Cellulitis and SWITCH How long to treat? Dr James Pollard

Infectious Diseases Physician and HITH Medical Lead

IIR Conference – May 27 2014

Background

• cellulitis is common

• 16-24 per 1000 person years (1)

• lower limb most common

• one of the “key” treatment groups for HITH

• 10% all HITH separations in Victoria (2)

• extrapolated to a diverse range of presentations

(1) Simonson et al, Epidemiol Infect. 2006 Apr;134(2):293-9

(2) DoH Victoria – data supplied

Cellulitis & Erysipelas

• diffuse, spreading skin infections

• erysipelas affects the upper dermis, including the superficial

lymphatics. Lesions are raised above the level of the

surrounding skin, with a clear line of demarcation between

involved and uninvolved tissue. Caused by ß-hemolytic

streptococci (Groups A, B, C, G)

• cellulitis involves the deeper dermis, as well as subcutaneous

fat. Caused by Strep spp. and many other organisms.

• excludes infections associated with underlying suppurative foci:

– cutaneous abscesses, necrotising fasciitis, septic arthritis, and

osteomyelitis

• unfortunately, physicians use the words “cellulitis” and

“erysipelas” inconsistently

Background

• cellulitis remains the most common skin and soft tissue infection

seen in primary care.

• predisposition to erysipelas and cellulitis:

– skin breaks

– tinea infection

– limb oedema

– obesity

– diabetes mellitus

– suppressed immunity

• overall is considered a paucibacillary infection

• systemic manifestations are usually mild

Management

• antibiotics with activity against Strep and Staph

• wide variation in treatment route & duration

• MJA 1996:

• 40% of cases IV therapy was continued for > 6 days

• 10% of cases IV therapy was continued for 10 days or more

• No significant difference in outcome

“Management of inpatients with cellulitis is inefficient, with

excessive use of microbiological investigations, inadequate

investigation and treatment of underlying disease, prolonged use of

intravenous antibiotics, unnecessarily long hospital stays,

questionable use of combination antibiotic therapy and excessive

outpatient review.”

Aly AA, et al. Med J Aust 1996

Common Guidelines

Therapeutic Guidelines

“Mild early cellulitis and erysipelas”

• 7-10 days

• all oral therapy

• di/flucloxacillin, cefalexin, clindamycin

“Severe cellulitis”

• no duration other than “until systemic features have improved”

• intravenous flucloxacillin, cefazolin,

clindamycin/lincomycin/vancomycin

IV or Oral Therapy

IDSA

• results of blood cultures are rarely positive (<5% of cases).

• diseases confused with cellulitis:

– Venous eczema

– Acute dermatitis

– Gout with marked cutaneous inflammation

– Herpes zoster

– Acute lipodermatosclerosis (typically in obese patients with venous

insufficiency)

• a large percentage of patients can receive oral medications from

the start. Parenteral therapy is indicated for severely ill patients

or for those unable to tolerate oral medications

• if patients are sent home receiving antibiotics, it is prudent to

reevaluate them in 24–48 h to verify a clinical response

Clin Infect Dis, 2005

Evolution to Home-Based Therapy

• inpatient IV therapy for cellulitis has over time evolved into

home-based delivery of therapy

• twice daily cefazolin delivered in the patient’s home was studied

in 1996-1997

• favorable peak and trough antibiotic concentrations

• clinical efficacy comparable with other treatment regimens

• intravenous antibiotics can be safely delivered at home

• patients prefer home treatment

• ideal condition for “bed substitution”

Leder K, et al. Med J Aust 1998

Barwon Health HITH Data

Proportion of

Separations Separations (with

HiTH Bed Days)

Average LOS

(with HiTH Bed

Days) HiTH Bed Days

BHCurrentYear

2013-14

Barwon Health 53% 124 3.6 389

PreviousYears

2012-13 43% 106 4.2 371

2011-12 26% 41 4.3 149

2010-11 33% 52 4.1 192

Statewide comparisons

Proportion of

Separations Separations (with HiTH Bed Days)

