Herold BC, Immergluck LC, Maranan MC, Lauderdale DS, Gaskin RE, Boyle-Vavra S, Leitch CD, Daum RS. Community-Acquired Methicillin-Resistant Staphylococcus aureus in Children With No Identified Predisposing Risk. JAMA. 1998;279(8):593-598. doi:10.1001/jama.279.8.593
From the Department of Pediatrics (Drs Herold, Immergluck, Maranan, Boyle-Vavra, and Daum), Department of Health Studies (Dr Lauderdale), and the Clinical Microbiology Laboratories (Ms Leitch), The University of Chicago Hospitals, Chicago, Ill, and the Research Service, Veterans Affairs Medical Center, Boston, Mass (Mr Gaskin). Dr Immergluck is now with the Department of Pediatrics, University of Illinois at Chicago.
Context.— Community-acquired methicillin-resistant Staphylococcus
aureus (MRSA) infections in children have occurred primarily in individuals
with recognized predisposing risks. Community-acquired MRSA infections in
the absence of identified risk factors have been reported infrequently.
Objectives.— To determine whether community-acquired MRSA infections in children
with no identified predisposing risks are increasing and to define the spectrum
of disease associated with MRSA isolation.
Design.— Retrospective review of medical records.
Patients.— Hospitalized children with S aureus isolated
between August 1988 and July 1990 (1988-1990) and between August 1993 and
July 1995 (1993-1995).
Setting.— The University of Chicago Children's Hospital.
Main Outcome Measures.— Prevalence of community-acquired MRSA over time, infecting vs colonizing
isolates, and risk factors for disease.
Results.— The number of children hospitalized with community-acquired MRSA disease
increased from 8 in 1988-1990 to 35 in 1993-1995. Moreover, the prevalence
of community-acquired MRSA without identified risk increased from 10 per 100000
admissions in 1988-1990 to 259 per 100000 admissions in 1993-1995 (P<.001), and a greater proportion of isolates produced clinical
infection. The clinical syndromes associated with MRSA in children without
identified risk were similar to those associated with community-acquired methicillin-susceptible S aureus. Notably, 7 (70%) of 10 community-acquired MRSA
isolates obtained from children with an identified risk were nonsusceptible
to at least 2 drugs, compared with only 6 (24%) of 25 isolates obtained from
children without an identified risk (P=.02).
Conclusions.— These findings demonstrate that the prevalence of community-acquired
MRSA among children without identified risk factors is increasing.
INFECTIONS CAUSED BY Staphylococcus aureus
resistant to methicillin (MRSA) are increasing in prevalence in adults and
children.1 Although such infections were once
concentrated in relatively few large, university-based teaching hospitals,
now 97% of such institutions report the presence of MRSA isolates.2
The epidemiology of MRSA infections is complex. Acquisition of the organism
in a hospital or a long-term care facility is well documented in adults and
children.3 In adults, other risk factors identified
for MRSA infection include chronic liver, lung, or vascular disease, dialysis,
malignancy, or prolonged exposure to antimicrobial agents.4- 9
Despite fewer descriptive data, predisposing risk factors for MRSA infections
in pediatric populations include prolonged hospitalization, invasive or surgical
procedures, indwelling catheters, endotracheal tubes, and prolonged or recurrent
exposure to antibiotics, factors similar to those documented in adults.10- 12
Community-acquired MRSA infections among hospital inpatients, ie, isolates
obtained within 72 hours of hospitalization, have been described among adults.
The majority of these, however, have occurred in individuals with a recognized
predisposing risk factor, such as recent contact with a health care–providing
environment or parenteral substance abuse.13- 17
Community-acquired MRSA infections in the absence of identified risk factors
have been reported infrequently.17
Thus, we were surprised when we recently observed several community-acquired
MRSA infections among children without risk factors hospitalized at a university-based
teaching hospital. This clinical observation prompted a retrospective review
of available medical records of hospitalized children from whom S aureus was isolated from any site between August 1988 and July 1990
(1988-1990) and between August 1993 and July 1995 (1993-1995). We sought to
determine whether community-acquired MRSA infections in hospitalized children
with no identified predisposing risks were increasing in prevalence and whether
the clinical spectrum of disease associated with community-acquired MRSA infection
differed from that of community-acquired methicillin-susceptible S aureus (MSSA) disease or nosocomially acquired (NA) MRSA disease.
