Antonie van Leeuwenhoek (2009) 95:387–394
DOI 10.1007/s10482-009-9318-7
SHORT COMMUNICATION
Epidemiological investigation of nosocomial outbreak
of staphylococcal skin diseases in neonatal ward
J. Kurlenda Æ M. Grinholc Æ
J. Krzysztoń-Russjan Æ K. Wiśniewska
Received: 9 July 2008 / Accepted: 9 February 2009 / Published online: 21 February 2009
Ó Springer Science+Business Media B.V. 2009
Abstract During a 1-month period, eight neonates
developed staphylococcal skin disease diagnosed as a
bullous impetigo in the maternity unit of the Provincial
Hospital in Gdansk. An epidemiological investigation
based on phenotyping and genotyping methods was
performed. All neonates involved in the outbreak, their
mothers and 15 staff members were screened for
carriage of Staphylococcus aureus by nasal swabs.
Isolated strains were compared with strains cultured
Electronic supplementary material The online version of
this article (doi:10.1007/s10482-009-9318-7) contains
supplementary material, which is available to authorized users.
J. Kurlenda
Department of Clinical Bacteriology in Hospital, Monte
Cassino 13, 75-340 Koszalin, Poland
J. Kurlenda (&) M. Grinholc
Intercollegiate Faculty of Biotechnology, Laboratory
of Molecular Diagnostics, Department of Biotechnology,
University of Gdansk and Medical University of Gdansk,
Kladki 24, 80-822 Gdansk, Poland
e-mail: bakteriologia@op.pl
J. Krzysztoń-Russjan
National Medicine Institute, Chelmska 30/34, 00-725
Warsaw, Poland
K. Wiśniewska
Department of Microbiology, Medical University,
Do Studzienki 38, 80-227 Gdansk, Poland
from affected skin and purulent conjunctiva of
infected newborns. Isolates were analyzed for the
presence of the etA and etB genes using polymerase
chain reaction and genotyped by pulsed-field gel
electrophoresis (PFGE) and coa gene polymorphism.
The analyzed S. aureus strains were methicillinsensitive and could be divided into two groups
according to antibiotyping, phage typing, coa polymorphism and PFGE pattern. The first group consisted
of etA and etB negative strains, and the second one
involved only the etB positive ones. Our results have
shown that there were two different clusters of
infection caused by two populations of S. aureus
strains. Among the 15 medical staff members screened
we have found seven carriers. However, phage typing
revealed that distinct strains unrelated to the outbreak
isolates were carried. Although we have not been able
to establish the source of bacteria involved in the
outbreak, our results suggest that for both groups,
mothers could be the source of the infecting strains.
Keywords Bullous impetigo
Epidemiological investigation
Staphylococcal skin diseases
Staphylococcus aureus causes a variety of infectious
diseases, ranging from superficial skin infections to
severe, toxin-mediated systemic infections (Kurlenda
et al. 2008). S. aureus produces many extracellular
products, including toxins that affect host cell
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function. Staphylococcal scalded skin syndrome
(SSSS) and bullous impetigo are toxin-mediated
diseases common in neonatal wards as outbreaks.
SSSS is used to describe a collection of blistering skin
diseases caused by the exfoliative toxins (ETs) that
cause exfoliation without necrolysis or inflammatory
response of the skin (El Helali et al. 2005). Serologically, the toxins are distinguished into two types,
chromosomally encoded exfoliative toxin A and
plasmid born toxin B (Kaplan et al. 1986; Ladhani
et al. 1999, 2001; Dinges et al. 2000; Hanakawa et al.
2002). Clinically SSSS ranges from a few localized
blisters to a generalized disease affecting a large area
of the skin surface. In the generalized SSSS, blister
fluid tends to be sterile, and the infecting strain is
usually recovered from distant sites, such as throat
and/or nose. Blood cultures are usually negative
(Ladhani et al. 1999; El Helali et al. 2005). Bullous
impetigo is diagnosed as localized bullous lesions and
exfoliation without fever. Infecting strains are recovered from bullae (Acland et al. 1999; El Helali et al.