Average LOS (with HiTH Bed

Days) HiTH Bed Days

BHCurrentYear

2013-14

Barwon Health 53% 124 3.6 389

PreviousYears

2011-12 State Average 47% 2,152 7.0 13,137

2011-12

57% 137 6.9 804

53% 139 6.5 791

48% 37 6.5 229

49% 54 6.4 286

Barwon Health 26% 41 4.3 149

41% 66 6.5 354

59% 115 7.0 692

65% 117 6.4 686

34% 76 7.8 532

57% 165 4.8 698

76% 130 6.6 784

74% 120 9.2 1,028

50% 118 6.6 688

64% 101 7.2 586

49% 86 7.8 591

48% 54 9.6 401

0% 0 0

10% 16 9.5 128

63% 157 5.6 817

0% 0 0

67% 87 8.0 604

20% 18 7.7 134

37% 61 5.3 301

27% 67 7.9 390

27% 52 10.3 461

7% 13 4.2 38

67% 40 8.5 314

24% 26 9.2 194

60% 59 8.8 457

Are we all treating the

same condition?

10 days vs 4.3 days

What is “best”???

Statewide comparisons

Code J64B (Cellulitis w/o comp)

- FY 11-12 41 seps los 4.29 days

- FY 12-13 114 seps los 4.18 days

State ave los for J64B = 7.02 days (10-11)

BH ALOS data

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

0

20

40

60

80

100

120

140

2010-11 2011-12 2013-14 2013-14 (YTD)

BH HITH separations - (VIC DRG) J64B

Separations (with HiTH Bed Days)

Average LOS (with HiTH Bed Days)

SALOS for HITH programs

Why “look” at cellulitis

• common condition

• wide variation in practice

• no interventional drugs

• easy to manage clinical study with modest budget

• skin “looks worse” before it looks better ? Over treating

• local change in HITH Model

Design & Power Calculation

• randomised, non-inferiority trial

• the primary efficacy measure is comparison of resolution of

cellulitis between the groups with a <10% difference in

resolution indicative of non-inferiority

• sample size is calculated based on the one-sided hypothesis

test for the difference of two proportions. Assuming an efficacy

rate of 90% for both treatment arms, a one-sided significance of

2.5% and 80% power, to reject the null hypothesis of inferiority

with a margin of 10% requires a sample size of at least 284 (142

in each arm)

• assuming a 10% dropout rate requires at least 316 participants

(158 in each arm) be recruited

Number of Cellulitis Cases

• to determine the feasibility of a prospective trial

• review of hospital coding for cellulitis

– Over 300 cases per year over several years

• considered likely to be feasible to study this condition

• assumed requirement of 12-15 months to complete

The Complexities of Studying Cellulitis

• Diagnosis?

– Clinical, without diagnostic tests

– Misdiagnosis can be common

– Other conditions may look like cellulitis but require different therapy

(necrotising infection, diabetic foot infection, penetrating wound,

abscess)

• Which outcome measures to use?

– Temperature decrease

– Diameter decrease of affected area

– Patient subjective assessments on a visual analogue scale of

pain/discomfort

– Patient overall subjective feelings of improvement

– Time to when cellulitis fails to advance

Leman P, et al. Emerg Med J 2005.

Corwin P, et al. BMJ 2005.

Eron LJ, et al. J Antimicrob Chemother 52 (Suppl S1):i3–i17.

SWITCH

SWITCH

• Randomised non-inferiority trial of 24 hours intravenous

(IV) therapy followed by oral therapy versus 72 hours or

more IV therapy for the treatment of spontaneous

erysipelas and cellulitis of the lower limb

SWITCH

Primary outcome measures:

Resolution of cellulitis, defined by the following 3 criteria:

1) absence of progression of skin & subcutaneous abnormalities at

visit 2

2) resolution of fever at visit 2

3) absence of ongoing requirement for antibiotic therapy beyond

study period of 10 days

SWITCH

Secondary outcome measures:

1) assessment of self-reported pain using Wong-Baker face scale

2) blinded photographic assessment of affected limb

3) adverse events

4) disease recurrence within 30 days

Design

• Randomised, controlled, open-label

• Pilot – 40 patients, consecutive

• Blind allocation, then unblinded

• Blinded assessor (photograph)

Study Drugs

Intravenous Agents

• Anti-staphlococcal penicillin

• 1st generation cephalosporin

Oral agents

• flucloxacillin, dicloxacillin, cefalexin

Minimum 7-10 days total therapy (IV and Oral)

