La terapia antibiotica delle infezioni della

cute e dei tessuti molli

Matteo Bassetti, MD, PhD
Infectious Diseases Division
Santa Maria Misericordia University
Hospital
Udine, Italy

Disclosures
h

Research grants
- Astellas, Pfizer, MSD, Gilead

Advisor/consultant
- Angelini, Astellas, AstraZeneca, Bayer, Basilea, Cubist,
Gilead, MSD, Pfizer, Novartis, Shionogi, Vifor,
Medicines company, Tetraphase

Speaker/chairman
- Astellas, AstraZeneca, Pfizer, MSD, Gilead, Angelini,
Vifor, Novartis, Bayer, Cubist

Clinical presentations of skin and soft tissue

infections (SSTIs)
Surgical
site
infection

Necrotising
fasciitis

Cellulitis and
erysipelas

Skin and soft tissue

infections1

Pyomyositis
Furuncles
and
carbuncles

Impetigo

Cutaneous
abscess

1. May AK, et al. Surg Infect 2009;10:46799; 2. Arias CA, et al. N Engl J Med 2009; 360:43943

SSTI by anatomical layer

Comparison of Prior and New FDA Guidance

Indication
Infection Type
Infection Severity
Primary Endpoints

Prior Guidance (1998)

New Guidance* (2013)

cSSSI

ABSSSI

Large Abscess, Wound,

Cellulitis, DFI, Chronic Ulcer

Large Abscess, Wound,

Cellulitis

Intermediate/Severe

Severe

Subjective
(Clinicians Assessment at 7-14
Days After EOT)

Objective
(20% reduction in lesion size at
4872 hours)

Secondary
Endpoints

Varied

Low Potential for Differentiation

Primary Endpoint Sustained to EOT

Clinicians Assessment at EOT

Higher Potential for differentiation

** 2010
2010 FDA
FDA Guidance
Guidance primary
primary endpoint:
endpoint:
Cessation
of
lesion
spread
&
fever
Cessation of lesion spread & fever at
at 48-72
48-72 hrs
hrs was
was
updated
updated in
in 2013
2013

Recognising cSSTI: local, systemic

and microbial risk factors

HOST
Systemic

BUG
Microbial

Local
Dynamic process

Recognising cSSTI: local risk

factors
HOST
Systemic

BUG
Microbial

Local

Peripheral vascular disease

(ischaemia) and venous
hypertension1
Depth of tissue penetration1
Involvement of contiguous
structures1
Involvement of foreign
bodies (eg prosthesis,
grafts)1

Dynamic process

1. Tognetti et al. J Eur Acad Dermatol Venereol 2012;26:931-41

Recognising cSSTI: systemic

risk factors
HOST
Systemic

BUG
Microbial

Local

Malnutrition1-3
Generalised sepsis5
Diabetes1-5
Obesity1-3,5
Chronic renal failure3,6
Malignancy1,4
Transplantation4
Immunosuppression 3,4
Older age1,3
Cardiovascular disease3-5
Smoking1-3

Dynamic process
1. Bandyk. Semin Vasc Surg 2008;21:119-23;
2. Moucha et al. J Bone Joint Surg Am 2011;93:398-404;
3. Tognetti et al. J Eur Acad Dermatol Venereol 2012;26:931-41;
4. Fish et al. Ther Clin Risk Manag 2006;2:401-15;
5. Eron et al. J Antimicrob Chemother 2003;52 Suppl 1:i3-17;
6. Pesanti. Infect Dis Clin North Am 2001;15:81332

Recognising cSSTI: microbial

risk factors
HOST
Systemic

BUG
Microbial

Resistance1
Synergistic infections2
Toxin production eg. PVL3

Local
Dynamic process
PVL, PantonValentine leukocidin

;
1. Itani et al. Am J Infect Control 2011; 39:42-49;

