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Journal of Clinical Microbiology, September 1998, p. 2485-2490, Vol. 36, No. 9
0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Persistence of Clones of Coagulase-Negative Staphylococci among
Premature Neonates in Neonatal Intensive Care Units: Two-Center
Study of Bacterial Genotyping and Patient Risk Factors
Clementien L.
Vermont,1
Nico G.
Hartwig,1,*
André
Fleer,2
Peter
de
Man,3
Henri
Verbrugh,3
John
van den
Anker,4
Ronald
de
Groot,1 and
Alex
van Belkum3
Department of Medical Microbiology,
Wilhelmina Children's Hospital, University Hospital Utrecht,
Utrecht,2 and
Divisions of Pediatric
Infectious Diseases1 and
Neonatology,4
Department of
Pediatrics, Sophia Children's Hospital, and Department of Medical
Microbiology and Infectious Diseases,3
University Hospital Rotterdam, Rotterdam, The Netherlands
Received 2 February 1998/Returned for modification 15 March
1998/Accepted 29 May 1998
 |
ABSTRACT |
From 1 January 1995 until 1 January 1996, we studied the molecular
epidemiology of blood isolates of coagulase-negative
staphylococci (CoNS) in the Neonatal Intensive Care Units (NICUs) of
the Sophia Children's Hospital (SCH; Rotterdam, The Netherlands) and
the Wilhelmina Children's Hospital (WCH; Utrecht, The
Netherlands). The main goal of the present study was to detect
putatively endemic clones of CoNS persisting in these NICUs.
Pulsed-field gel electrophoresis was used to detect the possible
presence of endemic clones of clinical significance. In
addition, clinical data of patients in the SCH were analyzed
retrospectively to identify risk factors for the acquisition of
positive blood cultures. In both centers, endemic CoNS clones were
persistently present. Thirty-three percent of the bacterial isolates
derived from blood cultures in the SCH belonged to a single genotype.
In the WCH, 45% of all bacterial strains belonged to a single clone.
These clones were clearly different from each other,
which implies that site specificity is involved. Interestingly, we
observe that the clonal type in the SCH differed significantly from the
incidentally occurring strains with respect to both the average pH and
partial CO2 pressure of the patient's blood at the time of
bacterial culture. We found that the use of
intravascular catheters, low gestational age, and a long
hospital stay were important risk factors for the
development of a putative CoNS infection. When the
antibiotic susceptibility of the bacterial isolates was assessed,
a clear correlation between the nature of the antibiotics most
frequently used as a first line of defense versus the
resistance profile was observed. We conclude that the intensive use
of antibiotics in an NICU setting with highly susceptible patients
causes selection of multiresistant clones of CoNS which subsequently
become endemic.
| |
INTRODUCTION |
Coagulase-negative staphylococci
(CoNS), formerly regarded as harmless inhabitants of the skin and
mucosal linings, are now recognized as a major cause of nosocomial
infections in neonatal intensive care units (NICUs) in the United
States as well as in Europe (7). The skin of newborn babies
is not colonized by bacteria, although it acquires this flora
quite rapidly during the first days after birth (9). In the
period immediately after birth, bacterial colonization of the throat
occurs, paving the way for subsequent invasive infections
(5). The emergence of CoNS as important pathogens in the
NICU setting is also due to major advances in perinatal and neonatal
care. Recently, survival rates of premature, very low birth weight
neonates have increased significantly. However, this is often
accompanied by prolonged periods of hospitalization, frequent insertion
of intravascular catheters, and the nearly unrestricted use of
antibiotics. This leads not only to increasing infectious problems in
the NICU but also to the development of antibiotic resistance in
bacteria present in the environment, patients, and hospital personnel.
Several recent studies have demonstrated a clear correlation
between (extremely) low birth weight and the risk of acquisition
of a nosocomial infection with CoNS (1, 12). The importance
of the infections caused by CoNS is emphasized by the observation that
these infections are associated with a huge increase in morbidity,
whereas the directly attributable mortality may be as high as 14%
(15).
The sites of origin and reservoirs of nosocomial bloodstream infection
by CoNS are not well defined. Another matter of concern is whether
these infections are caused by endemic clones of CoNS or by
incidentally occurring bacterial strains of these ubiquitous species.