Inclusion Criteria

• spontaneous cellulitis of lower limb with consistent clinical

features, including; erythema, pain, and swelling with onset

within 48 hours with either fever on clinical examination or

history consistent with fevers and/or chills, rigors, nausea within

48 hours prior to presentation

• age > 18 years

• patient is planned for hospital admission or hospital-in-the-home

IV treatment for cellulitis of the lower limb

Exclusion Criteria

• age < 18 years, pregnant, immunosuppression

• alternative diagnosis, including venous eczema, diabetic foot

infection, Surgical site (wound) infection or other open wound

• penetrating injury or bite

• suspected complication such as abscess or necrotising infection

• septic shock or other reasons for intensive care unit admission

• antibiotics effective against cellulitis for > 48 hours orally or > 24 hours

IV

• patient unwilling to participate or in the opinion of investigators will be

unable to comply

Study Design

Patient Requirements

• Informed consent

• Study diary completion:

– Pain score

– Use of Analgesia

– Temperature

• Attending 2 follow-up visits

• Digital photographs of the involved

lower limb at randomisation, and visits

Study Diary

Pilot of Trial

Prior Antibiotic therapy

• initially >24 hr of orals excluded – poor recruitment

• increased to >48hr – no real difference

• ? relevance

• screened: 243

• enrolled: 40 (16%)

• november 2012 – April 2014

Explanations for Slow Recruitment

• is true cellulitis not as common an entity as was thought?

• is a single centre unable to recruit adequate participants for this

type of non-inferiority trial?

• are we not being notified about cases?

• we were excluding large numbers based on 24/48hr of oral pre-

treatment

a retrospective review of 12 months of cases “coded as” cellulitis

was undertaken in order to review how many patients would have

fulfilled criteria for inclusion in the SWITCH trial

Retrospective Study

• cases coded as cellulitis of the lower limb from November 2011

through November 2012

• 311 patients were coded as having cellulitis of the lower limb.

• 46 excluded because of mis-coding

• 265 cases were analysed against the inclusion and exclusion

criteria for the SWITCH trial

Retrospective Results

• 59 cases (59/265= 22%) would have met criteria for inclusion in

the SWITCH trial

• 206 cases met one or more criteria for exclusion.

– Alternative diagnosis (75, 35%)

– Oral antibiotic therapy >48 hours (108, 52%)

– Suspected necrotising fasciitis or abscess (23, 11%)

– Penetrating injury or bite (16, 8%)

– Many patients met ≥1 exclusion criteria

Moving Forwards

• 40 patient pilot completed

• 20 each arm (24hr IV vs > 72hr IV)

• 24hr: 17 successfully treated; 3 withdrew (1 to ICU)

• 72hr: 19 successfully treated; 1 withdrew (protocol breach)

• Nil safety concerns

• 1 case developed C.difficile post visit 3

“Cellulitis”

• it is very common for patients to present to hospital for treatment

of presumed cellulitis after receiving >48 hours of oral antibiotics

– are expectations of clinical improvement out of keeping with reality?

(the lower limb redness and swelling can be slow to resolve even

when the treatment is successful)

– GPs often refer patients for therapy or tell patients to present if not

“cured” by a certain time

– is IV therapy beneficial in these patients with non-acute cellulitis? In

reality, it is often treated anyway

why not include these cases as this is what is being treated

anyway!

What’s next?

• Even if we included all pre-treated with oral antibitoics

Insufficient numbers for single-site trial

• Attempts to gather further funding

Need to expand to multi-centre trial

Commence new protocol May 2014 (1st patient now enrolled)

Multi-centre trial

• Ballarat

• Traralgon

• Flinders

• Christchurch

• Fremantle

• Royal Perth

• Royal Brisbane

• Wollongong

• One or two others pending

Funding?

• attempted to achieve further grants

• initial funding from DoH Victoria running out!

• current sites have agreed to go ahead without direct funding

Key lessons learnt

• Rigorous diagnostic criteria vs routine clinical reality

• Funding issues

• Practice variation

Acknowledgments

• N. Deborah Friedman (PI)

• Dept Infectious Diseases and HITH Colleagues

• Collaborating Sites

• Patients

Interested to be involved?

• Dr N. Deborah (Deb) Friedman

• deborahf@barownhealth.org.au

• Dr James Pollard

• jamesp@barwonhealth.org.au

Questions?