The University of Chicago Children's Hospital (UCCH) is a 156-bed, tertiary
care pediatric facility. The Clinical Microbiology Laboratories maintain records
of all S aureus isolates from hospitalized patients
and the proportion of them resistant to methicillin. With the use of data
from the Clinical Microbiology Laboratories, we compiled a list of all S aureus isolates (both MSSA and MRSA) for 1993-1995. We
then reviewed all available medical records for hospitalized children with
1 or more S aureus isolates from any site in the
designated interval. For comparison purposes, we also reviewed all available
records of hospitalized children from whom MRSA was isolated during a 24-month
period 5 years previous (1988-1990). The number of hospital discharges (about
4800 per year), payer mix (about 35% private insurance), age distribution,
and average length of stay of children hospitalized at UCCH remained stable
from 1988 through 1995.
From the medical records, we sought information regarding age, sex,
race/ethnicity, date of admission, site of culture specimen yielding S aureus, the date of specimen collection, antimicrobial
therapy administered prior to hospitalization, care rendered at another facility,
and any underlying medical condition or other relevant family history.
From the information found in the records, isolates were classified
as to whether they were acquired in the "community" or "nosocomially" and
"infecting" or "colonizing." A community-acquired MRSA isolate was defined
as one isolated from a specimen obtained within 72 hours of admission. A nosocomially
acquired isolate was one isolated from a specimen obtained beyond that time.
A "disease-associated" isolate was defined as one responsible for a clinical
syndrome (eg, osteomyelitis) as determined from consideration of the site
from which S aureus was isolated, the physical examination
findings, and other relevant clinical data.18
Isolates not associated with disease were said to be colonizing.
Hospitalized children with community-acquired MRSA were classified as
"with identified risk" if review of the medical record indicated any of the
following: previous hospitalization or antimicrobial therapy within 6 months
of the date of MRSA isolation, history of endotracheal intubation, underlying
chronic disorder, presence of an indwelling venous or urinary catheter, a
history of any surgical procedure, or a notation in the medical record of
a household contact with an identified risk factor. All other patients with
community-acquired MRSA isolates were classified "without identified risk."
We describe the epidemiology of community-acquired MRSA among hospitalized
children in 4 ways. First, we compared the prevalence of community-acquired
MRSA without identified risk in 2 time periods, 1988-1990 and 1993-1995. Second,
we compared the proportions of infecting vs colonizing isolates for 1988-1990
and 1993-1995 . Third, we compared the clinical spectrum of disease for infecting
isolates for 51993-1995 groups: community-acquired MRSA with identified risk,
community-acquired MRSA without identified risk, nosocomially acquired MRSA,
community-acquired MSSA, and nosocomially acquired MSSA. Fourth, for the 3
MRSA groups, we compared proportions of isolates susceptible to other antibiotics.
Statistical analysis was performed using Stata Statistical Software 4 (StataCorp,
College Station, Tex). Frequency data were compared with a 2-tailed Fisher
Susceptibility testing on S aureus isolates
was initiated on the Vitek system (bioMerieux Vitek Inc, Hazelwood, Mo) in
the Clinical Microbiology Laboratories at the University of Chicago Hospitals.
Briefly, the isolate was inoculated onto a gram-positive susceptibility-SA
card (SA indicates the combination of drugs available on the card) containing
1% sodium chloride and placed into the Vitek instrument for incubation and
reading. An isolate was further evaluated by disk diffusion testing when Vitek
testing revealed that it was resistant to methicillin but susceptible to clindamycin
and erythromycin. Disk diffusion testing was performed as recommended by the
National Committee for Clinical Laboratory Standards.19
Briefly, a broth culture suspension of the isolate to be tested was prepared
in trypticase soy broth and turbidity adjusted to a 0.5 McFarland standard.
The zone sizes were read after 24 hours of incubation in ambient air at 35°C.
Isolates were classified as either susceptible or nonsusceptible; the latter
classification included isolates with intermediate and resistant zone sizes.
Disk diffusion testing was performed for 51% of isolates designated MRSA by
Vitek in the 1993-1995 study interval and for 57% of isolates obtained in
the 1988-1990 interval. The MRSA isolates were usually tested for susceptibility
to the following additional antibiotics: clindamycin, erythromycin, gentamicin,
trimethoprim-sulfamethoxazole, and vancomycin.