2005). Usually, the diseases described above affect
infants and young children but they can also occur in
adults with serious underlying diseases (Florman and
Holzman 1980; Ladhani et al. 1999). Hospital
acquired SSSS and bullous impetigo are the consequence of cross-infection and may lead to outbreak
clusters, mainly in the nursery. Typically, the usual
source of the ET producing strains are the anterior
nares of asymptomatic carriers such as nursery staff
or, more rarely, inanimate objects (Kaplan et al. 1986;
Ladhani et al. 1999; Tenover and Gaynes 2000). In the
general population, nasal carriage occurs approximately in 35–60% of individuals (Ladhani et al. 1999;
Makhoul et al. 2001). Nursery-associated outbreaks
usually occur during the first month after discharge
from the hospital (Kaplan et al. 1986; de Lencastre
et al. 1994; Ladhani et al. 1999). Bacteriophage
typing, PFGE (pulse field gel electrophoresis) typing
and determination of specific gene polymorphisms,
e.g. coagulase (coa), are performed to investigate
outbreaks (Goh et al. 1992; Goering 1993; Tenover
et al. 1995; Ladhani et al. 1999; NCCLS 2004). To
support the clinical diagnosis, strains isolated from the
patients and carriers should be evaluated for the
production of ET A and/or B using a range of
available tests including radioimmunological assays
(RIA), ELISA, Ouchterlony immunodiffusion assay,
Western blot analysis or polymerase chain reaction
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Antonie van Leeuwenhoek (2009) 95:387–394
(PCR; Kaplan et al. 1986; Ladhani et al. 1999, 2001;
Dinges et al. 2000; Hanakawa et al. 2002).
In this study we have evaluated a 1-month long
outbreak of staphylococcal skin diseases in neonates
that were clinically diagnosed with bullous impetigo in
the Provincial Hospital in Gdansk. We have analyzed
the relatedness of isolated S. aureus strains by
phenotyping and genotyping methods, and assessed
their potency to produce ET.
The 70-beds obstetric and newborn unit is part of a
700-bed Provincial Hospital in Gdansk. The postpartum area is placed on two floors. On the first floor,
there are eight 4–7 bed rooms for mothers and
neonates (rooming in), two 2 beds for patients after
surgery delivery, and two rooms with 6 beds for
mothers with septic problems. On the same floor,
there is a 12-bed neonatal pediatric ward. On the
ground floor, a unit for pre-term babies (three rooms
with 2 beds) is located. Eight newborn children with
blistering and purulent skin diseases or conjunctivitis,
one child-carrier, eight mothers and fifteen persons
from the medical staff were screened. The material
specimens taken to bacteriological analysis were as
follows: swabs taken from anterior nares, affected
skin, conjunctiva, and pus from mother’s mamilla.
Demographic and clinical data are listed in Table 1.
The swabs or pus specimens from neonates, mothers and those from carriage screening were routinely
cultured on Columbia agar plates supplemented with
5% sheep blood (Oxoid). S. aureus was identified using
standard microbiological techniques along with Gram
staining, Slidex Staph Plus test (BioMerieux) and tube
testing method using rabbit plasma for free coagulase
determination. The antibiotic susceptibility of S.
aureus was determined by the disk-diffusion method
on Mueller–Hinton agar II (Oxoid) according to the
guidelines of the National Committee for Clinical
Laboratory Standards (CLSI; Hryniewicz et al. 2001).
A panel of antibiotic disks (Becton Dickinson) was
used, including gentamycin 10 lg, erythromycin
15 lg, clindamycin 2 lg, rifampin 5 lg, tetracycline
30 lg, chloramphenicol 30 lg, trimethoprim/sulfamethoxazole 1,25/23,75 lg, vancomycin 30 lg and
oxacillin 1 lg. For mupirocin 200 lg criteria accordingly to national recommendation were adopted (Blair
and Williams 1961).
