J Antimicrob Chemother 2011; 66: 1360 1364

doi:10.1093/jac/dkr102 Advance Access publication 9 March 2011

Impetigo in a population over 8.5 years: incidence, fusidic acid

resistance and molecular characteristics
Sverre Rrtveit 1,2*, Dag Harald Skutlaberg 3, Nina Langeland 4 and Guri Rortveit 2,5
1

Municipal Health Services of Austevoll, Bekkjarvik, Norway; 2Department of Public Health and Primary Health Care, University of Bergen,
Bergen, Norway; 3Department of Medical Microbiology, Haukeland University Hospital, Bergen, Norway; 4Institute of Medicine, University
of Bergen, Bergen, Norway; 5Research Unit for General Practice, Uni Health, Bergen, Norway
*Corresponding author. Tel: +47-41667539; Fax: +47-56180385; E-mail: sverre.rortveit@aknett.net

Received 27 December 2010; returned 22 January 2011; revised 16 February 2011; accepted 17 February 2011

Patients and methods: All encounters with general practitioners regarding impetigo were registered. Bacterial
swabs were taken in a high percentage of cases. Annual incidence was calculated. Phenotypic characteristics of
the bacteria were determined for the whole period, and in 2008 and 2009 we also performed PFGE and
spa typing.
Results: Outbreaks of impetigo were observed in 2002, 2003 and 2004, but since then the incidence decreased
greatly. S. aureus was cultured from the impetigo site in the majority of cases. The proportion of S. aureus isolates resistant to fusidic acid decreased from 80% in 200204 to 45% in 2008 09. For 28 S. aureus isolates
analysed by molecular methods in 200809, we found that nearly all cases of fusidic acid resistance were
due to the presence of the EEFIC.
Conclusions: S. aureus resistance to fusidic acid in relation to impetigo is now less frequent in this population
than at the start of the century. At present, most S. aureus bacteria resistant to fusidic acid in impetigo belong
to the EEFIC.
Keywords: population based, S. aureus, fusidic acid resistance, clone

Introduction
Impetigo is a superficial skin infection most commonly found in
children.1 Staphylococcus aureus and group A streptococci are
the bacterial agents commonly related to impetigo, the former
being in the majority. Superficial staphylococcal skin infections
are among the indications for use of the antibiotic fusidic acid.
Its antibacterial action is inhibition of bacterial protein synthesis
by interfering with dissociation of elongation factor G (EF-G) from
the ribosome. Resistance to fusidic acid in S. aureus is caused by
a genetic mutation causing alteration of the EF-G protein
(FusA class) or by expression of a protein that protects the
drug target on the EF-G (FusB and FusC classes).2 The corresponding gene determinants are designated fusA, which is considered to originate from spontaneous mutations in the
chromosomally located gene for EF-G, and fusB and fusC,
which may both be chromosomal- or plasmid-mediated, and
are considered acquired resistance genes.

In 2002 one Norwegian and one Swedish study were published reporting laboratory data from 2000 and 2001 on the
increasing incidence of impetigo-associated fusidic acid-resistant
S. aureus, and genetic analysis by PFGE showed that the great
majority of isolates from both countries belonged to a single
clone.3,4 In 2004 one study from the UK, reporting data from
1997 2001, demonstrated a high frequency of S. aureus resistance to fusidic acid in impetigo, and consecutive molecular analyses of isolates from 2002 showed that the fusidic acid-resistant
isolates belonged to one clone.5 The EPISA study of antimicrobial
susceptibility of S. aureus-related skin and soft tissue infections in
France, the UK and Ireland during 2003 04 also studied the
prevalence of the epidemic European fusidic acid-resistant
impetigo clone (EEFIC) in general practice. The proportion of
EEFIC was 78% for impetigo in UK and Ireland.6
During what was perceived as an epidemic outbreak of impetigo in 2003, 15 impetigo isolates from Norway, Sweden,
Denmark, Ireland and the UK were analysed by ONeill et al.7

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Objectives: From around year 2000, impetigo caused by fusidic acid-resistant Staphylococcus aureus was
observed in countries of Northern Europe. The bacteria were found to represent a clone, the epidemic European
fusidic acid-resistant impetigo clone (EEFIC). This study reports longitudinal data on the incidence and bacteriology of impetigo in a Norwegian island community during the years 2001 09.

