osteomyelitis
• OM due to contiguous spread
– Eg Trauma, Surgery or joint replacement
• OM due to vascular insufficieny
– Eg Following Soft tissue infection in a diabetic (associated
neuropathy)
• Haematogenous OM
– Eg Discitis
• Onset
– Acute; Days – weeks
– Chronic; Months - years
Lew and Waldvogel, Lancet 2004; 364369
Likely Organisms
• Device related
– Coagulase negative Staphylococci > Staph
aureus > Enterococci (sub-acute)
– Staph aureus, BHS, Gram negatives (acute)
• Non device related
– Staph aureus, BHS
– Gram negatives
How do bugs get in?
• Through the skin or wound
– Health care workers
– Environment
• From the Blood stream
– Community
– Cannulae / Catheters
• Via surgery
– Asepsis
– Foreign material
Mechanism of disease:
The bone
• Acute suppurative inflammation
• Micro-organism embedded
• Tissue necrosis and destruction of bone
trabeculae and matrix
• Vascular channels compressed and
obliterated
Pathogenesis: Host and
micro-organisms
• Staphylococcus aureus
– Most common and important
– Virulence through extracellular and cell-associated
factors:
• Attachment: Adhesins allow attachment to extracellular matrix
proteins
• Evading the host defence; Protein A, some toxins, capsular
polysaccharide
• Promote invasion or tissue penetration: Exotoxins and
hydrolases
Pathogenesis: Host and
micro-organisms
• Staphylococcal species
– Capacity to colonise and persist
– Promote own uptake by endothelial and
endocytic cells and can survive within
osteoblasts
– Can exist in metabolically altered status as
small colony variants
Pathogenesis: Host and
micro-organisms
• Staphylococcal species
– May persist in biofilm (“Slime”)
•
•
•
•
•
Cells attach to each other and substratum or interface
Matrix of extracellular polymeric substance
Altered growth, gene expression and protein production
Quorum sensing between organisms
Inherent resistance to antimicrobials
– Metabolic alteration
– Reduced cell division
– “Layered variation” in phenotype
BJI Management
• Microbiological Dx is essential
• Imaging: Xray, CT, MRI, Bone scan
• Acute Presentation
– Blood cultures / joint aspiration
– Management of sepsis: empirical therapy
– Identify and remove foci of infection
• Sub-acute presentation
– Sample off antibiotics
– Empirical Rx after sampling
Principles of antibiotic management
• Combined with surgical management
• Deliver to site of infection (bone/joint
penetration)
• Activity in biofilm
• Route of administration: IV (by convention not
evidence) initial and consider IVOST
• Length of Rx: ≥6 weeks BUT dependent on
surgical management
• Cure vs Suppression
• Maintenance of function
Choice of Antibiotic
• Best guess: Glycopeptide vs flucloxacillin
• Favour Flucloxacillin with Gentamicin if
acute presentation
• Consider 2nd oral agent
Rifampicin>Sodium fusidate/ Doxycycline/
TMP/ Pristinamycin
• Gram negative cover: Ciprofloxacin
OPAT
When to consider OPAT
•
•
•
•
When (prolonged) IV Rx anticipated
Ambulant / well supported patient
Stable comorbidity
Agreed plan between surgical team and
OPAT
• Clear lines of communication
• No logistic obstacles
• Usually self/ carer administration
Distribution of patients within the Glasgow
OPAT service (2001-2011)
a. OPAT patient episodes
OPAT days
b.
Seaton and Barr, EJIM, 2013
Good Practice Recommendations
3.2 The treatment plan is the responsibility
of the OPAT infection specialist, following
discussion with the referring clinician. It
should include choice and dose, frequency
and duration. Should take into account
flexibility based on clinical response
3.3 Antimicrobial choice within OPAT
should be subject to review by the local
antimicrobial stewardship programme
Relative frequency of first line antimicrobial
agent use in Glasgow OPAT service.
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
other
SSTI
BJI
CVS
Bacterae
mia
CNS
UTI
Abdo.