2. Stevens et al. Clin Inf Dis 2005; 41:1373-1406

3. Morgan. Injury 2010; 26:1565-1578

CAMPIONI DA EVITARE:
h

tamponi di ulcere da decubito,

ascessi perirettali,

Tamponi superficiali di ulcere ai piedi, escara;

ogni materiale adiacente mucose non ben decontaminate

Se necessario usare
TAMPONI: usare Tamponi
floccati con terreno di
trasporto adeguato per
ANAEROBI

SSTI: Aetiology
MSSA
Impetigo
Erysipelas
Cellulitis
Abscesses
Furuncles
Fasciitis
Pyomyositis
Bites
DFI
Decubit Ulcers

MRSA

Gram+

Gram-

Anaer

Common microbial species in cSSTI

in Europe
Identification of cSSTI isolates, Europe, 2003-2008a,1

Staphylococcus aureus

71%

77.5%

22.5%

MRSA cSSTIs are associated with significantly greater mortality

compared with non-MRSA cSSTIs2
Isolates were gathered from 33 centres in 13 European countries (Belgium, France, Germany, Greece, Ireland, Italy, Poland, Russia,
Spain, Sweden, Switzerland, Turkey, UK) and Israel
a

1. Sader et al. Int J Antimicrob Agents 2010:36:28-32

2. Itani et al. Am J Infect Control 2011; 39:42-49

Common Pathogens in hospitalized

SSTIs in Italy
20081, N=307

59%%
19%

40%

Methicillin-resistant
S. aureus (MRSA)

Enterococcus spp.

-Hemolytic streptococci

Methicillin-susceptible
S aureus (MSSA)
Pseudomonas aeruginosa

Coagulase-negative
staphylococci

Other

1. Tarricone R at al. Journal of Medical Economics 2008; 11: 265279.

Etiology of cellulitis cases:

1999-2002 vs 2003-2006
* p<0.01

30

Aged care facility (N=57)

Community (N=278)

Percentage (%)

25
20

* p<0.01
* p<0.01

15
10
5

S.
py
St
og
re
en
p.
es
no
nA
gr
ou
ps
P.
ae
ru
gi
no
En
sa
te
ro
ba
ct
er
ia
ce
ae

R
SA
*

M
R
SA
/N
O

M
SS
A

Figtree M et al. J Infection 2010;60;431-439

Risk factors for MRSA are

common
h
h
h
h
h

Known previous MRSA infection1,2

Previous exposure to antimicrobial agents3
Advanced age3
Chronic open wounds4
Underlying diseases or conditions, particularly:
-

Repeated contact with the health-care system

-

h
h
h

Chronic renal disease3

Diabetes3
PVD3
Cardiovascular disease3
Immunosuppression5
Including long-term care and skilled nursing homes, home care, haemodialysis
centres, and physicians offices3

ICU admission6
Invasive procedures, such as dialysis3 and CVC5
1.Bandyk.SeminVascSurg2008;21:11923;
Parenteral drug use3

2.Yanoetal.ActaOrthop2009;80:48690;
3.Viallonetal.AmJEmergMed2007;25:8806;
4.Yamakawaetal.BMCInfectDis2011;11:303;
5.Harbarthetal.InfectControlHospEpidemiol2008;29:8903;
6.IbelingsandBruining.EurJSurg1998;164:4118

MRSAinItaly:2013

Rate of invasive MRSA in Italy: 1999-2013

9
19
9

0
20
0

0
20
1

0
20
2

0
20
3

0
20
4

0
20
5

0
20
6

0
0
2
7

0
20
8

0
20
9

1
20
0

1
20
3

Classifying skin and soft tissue

infection

Factors increasing likelihood of

MRSA

Journal of Antimicrobial Chemotherapy (2003)

52, Suppl. S1, i3i17

% mortality in 189 hospitalised

patients with SSTI

Unadjusted mortality rate (%)

33%

17%
11%

1%

Severity class (n)

Unadjusted mortality at 30 days significantly increased with severity class but readmission did not vary.
Crude 30-day mortality rates (P<0.001)

Marwick, et al. J Antimicrob Chemother. 2011;

Empirical treatment 189 hospitalised

patients with SSTI

65%

Number of patients (%)

25%

14%
22%

39%

36%

39%
30%
30%

Severity class (n)

Adapted from: Marwick C, et al. J Antimicrob Chemother. 2011; 66:38797.