Bacteriophage typing was performed using the
international phage set, according to Blair and
Williams method (Aucken and Westwell 2002) at
Antonie van Leeuwenhoek (2009) 95:387–394
389
Table 1 Characteristic of the case patients and their mothers
Patient
1c
No of days
after birth
10
Specimen
Pus from conjuctiva
S. aureus
culture
P
Clinical features
Conjunctivitis
Nares
1m
2c
5
2m
a
Coa
pattern
PFGE
pattern
ETA
ETB
95
N
A1
N
N
95
N
Nd
Nd
Nd
I
I
95
N
A1
N
N
I
Affected skin
P
Single blisters with
infected fluid
95
N
A1
N
N
I
Pus from mamilla
P
Breast abscess
95
N
A1
N
N
I
P
Single blisters with
infected fluid
95
N
A1
N
N
I
95
N
Nd
Nd
Nd
I
NC
95
N
Nd
Nd
Nd
I
Nares
P
3cIIb
6
Nares
P
4m
Phage
type
NC
Affected skin
5
Group
P
6
4c
ETs
detection
Nares
3cI
3m
Strain typing
Nares
N
NC
–
–
–
–
–
–
Pus from conjunctiva
P
Conjunctivitis
95
N
A1
N
N
I
Nares
N
NC
–
–
–
–
–
–
5m
24c
Pus from mamilla
P
Breast abscess
95
N
A1
N
N
I
6c
34
Affected skin
P
Numerous blisters
with infected fluid
95
55/71
N
P
A2
B2
N
N
N
P
I
II
7c
7
Affected skin
P
Exfoliation
55/71
P
B1
N
P
II
Nares
P
55/71
P
–
–
–
II
Nares
N
NC
–
–
–
–
–
–
Affected skin
P
Exfoliation
55/71
P
B3
N
P
II
Nares
P
NC
55/71
P
B1
–
P
II
Affected skin
P
Exfoliation
55/71
P
B1
N
P
II
Nares
P
55/71
P
Nd
Nd
Nd
II
Nares
N
–
–
–
–
–
–
7m
8c
13
8m
9c
7
9m
a
First twin
b
Second twin
c
After delivery
NC
c child, m mother, P positive, N negative, Nd not determined, NC no clinical signs
Routine Test Dilution (RTD). When the investigated
strains displayed no lysis, a 100 times greater
concentration (RTD 9 100) was employed (Struelens
et al. 1996).
The coa gene polymorphism was determined by a
PCR method. Isolation of the genomic DNA was
performed according to methods designed for
S. aureus (Tenover et al. 1995). Two different
primers (Genset Oligos) C2 and C3 were used in
this typing assay. Their sequences were as follow,
C2: 50 -CGA GAC CAA GAT TCA ACA AG-30 and
C3: 50 -AAA GAA AAC CAC TCA CAT CA-30 . Each
amplification was performed in a final volume of
50 ll consisting of 200 lM of each dNTP, 2.5 pmol
of each primer, and 0.25 units of DyNAzymeTMII
DNA polymerase (Fermentas). Amplification was
performed in a Perkin–Elmer thermocycler (Norwalk,
Conn.) and consisted of the following steps: predenaturation at 95°C for 2 min followed by 30 cycles of
denaturation at 95°C for 1 min, annealing at 55°C for
2 min, primer extension at 72°C for 4 min, and final
elongation at 72°C for 2 min. The amplification
products were analyzed by 2% agarose gel electrophoresis. PCR products were digested with AluI
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390
restriction endonuclease (Fermentas) for minimum
3 h at 37°C. DNA restriction fragments were
resolved in 4% agarose gels. Band patterns were
interpreted visually by comparing to a DNA marker
(50 bp DNA Ladder Fermentas).
The presence of the etA and etB genes was
analysed by the PCR technique. The specific primers
(Tib Molbiol), 50 -CTA GTG CAT TTG TTA TTC
AA-30 and 50 -GTA ATA TTT CTT TGA CTT CA-30 ,
corresponding to nucleotides 61–80 and 50 -TGC ATT
GAC ACC ATA GTA CTT ATT C-30 corresponding
to nucleotides 428–447 of the etA sequence, and
primers 50 -GCA AAA GAA TAC ACG-30 corresponding to nucleotides 90–105 and 50 -CAG GTA
TAT TAG CTG G-30 corresponding to nucleotides
423–510 of the etB sequence were used. A single
reaction mixture contained 1 lg of DNA, 50 pmol of
each primer, 100 lM dNTPs, 1 U of Taq polymerase
(Boehringer Mannheim), and buffer with 2.5 mM
MgCl2 supplied by the manufacturer of the enzyme.