JAC

Incidence of impetigo in a general population

Throughout the study period, all the bacteriological specimens were

investigated at the Department of Medical Microbiology, Haukeland
University Hospital, Norway. Fusidic acid susceptibility was determined
by disc diffusion according to the routine procedures of the laboratory.
MICs of erythromycin, clindamycin, fusidic acid, ciprofloxacin,
tetracycline, co-trimoxazole and rifampicin were determined using
Etest (AB Biodisk, Solna, Sweden) on MuellerHinton II agar medium
according to the manufacturers instructions. The European Committee
on Antimicrobial Susceptibility Testing (EUCAST) breakpoint was used to
categorize the isolates as susceptible (MIC 1 mg/L) or resistant
(MIC. 1 mg/L) to fusidic acid.
PFGE using SmaI was carried out as described in the Nordic PFGE
protocol.8 Comparisons were made with a reference strain which
belongs to the EEFIC and is identical to a strain investigated by
Tveten et al.3 and ONeill et al.7 Band patterns were compared visually
and differences evaluated as described by Tenover et al.9 According to
the degree of relatedness to the reference strain, the isolates were
assigned as being identical, closely related, possibly related or not
related.
Isolates indicated by PFGE to belong to the EEFIC were further
analysed by staphylococcal protein A (spa) typing. This was done
in St Olavs University Hospital, Department of Medical Microbiology,
Trondheim, Norway, and was performed as previously described.10 The
spa types were assigned through the Ridom database. spa types that
shared identical repeat units arranged in an identical or similar order
were assigned as identical or closely related, respectively. spa types
with repeat units that differed markedly from the reference strain were
assigned as not related. Additionally, isolates showing resistance to
fusidic acid by Etest were spa typed. To be defined as EEFIC in the
present study, isolates had to show both PFGE pattern and spa typing
to be at least closely related to the EEFIC reference strain.
For comparison of the impetigo-causing strains of S. aureus with
strains causing other types of superficial skin infections, one of the
general practitioners (S. R.) collected swabs from such infections as
well. For those specimens yielding growth of S. aureus, a disc diffusion
test, Etest and PFGE analysis were performed as described above.
Data were registered and analysed in SPSS 18.0. We performed x2
analyses for comparison of proportions and for tests for trend. P values
,0.05 were considered significant.

Methods
The study was conducted as a long-term population-based investigation.
The population of the community was 4417 by 1 January 2009, and this
number was used to calculate incidence rates. Ferries and boats are the
only connection with the mainland. There are four general practitioners in
the municipality. They identified all patients with the clinical diagnosis of
impetigo and were urged to collect a swab for bacteriological analysis of
all cases.
The methods of identifying the patients and their inclusion in the
study have been described in detail previously.1 In short, we made an
operational definition of impetigo as being a superficial skin infection
with spontaneous erosions and/or crusts and/or bullae. The basis for
inclusion of impetigo cases was patients seen by the doctor and diagnosed as having impetigo. Incidence rates are given per person-year.

Table 1. Yearly incidence rates (per person-year) and microbial characteristics of impetigo in the total population (N 4419)a
EEFIC isolates

Year
2001
2002c
2003c
2004c
2005
2006
2007
2008
2009

Impetigo
cases (n)
20
115
85
72
42
42
25
35
17

Incidence

Swabs
taken,
n (%)

Growth of
S. aureus,
n (%)

Resistant
to fusidic
acidb,
n (%)

0.0091
0.0260
0.0192
0.0163
0.0095
0.0095
0.0057
0.0079
0.0038

10 (50)
90 (78)
63 (74)
53 (74)
39 (93)
38 (90)
18 (72)
35 (100)
15 (88)