8%

0%
92%

Adverse clinical outcomes are more likely in cSSTI

patients who receive inappropriate initial antibiotic
therapy

Initial antibiotic therapy failed for

47,219 patients with cSSTI1

10,782(22.8%) patients

449 patients with cSSTI2 83 patients (18.5%) received

inappropriate initial antibiotic therapy

Overall, there were no significant differences

Increased mortality
(OR2.91;95%CI2.343.62)

Increased readmission /
death within 30 days among
patients with decubitis ulcersa

1. Edelsberg et al. Infect Control Hosp Epidemiol 2008;29:160-9;

2. Zervos et al. J Clin Microbiol 2012;50:238-45

Antibiotics currently or soon to be clinically

available for infection caused by multidrug
resistant bacteria
Class

Glycopeptides

Agent

Dose

Route

Spectrum

Indications

Comments

Vancomycin

1-1.5gm bd
15mg/kg

IV

Gm+

MDR-Gm+
infections

Concern over MIC creep and

resistance. Avoid rapid infusion. Renal
toxicity and levels

Teicoplanin

400mg bd,od
6-10 mg/kg

IV

Gm+

MDR-Gm+
infections

By injection or infusion. Similar issues

as with vancomycin

Oritavancin

1200mg stat

IV

Gm+ in
VRE

ABSSI

Similar safety profile to vanc, excreted

unchanged in urine & faeces. Dose
change not necessary in renal
impairment

IV

Gm+

Dalbavancin

Once weekly dosing

Linezolid

600mg bd

IV/po

Gm+

ABSSI, CAP

Dose change not necessary in renal

impairment. Marrow toxicity and
nephropathy. Useful for IV oral switch

Tedizolid

200mg od

IV/po

Gm+

ABSSI

Possibly fewer adverse events than

linezolid

Glycylcycline

Tigecycline

100mg, then
50mgbd

IV

Gm+,
Gm-

ABSSI, IAI

Does not cover Pseud. and some

Proteus spp.

Lipopeptide

Daptomycin

4-6mg/kg

IV

Gm+

ABSSI, right
endocarditis

Check CK (and INR if required) before

treatment

Fluoroquinolones

Moxifloxacin

400mg od

IV/po

Gm+,
Gm-

ABSSI, CAP, PID,

DFI

Will not cover quinolone-resistant

MRSA

Ceftaroline

600mg bd

IV

Gm+,
Gm-

ABSSI, CAP

1st beta-lactam with anti-MRSA activity,

Possible more rapid early clinical
response. No ESBL, Pseud. spp cover.

Oxazolidanones

Beta-lactams

Dryden MS. Curr Opinion Infect Dis 2014; 27 116-124

International guidelines for the

management of skin infections

BassettiMetal.ClinMicrobiolInfect2014;20(Suppl.4):318

For MRSA infections

h

Most clinicians automatically turn to glycopeptides

Challenges in treating cSSTI

with vancomycin and teicoplanin
Moderately bactericidal

Less effective than betalactams against MSSA

Susceptibility of
Complicated dosing
S. aureus compromised?

hVISA are clinically associated

with vancomycin failure

Increased vancomycin MICs

(1.5 g/mL) are significantly
associated with increased
mortality for MRSA infections

Vancomycin MIC creep in MRSA

isolates may be associated with
cross-resistance to daptomycin

Aggressive vancomycin dosing

regimens are associated with
unacceptably high microbiological
failure rates and target attainment
at vancomycin MICs of 2 mg/l is
not possible

High-dose vancomycin has been

confirmed to be nephrotoxic

Brink AJ. Curr Opin Crit Care 2012, 18:451459

cSSTI, complicated skin and soft tissue infection; hVISA, heteroresistant vancomycin-intermediate S. aureus; MIC, minimum inhibitory concentration;
MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus

MRSA: Skin infections therapy

h
h

Vancomycin: drug of choice, but.