The reactions were run under the following conditions: 5 min at 94°C; 30 cycles of 15 s at 94°C, 15 s
at 55°C, and 30 s at 72°C; and finally 7 min at 72°C.
The PCR products were analyzed by 1% agarose gel
electrophoresis.
Preparations of genomic staphylococcal DNA and
SmaI (MBI Fermentas) digestion were performed as
described previously (Goering 1993). Separation of
DNA fragments was achieved using a CHEF DR II
apparatus (BioRad), in 1% Pulsed-Field-Certified
Agarose gels (BioRad). The total run time was 22 h
at 6 V/cm, with a linear ramped switch time from 1 to
30 s. Different PFGE types were identified using the
recently described criteria (Goh et al. 1992; NCCLS
2004). Pulsotypes were marked with the capital
letters, and the subtypes indicating closely related
strains with additional numbers (Table 1). The correlation coefficient was calculated according to Dice
(Plano et al. 2001).
Nine neonates, including a pair of twins and eight
mothers staying at the hospital during the 1-month
outbreak period were analyzed (Table 1). Six of nine
infants demonstrated localized skin changes such as
bullous impetigo and two of them only conjunctivitis. One neonate (the second twin) was identified
as a S. aureus carrier in nares without any signs of
infection. Six neonates developed the disease symptoms 5–7 days after delivery. In two cases the
symptoms were noticed 10 and 13 days after birth,
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Antonie van Leeuwenhoek (2009) 95:387–394
whilst one neonate developed the symptoms 34 days
after birth. In these cases readmission to the hospital
was necessary (Table 1). All children were term
delivered and with no identified underlying disease.
The newborns numbered from 1 to 5 (Table 1) were
grouped in the same room and those numbered 6–9
in another room ca. 1 week later. One mother was
also admitted to the gynecological ward because of a
mamillary abscess 24 days after she gave birth to
her child (Table 1). She was delivered to the
obstetric ward at the time of the outbreak (Table 1).
Apart from skin lesions, none of the neonates was
feverish. All children with infections and the patient
admitted to the gynecological ward were treated
parenterally with amoxicillin/clavulanic acid. When
the first two cases of skin lesions were reported,
strict hygiene rules such as barrier nursing techniques, minimal handling, hand-washing, cleaning of
stethoscopes and thermometers were introduced (See
Online Supplementary Material). Mothers caring for
their children themselves were instructed to oblige
with these procedures.
In the course of the epidemiological investigation,
18 S. aureus strains from the affected skin regions,
conjunctiva, mamillary pus and from the carriers
were isolated. All strains were sensitive to methicillin
and produced b-lactamases. On the basis of antibiotyping, two clusters of strains could be identified. The
first group consisted of 11 strains sensitive to
tetracycline and MLS (macrolides, lincosamides and
streptogramins). These strains were all determined to
be of phage type 95 (Table 1). They were negative
for restriction digestion by AluI and thus had no coa
polymorphism pattern (Fig. 1). With the use of
PFGE, 8 strains were determined to be the same
clone and assigned as A (seven as a subtype A1 and
one as subtype A2; Fig. 2). Subtype A2 differed from
Subtype A1 by absence of a single band (Fig. 2).
These strains were negative for the presence of two
ET genes (Fig. 3).