9 (90)
75 (83)
47 (74)
46 (87)
24 (62)
27 (71)
16 (89)
25 (71)
9 (60)

6 (67)
65 (87)
33 (70)
37 (80)
11 (46)
16 (59)
13 (81)
11 (44)
5 (56)

Non-EEFIC isolates

PFGE
performed

spa typing
performed

resistant
to fusidic
acid, n (%)

susceptible
to fusidic
acid, n (%)

resistant
to fusidic
acid, n (%)

susceptible
to fusidic
acid, n (%)

21
7

9
4

8 (89)
2 (100)

1 (11)
0 (0)

0 (0)
2 (40)

12 (100)
3 (60)

PFGE and spa typing were only performed in 2008 and 2009. In 2001, impetigo was registered for only the last half of the year.
Data from 2001 05 have been published previously.1
b
Proportion of swabs with fusidic resistance per number of swabs with S. aureus.
c
Years of epidemic impetigo outbreak.1
a

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They found these strains to represent a clone that carried a chromosomal fusB determinant. Resistance to fusidic acid in a collection of non-impetigo strains resulted, on the other hand,
primarily from mutations in fusA. The clone was designated
EEFIC. ONeill et al. later performed detailed characterization of
the clone. Molecular typing revealed the EEFIC to belong to the
genetic type ST123, spa type t171 and agr type IV. PCR analysis
identified genes encoding toxins implicated in impetigo (exfoliative toxins A and B and EDIN-C).
From Norway, we reported data from a longitudinal study of
impetigo in the entire population of the island community of Austevoll, Western Norway, during the years 2001 05,1 where we
documented outbreaks of impetigo in the seasons of summer
and early autumn in the period 200204, which were related to
fusidic acid-resistant S. aureus. We here present continued data
on impetigo from the same population, over a time span of
8.5 years. The aims of the present study were as follows: first, to
report the incidence of impetigo over a long time period; second,
to report changes in fusidic acid resistance in impetigo-related
S. aureus over time; and third, to investigate if the EEFIC is still
responsible for most impetigo cases in this population.

Rrtveit et al.

Ethics approval was obtained from the Regional Committee for

Medical Research Ethics, and the study was also approved by the
Ombudsman for Privacy in Research, Norwegian Social Science Data
Services.

Results and discussion

The annual incidences of impetigo for the period 200109
are given in Table 1. After a maximum in 2002, there was

Table 2. PFGE typing, spa typing and MIC determination for 28 impetigo and 11 non-impetigo S. aureus isolates, according to relatedness to the
EEFIC
MIC (mg/L) according to Etest
Isolate no.

spa relatedness

FUS

ERY

CLI

CIP

TET

SXT

RIF

Impetigo isolates
ref. strain
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28

CR
CR
CR
CR
CR
CR
CR
CR
CR
CR
CR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR

ID
ID
ID
ID
ID
ID
ID
ID
CR
CR
CR
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NR
NR
NA
NA
NA

4
4
4
4
4
4
4
3
4
0.064
4
4
0.047
0.125
0.094
0.125
0.094
0.047
0.094
0.064
0.064
0.064
0.064
0.094
3
4
0.064
0.094
0.064

0.19
0.25
0.047
0.125
0.125
0.19
0.19
0.125
0.19
0.125
0.19
0.125
0.25
256
0.19
0.25
256
0.19
0.125
0.125
0.125
0.125
0.125
0.125
256
0.19
256
0.125
0.125

0.064
0.047
0.19
0.047
0.047
0.064
0.047
0.047
0.047
0.047
0.047
0.047
0.094
0.064
0.064
0.125
0.047
0.047
0.047
0.047
0.064
0.047
0.047
0.032
256
0.032
0.047
0.032
0.064

0.38
0.25
0.38
0.38
0.38
0.38
0.38
0.38
0.38
0.38
0.25
0.38
0.25
0.38
0.25
0.25
0.25
0.25
0.38
0.38
0.38
0.38
0.064
0.25
0.25
0.25
0.38
0.19
0.25