Teicoplanin: same vancomycin problems,
more expensive
Tigecycline: satisfactory data, but for mixed
infections
Linezolid: very good opportunity, new data for
ES/ED
Daptomycin: rapid and cidal, very interesting
drug in severe infections
Ceftaroline: interesting option

Adequate tissue penetration is essential for

successful antibiotic treatment of cSSTI
h

Successful management of cSSTIs requires an antibiotic with

intrinsic ability to distribute to tissues of the skin and skin
structures1
Poor tissue penetration may lead to:
-

inadequate drug concentrations1

clinical and microbiological treatment failure1
the development of resistance among bacterial pathogens1

cSSTIs are commonly associated with vascular insufficiency due

to:
-

underlying comorbidities, eg peripheral vascular disease, cardiovascular

disease or diabetes1-5
disruption of normal blood and lymphatic flows1
areas of devitalized tissue1
1. Fish et al. Ther Clin Risk Manag 2006;2:401-15;
2. Hessen and Kaye. Infect Dis Clin North Am 2004;18:435-50;
3. Joukhadar et al. Clin Pharmacol Ther 2001;70:532-9;
4. Raymakers et al. Diabet Med 2001;18:229-34;
5. Powlson and Coll. J Antimicrob Chemother 2010;65:iii3-9

Antibiotics for MRSA cSSTIs have

different tissue penetration
Molecular weight

Ratio of skin and soft tissue: plasma penetration

Linezolid

337.351

104%7,a

Vancomycin

1485.742

10-30%8,b

Teicoplanin

1879.73

24-77%9,10,a

Daptomycin

1620.674

68%

11,a

Tigecycline

585.655

380%12,c

Ceftaroline

762.756

Not available

1. ZYVOX [package insert]. New York, NY: Pfizer Inc., 2012;

2. Vancomycin Hydrochloride [package insert]. Lake Forest, IL: Hospira, Inc., 2010;
3. Teicoplanin Complex [product data sheet]. Bioaustralis.com;
4. Cubicin [package insert]. Lexington, MA:
Cubist Pharmaceuticals, Inc., 2010;
5. http://www.drugbank.ca/drugs/DB00560;
a
6. Saravolatz et al. Clin Infect Dis 2011;52:1156-63;
Healthy volunteers/patients; bDiabetic vs non-diabetic post-cardiac
7.
Gee
et
al. Antimicrob Agents Chemother 2001;45:1843-6;
surgery patients;
8.
Skhirtladze
et
al.
Antimicrob Agents Chemother 2006;50:1372-5;
c
cSSTI patients requiring surgical intervention, 1 hr post infusion
9. Wise et al. J Hosp Infect 1986;7 Suppl A:47-55;
(peak);
10. de Lalla et al. Antimicrob Agents Chemother 1993;37:2693-8;
d
Healthy volunteers, after 5.5 days repeated oral administration (1g/d)
11. Wise et al. Antimicrob Agents Chemother 2002;46:31-3;;
12. Stein et al. Surg Infect (Larchmt) 2011;12:465-7;

New options

Gram-Positive Therapeutics: Latest Data on

Oral Antibiotics Awaiting Approval for ABSSSI
Tedizolid (TED)1
Phase 3 Study

ESTABLISH-1

Infection

ABSSSI

667

Evaluated

6-day oral tedizolid vs 10-day oral

linezolid therapy
Early Clinical
PTEb Clinical
Responsea (%)
Success (%)
TED

LIN

TED

LIN

Wound

85.6

83.7

84.5

89.8

Cellulitis

74.8

71.9

88.1

82.0

80

85.7

83.0

87.8

Major
cutaneous
abscess
TEAEs

Similar rates

Based on the
observed
minimum
inhibitory
concentrations,
tedizolid was
four-to eightfold more
active than
linezolid
against
Staphylococcus
spp including
MRSA, and
Streptococcuss
pp.