The second group consisted of 7 strains resistant to
tetracycline and MLSi (inducible). All of them were
identified to be of phage type 55/71. After restriction
analysis of the coa gene PCR product, these strains
revealed the same coagulase gene polymorphism
(Table 1; Fig. 1). When the PFGE technique was
applied, five strains were assigned to be the clone B
with subtypes B1, B2, B3 (Fig. 2). All of these strains
were etB-positive (Fig. 3). From one patient no 6
Antonie van Leeuwenhoek (2009) 95:387–394
Fig. 1 RFLP patterns of AluI restriction enzyme digestion of
the PCR—amplified coagulase gene products of representative
S. aureus strains. Lane 1—molecular weight marker (50 bp
ladder Plus); lanes 2, 3: pattern P, lanes 4, 5 (strains 7c and 8c);
pattern N (strains 4c and 5m)
Fig. 2 PFGE of SmaI digested genomic DNA of S. aureus
clinical isolates. Lanes 1, 15: lambda ladder; lanes 2, 3, 4, 5, 7,
8, 11: pattern A1; lane 6: pattern A2; lane 9: pattern B3; lane
10: pattern B2; lanes 12, 13, 14: pattern B1. Strains isolated
from patients no: lane 2: patient 1c; lane 3: patient 1m; lane 4:
patient 2c; lane 5: patient 2m; lane 6: patient 6c; lane 7: patient
3cI; lane 8: patient 4c; lane 9: patient 8c; lane 10: patient 6c;
lane 11: patient 5m; lane 12: patient 7c; lane 13: patient 8m;
lane 14: patient 9c
391
Fig. 3 Agarose gel electrophoresis of PCR products for
exfoliative toxin genes. Lanes M: DNA molecular size marker
(100 bp ladder). Tested isolates are listed as below: lanes 1, 2:
patient 6c; lanes 3, 4: patient 7c; lanes 5, 6: patient 8c; lanes 7,
8: patient 1c; lanes 9, 10: patient 8m; lanes 11, 12: patient 1m;
lanes 13, 14: patient 2c; lanes 15, 16: patient 9c; lanes 17, 18:
patient 2m; lanes 19, 20: patient 3cI; lanes 21, 22: patient 4c;
lanes 23, 24: patient 5m; lanes 25, 26: patient 6c; lanes 27, 28:
strain no 2915/00 used as a positive control
(Table 1) two strains from both groups were isolated
(Table 1).
Among 15 medical staff members screened we
have found seven S. aureus carriers. However, the
phage typing revealed isolates distinct from those
involved in the outbreak such as phage types 84, 84/
95, 29/79, and 53. Two of them were not typable. All
of these strains were sensitive to the antibiotic panel
tested and were b-lactamase positive.
SSSS and bullous impetigo is a frequently
observed, usually health-care associated infection in
infants and children (Kaplan et al. 1986; de Lencastre
et al. 1994; Ladhani et al. 1999; Tenover and Gaynes
2000). About 30% of neonates are colonized by S.
aureus within the first week after birth whilst some
studies have reported carriage rates as high as 60–
90% in neonates discharged from hospital (Kaplan
et al. 1986; Ladhani et al. 1999; Tenover and Gaynes
2000; Makhoul et al. 2001). In hospitals, neonatal
colonization is more likely to originate from care
attendants than mothers, although colonization may
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occur due to the acquisition from the maternal
vaginal flora and mothers are more likely to be
responsible for outbreaks (Sarai et al. 1977; Ladhani
et al. 1999; Ladhani 2003). It is likely that crosstransmission from neonate to neonate plays a role in
the spread of the epidemic strains, particularly in the
nursery and in double rooms where the swaddling
table is common (El Helali et al. 2005). In the
maternity unit of our hospital, routine S. aureus
colonization studies of mothers and infants were not
used. Infection prevention is based mainly on hygiene
procedures such as good hand washing and disinfection of hospital equipment and accessories (See
Online Supplementary Material).
In our study we have analyzed the outbreak of
staphylococcal skin infections in children born within
1 month in a hospital newborn nursery. Children with
S. aureus strains from group I (Table 1) developed
rather mild disease symptoms, observed as single
blisters with no exfoliation or purulent conjunctivitis.