The hospital environment, hospital personnel, and the nature of the
patient population contribute to the complex balance between infection
prevention and nosocomial endemicity and epidemics. It seems likely,
but is difficult to prove, that differences in patient's
characteristics contribute significantly to the occurrence of CoNS
infections (9). The fact that cross-infections occur is well
established (10, 14), and the epidemiology of infections has
been documented in detail in different clinical settings (11, 17). Persistence of CoNS types in single departments for periods ranging between 5 and 10 years has been documented (9, 13).
To provide answers to some of these questions, we performed
a study to determine whether endemic clones persist in two of the
largest Dutch NICUs. We compared the findings in the NICUs of the
Sophia Children's Hospital (SCH; Rotterdam, The Netherlands) and the
Wilhelmina Children's Hospital (WCH; Utrecht, The Netherlands). Since
pulsed-field gel electrophoresis (PFGE) is suggested to be superior to
both conventional and other molecular techniques (28), this
technique was chosen as the typing method for CoNS isolates collected
during the present study. In addition, risk factors were determined
with respect to patient characteristics and different types of
intravascular catheterization.
| |
MATERIALS AND METHODS |
Description of patients.
A retrospective study was performed
in the SCH NICU. Medical charts and laboratory results of 502 patients
admitted in 1995 were used as sources of information. A subgroup of 42 patients had one or more episodes of CoNS-positive blood cultures.
Seventy strains isolated from blood cultures of these 42 patients were used for analysis. In addition, 31 strains from 22 patients with CoNS-positive blood cultures which occurred within 1 year in the WCH
NICU were also analyzed to determine possible differences between the
situations concerning CoNS endemicity in the Rotterdam and Utrecht
NICUs.
Laboratory analysis.
Several clinical-chemical
characteristics were determined for all of the blood samples. Two of
these, the partial CO2 pressure (pCO2) and pH
of the blood, turned out to be of particular importance (see Results).
The pCO2 and pH values were determined electrochemically in
an automated fashion by using Acid Base Laboratory equipment (Radiometer, Zoetermeer, The Netherlands). Electrodes were rinsed extensively after each assay, and calibration of the Acid Base Laboratory was performed three times per day for both pH and
pCO2 measurement consistency.
The susceptibility of the bacterial isolates from the Rotterdam
patients to the following antibiotics was assessed: penicillin, flucloxacillin, tobramycin, cefuroxime, erythromycin, clindamycin, vancomycin, fusidic acid, and rifampin. Assays for MIC determination were performed in accordance with National Committee for Clinical Laboratory Standards guidelines (16).
Blood cultures were performed with the BacTec 9240 System using
pediatric bottles (Becton Dickinson, Meylan, France). Per bottle,
between 1 and 3 ml of blood was inoculated. Bottles were incubated at
37°C for a maximum of 4 days, except for those cultures becoming
positive at an earlier time. After Gram staining,
staphylococci were identified to the species level on the basis of a
Staphaurex test (Murex Biotech, Darford, United Kingdom) and Api Staph
analysis (BioMerieux, Marcy l'Etoile, France). CoNS isolates were
stored in glycerol-containing liquid media at 
80°C in the
microbiology laboratories of both hospitals. Prior to strain
identification by PFGE, cultivation took place on Columbia blood agar
plates at 37°C for 18 h. Culture purity was assessed by visual
examination, and all further laboratory analyses were carried out at
the Department of Medical Microbiology & Infectious Diseases,
University Hospital Dijkzigt, Rotterdam, The Netherlands.
PFGE was used as a molecular typing technique. This procedure allows
the separation of chromosomal DNA fragments differing
in size by the
use of rarely cutting restriction enzymes and the
application of
multidirectional electrical pulses through an agarose
matrix
(
6). A protocol developed for CoNS and used in our
laboratory
on previous occasions was employed (
26,
27). In
short, a suspension
of bacteria in 10 mM Tris-HCl (pH 8.0)-100 mM
EDTA-10 mM EGTA
was mixed with a solution of 1% InCert agarose (FMC
Bioproducts,
Rockland, Maine). Agarose plugs were incubated with
lysostaphin.