Early clinical evaluation or response endpoints occurred at 48-72 hours after treatment initiation
evaluation (PTE) occurred at 7-14 days after end of therapy .
1.. Prokocimer P et al. JAMA. 2013;309(6):559-69
a

Post therapy

Oritavancin Phase III Clinical Studies

Single Dose Oritavancin Similar Efficacy to 7-10 Days of
Vancomycin
Key Efficacy Endpoints: n=1959

Composite
endpoint at ECE

Early
48-72 h

Post Rx
7-14 d

20% reduction
in lesion size

Investigator
Assessed Clinical
Cure at PTE

Vancomycin
better

ICAAC 2013

Oritavancin
better

Dalbavancin - Phase 3 study design

Primary Endpoint: early response at 48-72 hours post initiation of therapy
cessation of spread of the erythema of the lesion, and resolution of fever.

*Primary

endpoint
for
EMA;
CE=Clinically Evaluable; ITT =Intent to
Treat;

Secondary Endpoint: Clinical Status at End of Therapy (Day 14-15, EMA primary
endpoint).

Boucher et al. (2014) N Engl J Med 370:2169

Dalbavancin for infections of the skin compared

to Vancomycin/Linezolid

Boucher et al. (2014) N Engl J Med 370:2169

Skin Infections: Approach to

Treatment
Hospital Admission

Severity
of Infection

Switch Therapy
Hospital Discharge

IV
Therapy
PO
Therapy

Cure

Inpatient Outpatient Time

Treatment Treatment
The Annals of Pharmacotherapy 1998; 32: S22-26.

Country-Specific Patterns for Observed IV

Days and Length of Stay From cSSTI Index
h
h

Mean IV LOT ranged from 10-19 days

Mean LOS ranged from 15-25 days
IV days- Random Cohort

20.6
14

Days

22.1

19.4
15.2
11.7

15

25

23.1

22.1

22

19.4
13.4

LOS- Random Cohort

18.2 18.6

14.8

21.8
16.4

12.1

Eckmann C, et al. Int J Antimicrob Agents. 2014;44(1):56-64

18.3
12.7

13.9

15.2
10.1

Pan-European early switch/early discharge

opportunities exist for hospitalized patients with
MRSA cSSTI
h

Literature review with expert validation formed the basis for 14 criteria used in the study;
inclusive of Desai & Parodi criteria

The key (essential) criteria were selected by KOLs, and were used to estimate ES/ED
hypothetical opportunities

Stable clinical
infection

Afebrile/Temp
<38o C for 24 hrs

White cell count

normalizing
(WBC 4-12 x 109/L)

No unexplained
tachycardia

Systolic BP
100 mm Hg

Patient tolerates
oral fluids/diet

ES
ED

No other reason to
stay in hospital
except infection
management

Nathwani D, et al. Clin Microbiol Infect. 2014 Mar 27. doi: 10.1111/1469-0691.12632..

Possibility of Early Switch to Oral Antibiotics for

Patients With MRSA cSSTI in a Pan-EU Studya
h

33.6% of MRSA cSSTI patients

treated with IV antibiotics met ES
criteria and potentially could
have discontinued IV therapy
6.0 5.5 days sooner

1502 patients hospitalized with MRSA cSSTI

ES eligibleb patients, n=504/1502

Potential to save
6.0 IV line days
due to ES
eligibility

Nathwani D, et al. Clin Microbiol Infect. 2014 Mar 27. doi: 10.1111/1469-0691.12632.