The Clinical Microbiology Laboratories retain only isolates from blood
for long-term storage. Seven MRSA blood isolates from 1993-1995 were available
for further analysis by pulsed-field gel electrophoresis (PFGE) and for presence
of the mecA gene by polymerase chain reaction (PCR)
assay. For PFGE, genomic DNA was prepared using previously described methods20,21 and digested with the restriction
endonuclease SmaI. Band patterns were visualized
by ethidium bromide staining and UV illumination and compared visually. For
the PCR assay, template DNA was obtained from colonies after lysis in achromopeptidase
as previously described.22 Synthetic oligonucleotides
used as primers were 5′-CTTTGCTAGAGTAGCACTCG-3′ and 5′-GCTAGCCATTCCTTTATCTTG-3′,
which correspond to nucleotides from position 1538-1557 and 2049-2069, respectively,
of the mecA gene sequence.23
We identified 32 cases of MRSA in 1988-1990 and 56 cases in 1993-1995.
Fifty-two (93%) of 56 charts were available from the patients hospitalized
in 1993-1995 and all 32 (100%) from those hospitalized in 1988-1990. Of those
with available charts, 8 of the 1988-1990 MRSA isolates were community acquired,
and 35 of the 1993-1995 isolates were community acquired. Patients with community-acquired
isolates in the 2 time periods did not differ significantly with respect to
sex or race/ethnicity, but did differ in age distribution (Table 1). When the community-acquired cases were classified by the
absence or presence of identified risk factors, only one of the 1988-1990
cases lacked an identified risk factor, whereas 25 of the cases in 1993-1995
lacked an identified risk factor (Table
1). The prevalence of community-acquired MRSA without identified
risk factors increased from 10 per 100000 admissions in 1988-1990 to 259 per
100000 admissions in 1993-1995 (P<.001).
To determine whether the isolation of 1993-1995 community-acquired MRSA
was clustered or scattered throughout the 24-month time period, we stratified
the isolates by month of isolation. The 35 isolates obtained from children
with or without identified risk in 1993-1995 were detected throughout the
2-year period, an observation suggesting that the increase did not represent
To compare the proportion of MRSA isolates associated with clinical
disease in 1988-1990 and 1993-1995, we classified them as colonizing or disease
associated according to relevant clinical features associated with isolation
of MRSA. In 1993-1995, 8 (80%) of 10 community-acquired isolates obtained
from children with identified risk and 22 (88%) of 25 community-acquired isolates
obtained from children without identified risk were associated with a clinical
disease. Similarly, 12 (71%) of 171993-1995 nosocomially acquired isolates
were associated with clinical disease. In contrast, in 1988-1990, only 3 (43%)
of 7 community-acquired isolates obtained from children with an identified
risk factor and 9 (37.5%) of 24 nosocomially acquired isolates obtained were
associated with a clinical illness. Thus, the increase in community-acquired
MRSA isolates in 1993-1995 compared with 1988-1990 represents primarily an
increase in disease-associated isolates and not increased collection of specimens
not associated with disease.
Next we examined the clinical spectrum of disease associated with MRSA
and MSSA isolates in 1993-1995 (Table 2). The distribution of clinical syndromes associated with community-acquired
MRSA in children with identified risk was similar to that of children with
nosocomially acquired MRSA. The clinical spectrum of disease for the community-acquired
MRSA without identified risk appears to be different. First, none of the 22
children with community-acquired MRSA isolates without identified risk had
bacteremia without a focus of infection, whereas 2 (20%) of 10 children with
community-acquired MRSA with identified risk and 4 (33%) of 12 children with
nosocomially acquired MRSA had bacteremia without a focus. Second, abscess
was more common among the children with community-acquired MRSA isolates without
identified risk compared with the children with community-acquired MRSA with
identified risk and children with nosocomially acquired isolates. Abscess
was the diagnosis in 6 (27%) of 22 children with community-acquired isolates
without identified risk compared with none of the 10 children with community-acquired
isolates with identified risk and only 1 (8%) of 12 children with nosocomially
To compare the distribution of clinical syndromes associated with MRSA
in 1993-1995 with that associated with MSSA for the same time period, we reviewed
all available charts from children hospitalized in 1993-1995 from whom MSSA
was isolated. The charts of 233 (87%) of these 268 patients were available.
We classified them as community acquired and nosocomially acquired (145/233
and 88/233, respectively), using the same 72-hour criterion, and identified
those that were colonizing or disease associated. Eighty-seven (60%) of 145
community-acquired MSSA isolates and 47(53%) of 88 nosocomially acquired MSSA
isolates were disease associated. The distribution of clinical syndromes associated
with community-acquired MSSA was similar to that associated with community-acquired
MRSA in children without an identified risk. For example, cellulitis and abscess
predominated among both community-acquired MRSA without identified risk and
community-acquired MSSA patients, whereas bacteremia without a focus predominated
among nosocomially acquired MRSA and nosocomially acquired MSSA (Table 2).