0.19
0.125
0.19
0.19
0.19
0.19
0.19
0.125
0.19
16
0.19
0.125
0.19
0.38
0.19
0.25
0.25
0.25
0.19
0.19
0.19
0.25
0.38
0.125
6
6
0.19
0.25
0.125

0.094
0.064
0.064
0.094
0.094
0.064
0.094
0.064
0.094
0.047
0.064
0.064
0.047
0.047
0.047
0.047
0.047
0.047
0.064
0.064
0.064
0.047
0.125
0.047
0.032
0.032
0.064
0.032
0.047

0.008
0.006
0.006
0.008
0.006
0.006
0.008
0.008
0.008
0.008
0.008
0.006
0.012
0.016
0.006
0.012
0.012
0.25
0.012
0.006
0.006
0.006
0.032
0.006
0.008
0.008
0.006
0.006
0.012

Non-impetigo
isolates
29
30
31
32
33
34
35
36
37
38
39

NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR

NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA

0.064
0.094
0.064
0.094
0.064
0.094
0.094
0.064
0.064
0.064
0.094

0.19
0.19
0.125
0.125
0.125
0.125
0.125
0.25
0.125
0.094
0.125

0.047
0.064
0.064
0.047
0.047
0.032
0.047
0.064
0.047
0.047
0.032

0.38
0.5
0.38
0.25
0.38
0.19
0.125
0.25
0.25
0.25
0.25

0.19
0.38
0.125
0.25
0.25
0.19
0.19
0.125
0.19
0.19
0.19

0.047
0.047
0.047
0.047
0.047
0.047
0.047
0.064
0.047
0.064
0.047

0.008
0.012
0.006
0.012
0.006
0.012
0.012
0.008
0.012
0.008
0.008

CR, closely related; ID, identical; NR, not related; NA, not applicable; FUS, fusidic acid; ERY, erythromycin; CLI, clindamycin; CIP, ciprofloxacin; TET,
tetracycline; SXT, trimethoprim/sulfamethoxazole; RIF, rifampicin.
EEFIC isolates are marked in bold.

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PFGE relatedness

JAC

Incidence of impetigo in a general population

The strength of the present study is the consistent and maintained ascertainment of impetigo diagnoses in the total population of a geographically demarcated community over a long
time span, thus being able to present incidence and proportions
with a high reliability. The main weakness is that we have molecular data only for the last 2 years.

Acknowledgements
We thank Yvonne Muller and Aud Lysberg (Department of Medical
Microbiology, Haukeland University Hospital) for technical assistance
with the PFGE and Etest analyses, Lillian Marstein (Department of
Medical Microbiology, St Olavs University Hospital) for technical
assistance with the spa typing and the general practitioners of
Austevoll who diagnosed and treated the patients in this study.

Funding
This work was supported by the Foundation for Research in General Practice (grant number 07/698) and the Norwegian Surveillance System for
Antimicrobial Resistance (grant 22.12.2008).

Transparency declarations
None to declare.

References
1 Rrtveit S, Rortveit G. Impetigo in epidemic and nonepidemic phases:
an incidence study over 412 years in a general population. Br J Dermatol
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2 Lannergard J, Norstrom T, Hughes D. Genetic determinants of
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3 Tveten Y, Jenkins A, Kristiansen BE. A fusidic acid-resistant clone of
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resistant to fusidic acid from community-acquired skin and soft tissue
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7 ONeill AJ, Larsen AR, Henriksen AS et al. A fusidic acid-resistant
epidemic strain of Staphylococcus aureus carries the fusB determinant,
whereas fusA mutations are prevalent in other resistant isolates.
Antimicrob Agents Chemother 2004; 48: 35947.
8 Zinn CE, Salmelinna S, Fussing V et al. A multicenter study in Denmark,
Finland, Sweden and Norway: reproducibility of methicillin-resistant
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a marked decline in incidence (P,0.001). Bacterial swabs