In the case of children infected with S. aureus strains
from group II (Table 1), the clinical picture of the
disease was diagnosed as bullous impetigo with
exfoliation. In this group the disease symptoms
occurred later, 7, 13 and 34 days after birth. Accordingly to the previously published data, the age of onset
in neonates is usually between 3 and 18 days (Ladhani
et al. 1999; Ladhani 2003; El Helali et al. 2005). In our
study the EF-positive strains all demonstrated phage
pattern 55/71. This is in accordance with published
data indicating that most S. aureus strains responsible
for SSSS and bullous impetigo in Europe and the
United States belong to phage group II and particularly types 71 and 55/71, which account for 7–25% of
human strains. However, only 30–40% of them
produce ETs (Kaplan et al. 1986; Ladhani et al.
1999; Tenover and Gaynes 2000). Strains belonging
to phage groups I and III are mainly isolated in Japan.
No differences in the clinical picture of the infections
caused by strains from different phage groups was
observed (Ladhani 2003). Moreover, the serological
type of ET does not correlate with the severity of the
disease and is not restricted to the specific phage type
(Kaplan et al. 1986; Ladhani et al. 1999; Tenover and
Gaynes 2000; Ladhani 2003). However Ladhani et al.
(1999) suggest that in children with generalized SSSS
ETB-positive strains are more frequently isolated than
ETA-positive strains. Similar results were obtained by
Yamasaki et al. (2005), who reported that the presence
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Antonie van Leeuwenhoek (2009) 95:387–394
of etB gene was significantly associated with generalized SSSS.
According to the previously published data S.
aureus strains from II phage group are rarely
multiresistant (Krzywinska et al. 1999; Ladhani
et al. 1999). Ladhani et al. (1999) reported that
among ETs producing strains, 7% were resistant to
tetracycline, 5% to gentamycin, and 2% to chloramphenicol. In our study, all analyzed strains were
methicillin-sensitive (MSSA) and strains of Group II
were resistant to tetracycline and MLSi. Methicillinresistant S. aureus (MRSA) infections in the newborn nursery and obstetric ward occur rarely.
Usually, the period of hospitalization in a newborn
nursery is very short and thus the possibility of
acquiring strains belonging to the hospital flora is
reduced (Florman and Holzman 1980; Ladhani et al.
1999). During an MRSA outbreak in our hospital
lasting 7 years, no case was found in a newborn ward
(Kurlenda et al. 2007). Additionally, ET producing
MRSA strains occur rarely. Among 82 MRSA strains
isolated from outbreaks in neonatal intensive care
units in Japan only one produced ETA and none of
them was ETB-positive (Florman and Holzman
1980; Ladhani et al. 1999). Nevertheless, in the
United States a hospital outbreak of skin and softtissue infections among 8 postpartum women caused
by community acquired-MRSA was reported (Saiman et al. 2003). Thus, the neonate MRSA-caused
infections could be observed.
The conclusion that mothers were the source of
infection in both groups was drawn as each group
included S. aureus-colonized mothers (m1 with
S. aureus type A and m8 with S. aureus type B,
respectively). Additionally we have found that two
mothers (m2 and m5) were infected with S. aureus
type A. Among the staff, no carriers of S. aureus
phage type 55/71 or 95 was reported. Usually, the
transmission of bacteria occurs mainly by handling
infants colonized healthcare workers but it can
happen from colonized mothers as well. With
cohort isolation, mothers are more likely to be
responsible for the outbreaks and the cross-infections tend to occur in outbreak clusters (Ladhani
et al. 1999; Makhoul et al. 2001; de Lencastre et al.
1994).
Bacteriological swabs of the hospital environment
were performed (i.e. hospital equipment) and no S.
aureus reservoir was found in either room occupied
Antonie van Leeuwenhoek (2009) 95:387–394
by infected children. The hygiene procedures concerning infants over the maternity unit in our hospital
are mainly performed by handling mothers (apart two
first days after delivery) and thus the mother-related
transmission seems probable.
Our study has resulted in the introduction of
additional procedures within the hospital (Online
Supplementary Material).The introduction of these
additional hygiene procedures and contact barriers
limited the spread of the infection and the last case
was reported 34 days after birth. There have been no
further cases.
Acknowledgments We acknowledge Ms Joanna Potrykus
for careful review of the manuscript.
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