Spheroplasts were lysed by sodium dodecyl sulfate and
proteinase
K (Boehringer, Mannheim, Germany), washed six times for 30 min
each time in 10 mM Tris-HCl (pH 8.0)-1 mM EDTA, and
stored at
4°C until further use. Prior to electrophoresis, DNA was
digested
overnight with the restriction enzyme
SmaI
(Boehringer). PFGE
was carried out with 1% SeaKem GTG agarose gels
(FMC Bioproducts)
in 0.5× Tris-borate-EDTA at 14°C in a
contour-clamped homogeneous
electric field mapper (Bio-Rad, Veenendaal,
The Netherlands).
The running time was 24 h. Gels were stained
with ethidium bromide
and photographed. Differences in banding
patterns were documented
by visual examination by two independent
observers and indexed
by capital lettering. Isolates were considered
indistinguishable
if there were no chromosomal band differences,
related if they
differed by one to three bands, and unrelated if they
differed
by four or more bands. Interpretation of the experimental data
in accordance with these guidelines is supported by recent consensus
publications (
24,
25).
Risk factor assessment.
To determine risk factors, clinical
characteristics of neonates without CoNS-positive blood cultures
admitted to the SCH NICU in 1995 (n = 460) were
collected and used as controls. They were compared with the
characteristics of patients (n = 42) from whose blood
CoNS strains were isolated. These data were analyzed by the
nonparametric (two-tailed) Mann-Whitney test, since normality test
(Kolmogorov-Smirnov one-sample test for normality) data, except for the
catheter data, showed small P values. The catheter data were
analyzed by the Chi-square test. P values smaller than 0.05 were considered to be significant. A logistic regression analysis was
performed on the significant parameters. To relate laboratory results
to clinical data, the data for SCH patients carrying the epidemic clone
were identified and compared with the data from the other patients from
whom incidentally occurring isolates were cultured, using Mann-Whitney
tests to compare demographic and various clinical parameters. All
statistical manipulations were performed with software from the
Statistical Package for the Social Sciences.
| |
RESULTS |
Characteristics of patients.
Forty-six episodes of potential
CoNS septicemia were identified in 42 patients. Sixteen patients had a
single positive blood culture, and 26 infants had multiple positive
blood cultures. Altogether, 70 strains were isolated. Of
these cultures, blood samples for 12 isolates were drawn through
arterial catheters, 3 were drawn through intravenous catheters, 1 was
drawn through an umbilical venous catheter, and 1 was drawn through
an umbilical arterial catheter. The remaining 53 samples were
drawn from peripheral veins. Genuine episodes of septicemia are hard to
define in this particular group of very small patients. The genotyping
data as described in the present communication can be considered
helpful. Clinically suspected sepsis syndrome could be experimentally
corroborated in 10 of 16 cases: all bacterial isolates obtained from
positive blood cultures derived from different samples displayed the
same genotype. In 6 of these 16 cases, different genotypes were found, indicating the presence of mixed infections or, more likely,
contamination of the culture medium with skin flora. Although strict
guidelines for definition of sepsis were not implemented throughout the
present study, it is suggested that on the basis of more than 60% of
the positive blood cultures described here, patients could be diagnosed as having septicemia. To avoid miscommunication, the term sepsis will
be avoided as much as possible and positive blood cultures will be
discussed mainly.
Apnea, bradycardia, and temperature instability occurred most
frequently as clinical symptoms of bacteremia. Demographic
data
and relevant laboratory parameters of the patients are shown
in
Table
1. Table
2 shows the percentage of patients
needing ventilatory
support or intravascular catheters. In
addition, the duration
of the intravascular residence of the
catheters is noted. Three
patients also had positive urine
cultures, one of which was highly
positive, identifying a genuine
urinary tract infection. Finally,
six patients also had other cultures
from which CoNS were isolated,
like a tube culture or a wound aspirate
culture. In Table
3,
antibiotic therapy
prior to CoNS-positive blood cultures is listed.
Broviac catheters were
not taken into account, since they were
used in a very small
number of patients only.
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TABLE 1.
Demographic data and laboratory values during CoNS
positivity of blood cultures of 42 patients admitted to the SCH
NICU in 1995
|
|
Laboratory analysis.
The antibiotic susceptibility data
showed large proportions of the strains to be resistant to
penicillin, flucloxacillin, tobramycin, and cefuroxime (99, 90, 89, and 90%, respectively). Various but limited numbers of
strains appeared to be resistant to erythromycin, clindamycin, fusidic
acid, and rifampin (44, 23, 6, and 9%, respectively). All strains
were susceptible to vancomycin.