were taken from 79% of the patients, and S. aureus was
grown in 77% of the cases where swabs were taken
(Table 1). The proportion of S. aureus isolates resistant to
fusidic acid decreased during the period 2002 09
(P,0.001), with a mean of 80% in the epidemic years of
2002 04 and a mean of 55% in the non-epidemic years
of 200509. For the years when supplementary molecular
analyses were performed (2008 09), this proportion was
45%.
From the 52 impetigo cases in 2008 and 2009, 50 swabs
were taken and S. aureus isolated in 33. Of these, 28 were investigated by Etest and PFGE analysis and 13 were consecutively
spa typed. Of the 28 S. aureus isolates that were subject to molecular analyses, 11 were found to be related to the EEFIC
(Table 2). None showed PFGE identity with the reference strain
collected in 2001, but eight had an identical spa type (t171),
while three isolates had closely related spa types. One of
these was susceptible to fusidic acid. The others were resistant
to fusidic acid, with MIC values of 34 mg/L. The EEFIC clone
was responsible for 83% (10 out of 12) of S. aureus isolates
with resistance to fusidic acid, and 91% (10 out of 11) of
EEFIC isolates were resistant to fusidic acid.
From 11 S. aureus isolates from skin infections other than
impetigo analysed by Etest and PFGE, all turned out to be
fusidic acid susceptible, and none was related to the EEFIC.
The results of Etest analysis are shown in Table 2.
Generally, previous studies of the prevalence of EEFIC-related
impetigo have reported data from hospitals or general practice
without access to the denominator of the population they are
recruiting from, and hence cannot provide incidence statistics.
Thus, the notion that there has been an epidemic of impetigo
in Scandinavia, the UK and Ireland caused by the EEFIC has scarcely been supported by evidence until now. Our data are based
on the total number of impetigo cases registered in general practice in a well-defined community, which allows precise estimates
of incidence. In this community there were outbreaks of impetigo related to fusidic acid-resistant S. aureus during the years
2002 04, and marked declines in the incidence of impetigo
and also of fusidic acid resistance in impetigo-related S. aureus
have occurred in the years after that. Our data show that for
the years 2008 09 the EEFIC was still responsible for the
majority of cases of fusidic acid-resistant impetigo in our
community.
An important question is what has happened to fusidic acid
resistance in S. aureus related to superficial skin infections and
to the EEFIC. Recently, a Swedish study in patients attending a
dermatological outpatient clinic for impetigo and infected
atopic dermatitis in the years 2004 08 showed that in 2004,
33% and 12% of the S. aureus isolates were resistant to fusidic
acid in impetigo and infected atopic dermatitis, respectively. In
2008 the corresponding figures were 24% and 2.2%, indicating
a diminishing rate of S. aureus resistance to fusidic acid in superficial skin infections.11 No molecular typing was performed. The
Norwegian Surveillance System for Antimicrobial Resistance
reported that the proportion of S. aureus from skin and soft
tissue infections being resistant to fusidic acid was steadily
falling from a maximum of 25% in 2004 to about 10% in
2008, interpreting this as probably stemming from reduced
presence of the EEFIC.12

Rrtveit et al.

9 Tenover FC, Arbeit RD, Goering RV et al. Interpreting chromosomal DNA

restriction patterns produced by pulsed-field gel electrophoresis: criteria
for bacterial strain typing. J Clin Microbiol 1995; 33: 2233 9.

11 Alsterholm M, Flytstrom I, Bergbrant IM et al. Fusidic acid-resistant

Staphylococcus aureus in impetigo contagiosa and secondarily infected
atopic dermatitis. Acta Derm Venereol 2010; 90: 52 7.

10 Harmsen D, Claus H, Witte W et al. Typing of methicillin-resistant

Staphylococcus aureus in a university hospital setting by using novel
software for spa repeat determination and database management.
J Clin Microbiol 2003; 41: 54428.

12 NORM/NORM-VET 2008. http://www.vetinst.no/nor/Forskning/Publikasjoner/

Norm-Norm-Vet-rapporten/Norm-Norm-Vet-rapporten-2008 (11 December
2010, date last accessed).

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