Abscess
17
72
9
2
6
7
2
ertapenem
1
15
1
6
0
37
10
daptomycin
20
35
9
6
0
0
0
teicoplanin
62
223
12
9
0
0
2
ceftriaxone
521
99
30
10
28
0
2
Seaton and Barr, EJIM, 2013
Lamont E et al. J Antimicrob Chemother
2009;doi:10.1093/jac/dkp147
Lamont E et al. J Antimicrob Chemother
2009;doi:10.1093/jac/dkp147
Duncan et al, Int J Clin Pharm
DOI 10.1007/s11096-012-9637-z
Multivariate odds ratio of failing initial OPAT therapy
Odds Ratio 95% C. I.
P
Diabetic foot infection
5.94
2.14-16.48
0.001
MRSA infection
3.30
1.15-9.46
0.026
CoNS/Diptheroids
4.53
1.18-17.47
0.028
80-89 yrs
5.32
1.41-20.11
0.014
Goodness of fit: log likelihood -66.5, r2 0.144 P=0.0004
Mackintosh CL, White H.A, and Seaton R.A, JAC 2011
1 .0 0
Kaplan-Meier survival estimate of time to treatment
failure for all patients per diagnosis
MW I
0 .7 5
VO M
SA
0 .5 0
P K /P H /O M
0 .0 0
0 .2 5
DFI
20
0
40
60
80
100
analysis tim e (weeks)
w eeks
n um ber at
0
100
80
60
40
20
Mackintosh
CL,
White H.A,
and Seaton
R.A, JAC 2011
Association of the initial IV Antibiotic
with failure over the follow up period in
OPAT BJI (Cox regression)
Initial IV Rx
No. No.
Hazard
Failing ratio
Teicoplanin
140 48
1
Ceftriaxone
Other
51
5
0.54
10
1
CI
p
0.27-1.06
0.074
Outcome @ 28 days
Relative frequency of adverse drug reaction (ADR) types,
in all first OPAT episodes over 10 year study period.
Rash
Severe gastro-intestinal
Chills or fever
Leucopenia, thrombocytopenia…
Nephrotoxicity
Hepatotoxicity
Nature of ADR unrecorded
Other
Anaphylactoid
0
20
40
60
Frequency of ADR type
80
100
Note: An ADR in an individual patient in some instances involved multiple drug reaction types
(e.g. rash and fever); each ADR type is counted separately in frequency bars even where they
stem from one ADR event.
ADRs, Infection Type and AB Used (GGC OPAT)
18
16
% with ADR
14
12
10
8
6
4
2
0
Daptomycin
Ceftriaxone
Teicoplanin
OVIVA study
• Randomised to IV vs oral before
completion of 1 week of IV Rx
• Use of bio-available antibiotics with good
bone penetration (Rifampicin,
Ciprofloxacin, Tetracyclines)
• Staph aureus bacteraemia excluded (and
those in whom only IV Rx available)
Conclusions
• SSTIs and BJIs: Gram positive infections
(MSSA, BHS and CNS)
• Initial IV therapy is usual standard of care
• OPAT is useful for both patient groups
• In SSTI Teicoplanin associated with
poorer OPAT outcome cf ceftriaxone
• Antimicrobial Stewardship principles
important in OPAT esp IVOST in SSTI
• Role of oral therapy in BJI currently being
explored
Acknowledgements
OPAT Nurses: Lindsay Semple, Claire
Vallance, Deepa Matthew, Emma Sharp
Antimicrobial Pharmacist: Fiona Robb
OPAT Medics past and present: David Barr,
Chris Duncan, Claire Mackintosh
Current Practice: Gram Positive
Infections
INFECTION
AGENT
DOSE
Ceftriaxone
1-2 g OD
Teicoplanin
Variable dose
Daptomycin
4-6mg/kg
Ertapenem
1g OD
Daptomycin
6-8mg/kg
Teicoplanin
15-20mg/Kg 3 xs
/ week
Ceftriaxone
2g OD
Cellulitis/ SSTI
Bone/Joint
infection
COMMENT
Review daily: Oral
switch Clinda/ fluclox/
Linezolid
+ Oral RIF or Sodium
fusidate or Doxy
Clostridium difficile and
OPAT
• 4 per 3,356 UK OPAT episodes (0.1%)
• 2 per 2,233 Glasgow OPAT episodes
(0.05 events per 1000 OPAT patient days)
Chapman et al JAC 2009; 64:1316
Mathews et al JAC 2007; 60: 356
Seaton et al IJAA 2011; 38: 243
Barr et al IJAA 2012; 39: 407