Figure
1 shows an example of the data
obtained by PFGE. Endemic strains can be easily identified. The
interpretation of the
experimental data is summarized in Fig.
2A. The PFGE analysis
revealed that 16 (23%) of 70 strains from the SCH were similar
(either
indistinguishable or related). These 16 strains were isolated
from 14 different patients. Thus, this type (designated B) was
responsible for one-third of all positive blood cultures in that
year
(14 of 42). Clone B and the less prevalent clone C together
were
responsible for 62% of all cases in which blood cultures
grew CoNS in
the NICU during the study period. The clinical data
from cases with
clone B were compared with those from the cases
associated with the
other types. Parameters analyzed were birth
weight, gestational
age, duration of ventilation, length of stay,
clinical symptoms, and
laboratory parameters such as complement-reactive
protein, leukocyte
counts, and base excess. No significant differences
were found between
these two groups with respect to these data.
However, patients infected
with clone B had a higher average pCO
2 value in the blood
(6.9 kPa) than did patients infected by one
of the other types (5.8 kPa; Mann-Whitney test,
P < 0.05). Moreover,
clone B
was also associated with increased blood acidity values.
The pH during
infection with this type was 7.26, on average, whereas
during
infection with another type, the average pH was 7.35 (Mann-Whitney
test,
P < 0.01). Finally, no differences between the
two groups
in duration of catheter stay (either arterial, intravenous,
or
umbilical) were found.
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FIG. 1.
PFGE fingerprints for a random selection of the CoNS
isolated from blood samples obtained from patients nursed in the SCH
NICU. The pattern obtained for the endemic clone with PFGE type B can
be observed in the lanes marked by a triangle. Some of the molecular
sizes of the markers in lanes M are indicated on the right in kilobase
pairs.
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FIG. 2.
(A) Frequency distribution of the different PFGE types
of CoNS in the SCH NICU (left) and the WCH NICU (right). PFGE types are
identified by capital-letter codes. Bar height shows the number of
clinical isolates identified in 1995. The "others" column accounts
for the number of unique types encountered (i.e., those types occurring
only once in 1995). (B) Longitudinal persistence of endemic clones of
CoNS in the SCH NICU (top bar) and the WCH NICU (bottom bar). The
period depicted covers the year 1995. The most prevalent strain of type
AA is identified by the letter A. Note that this strain was introduced
into the WCH NICU in the month of May and subsequently persisted.
|
|
In the WCH, as shown in Fig.
2, 13 (42%) of 31 strains were typed AA,
indicating that 10 (45%) of 22 patients were infected
with similar
strains of CoNS. All other identified isolates were
unique and were
encountered only in individual patients. Figure
2B depicts how the
epidemic clones in both hospitals persisted
during the study period. It
appears that strain AA was introduced
into the WCH in May and persisted
thereafter. Apparently, this
strain has a significant ecological
advantage over the other CoNS
strains. In the SCH, the endemic strain
was present all year round.
Risk factors.
Mann-Whitney U tests showed that gestational age
and birth weight were significantly lower, whereas duration of
ventilation and length of hospital stay were significantly longer in
patients with CoNS-positive blood cultures (Table
4). The data on the use of the various
catheters among neonates included in the study are shown in Table
5. Except for the arterial catheters, all catheters were used more frequently in neonates infected with CoNS than
in neonates from the control group. However, no differences were found
in the average length of stay of any of the catheters involved. A
forward inclusion selection of variables was performed to identify the
most important predictors for the development of blood cultures
positive for CoNS. Variables were entered until no remaining candidate
variable met a significance level of 0.05 or lower. Logistic regression
analysis performed on the important parameters revealed that
gestational age, hospital stay before onset of positive blood cultures,
and insertion of a venous umbilical catheter significantly differed
between the subgroup and the controls (P values of 0.01, 0.05, and 0.001, respectively). Table 6
summarizes the data on all of the catheters inserted. This shows the
percentages of the respective catheter types colonized by CoNS.
| |
DISCUSSION |
CoNS are now recognized to be the most common cause of serious
nosocomial infections in NICUs (23). Large-scale prevalence studies carried out in a concerted fashion in several European countries demonstrated an extremely high prevalence of nosocomial bloodstream infection by CoNS (22). The clinical data of
neonates with CoNS infections in the SCH show that most of them were
critically ill. Apnea, bradycardia, and temperature instability, which
are strong indications of CoNS septicemia, frequently occurred.
Although encountered on an occasional basis only, urine, wound fluid,
and even CSF cultures demonstrating viable CoNS demonstrate that CoNS infections can cause serious invasive disease in these highly vulnerable neonates.
When studying the epidemiology of CoNS infections, it is advisable to
analyze the bacterial strains by multiple typing procedures (18). It has been demonstrated on several occasions that
phenotyping is less satisfactory than genotyping (4) and
that with respect to genotyping, application of a single technique such
as PFGE may suffice (26, 27). The PFGE results of the
present study clearly show that certain strains of CoNS can become
predominant in the NICU setting. PFGE genotypes B and C were
responsible for two-thirds of all CoNS-positive blood cultures in the
SCH NICU, while PFGE genotype AA was associated with nearly half (45%)
of all cases in the WCH NICU. Such endemic strains seem to persist for
prolonged periods, although they also appear to be NICU specific. The
PFGE patterns of strains found in the SCH NICU were totally different
from the PFGE patterns of strains found in the WCH NICU, indicating
that the CoNS strains found in the two centers were not related to each
other. Clonal persistence occurred in both centers, and even the
persistence of multiple clusters in a single environment has recently
been demonstrated (3).
Combinations of penicillins and aminoglycosides or expanded-spectrum
cephalosporins and aminoglycosides are widely used as empiric
antibiotic strategy in neonates. These regimens do not adequately cover
infections by CoNS. This will cause selection of multiresistant CoNS
strains, which, according to the current study, can become endemic in
the NICU setting. The antibiograms of the prevalent strains precisely
mirror the antibiotic therapy regimen executed in the departments
(3). Standard therapy consists of a penicillin-tobramycin
combination eventually followed by flucloxacillin and cefuroxime
treatment. As stated in Results, most of the strains studied resist
precisely these antibiotics. Clinical symptoms associated with
infection by an endemic strain, however, do not seem to be different
from those correlated with infection by nonendemic strains.
Assessment of risk factors showed that the more premature infants were
at increased risk of acquiring CoNS bacteremia. Their stay in the NICU
before detection of CoNS in the blood was significantly longer than the
average hospital stay in the control group. This indicates that length
of stay is a major risk factor for acquiring a CoNS strain that gives
rise to bacteremia. This is in agreement with data of Martin et al.
(15), who performed a study in the late 1980s, a period in
which invasive CoNS were not as prevalent in the NICU setting as they
are now.
CoNS account for a major part of nosocomial bacteremias,
especially those events related to the insertion and maintenance of intravascular catheters (20). Although we did not
systematically use the semiquantitative catheter tip culture technique
for the diagnosis of catheter-related bacteremia (19), a
catheter still remains one of the most obvious entry sites for CoNS in
neonates. Previous studies indicated that the site of catheter
insertion largely determines the risk for acquiring catheter-related
septicemia. The subclavian site is considered favorable because of
lower bacterial densities on the skin at this site (2). The
fact that this skin site seems to be preferentially colonized by CoNS
species may be contraindicative, although nothing is known about
population densities. The present study clearly shows that insertion of
a venous umbilical catheter is also a significant risk factor for the
development of CoNS septicemia. Table 6 shows that 10 to 20% of all
catheters become contaminated with CoNS in the end. Although continuous
infusion of antibiotics such as teicoplanin or vancomycin through the
catheter clearly reduces the incidence of bacteremia (21),
this approach is not generally accepted due to the risk of selecting
for (intermediately) vancomycin-resistant staphylococci (8).
Relatively little is known about the propensity of CoNS to induce
clinically significant bacteremia. Specific virulence factors seem to
play an important role (11), but general means of
identification of potentially detrimental strains of CoNS have not been
defined. It is interesting that the epidemic strains in the SCH seem to prefer or induce altered blood pH and pCO2 values in
affected individuals. This observation warrants further
analysis.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Pediatrics, Sophia Children's Hospital, University Hospital Rotterdam, Dr. Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands. Phone: 31-10-4636948. Fax: 31-10-4636449. E-mail:
hartwig{at}alkg.azr.nl.
| |
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Journal of Clinical Microbiology, September 1998, p. 2485-2490, Vol. 36, No. 9
0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