Thus, the clinical syndromes associated with S aureus isolation are independent of methicillin susceptibility and relate
more closely to the predisposing risks or their absence. A notable exception
was in children with cystic fibrosis (CF). In 1988-1990, no patient hospitalized
with CF had an MRSA isolate. However, in 1993-1995, 4 (19%) of 21 MRSA isolates
were recovered from children with CF hospitalized for acute respiratory infection;
3 of the children had community-acquired infection with identified risk (previous
antibiotics and hospitalizations), and 1 had nosocomially acquired MRSA. Notably,
1 child had MRSA isolated from blood. In contrast, no child with CF was hospitalized
for a pulmonary exacerbation associated with isolation of MSSA from tracheal
secretions or sputum (P=.007).
Several differences were observed among the 1993-1995 groups when the
MRSA isolates were compared with respect to susceptibility to other antibiotics.
First, the isolates obtained from children with community-acquired MRSA and
without identified risk were more likely to be susceptible to other antibiotics
compared with isolates obtained from children with community-acquired MRSA
with identified risk or with nosocomially acquired MRSA. For example, the
number of isolates that were nonsusceptible (intermediate or resistant) to
2 or more additional antibiotics were 6 (24%) of 25 community-acquired MRSA
without identified risk; 7 (70%) of 10 community-acquired MRSA with identified
risk; and 13 (76%) of 17 nosocomially acquired MRSA. These proportions are
not significantly different between the community-acquired MRSA with identified
risk and the nosocomially acquired MRSA (P=.53),
while they are different between the community-acquired MRSA with identified
risk and the community-acquired MRSA without identified risk (P=.02) as well as between the community-acquired MRSA without identified
risk and the nosocomially acquired MRSA (P=.001).
When we examined susceptibility to specific antibiotics, the same pattern
was evident (Table 3). For example,
only 6 (24%) of 25 community-acquired MRSA isolates obtained from children
without identified risk were nonsusceptible to clindamycin compared with 6
(60%) of 10 community-acquired isolates obtained from children with identified
risk and 13 (76%) of 17 nosocomially acquired isolates. Similarly, only 1
(7%) of 15 community-acquired MRSA isolates obtained from children without
identified risk were nonsusceptible to gentamicin compared with 6 (55%) of
11 nosocomially acquired isolates tested. None of the community-acquired MRSA
isolates obtained from children without identified risk in 1993-1995 was resistant
to trimethoprim-sulfamethoxazole compared with 3 (30%) of 10 community-acquired
MRSA isolates obtained from children with identified risk and 5 (29%) of 17
nosocomially acquired MRSA isolates. The nosocomially acquired isolates and
the community-acquired isolates obtained from children with identified risk
tended to be multiply resistant, whereas the community-acquired MRSA isolates
obtained from children without identified risk did not.
A limited sample of 7 MRSA isolates was available to assess for the
presence of the mecA gene and for evaluation by PFGE.
Six were obtained from blood cultures, and 1 was obtained from aspiration
of an infected hematoma. Five of the isolates were nosocomially acquired;
2 were community-acquired isolates obtained from children without identified
risk. As indicated by the 530–base pair PCR amplimer in all isolates
(Figure 1, left), the mecA gene was present in all 7 isolates, an observation suggesting
the identical, classical mechanism for methicillin resistance among the isolates.
Four distinct patterns were recognized by PFGE among these 7 isolates (Figure 1, right). The isolates in lanes 1
and 2 appear to be genetically closely related but were obtained from 2 patients
hospitalized 6 months apart, on different hospital wards, and on different
medical services. Both patients had multiple previous hospitalizations; the S aureus isolates in both cases represented nosocomially
acquired bacteremia. The isolate in lane 1 was obtained from a patient who
had CF, and the isolate in lane 2 was obtained from a patient who had received
a liver transplant. The antibiotic susceptibilities of these 2 isolates, however,
were different in that the isolate in lane 1 was resistant to clindamycin,
whereas the isolate in lane 2 was not. The isolates in lanes 3 and 4 may be
genetically related. These 2 isolates were obtained from patients hospitalized
1 month apart, also on different wards and different medical services. The
isolate in lane 3 was obtained from a newborn transferred from another hospital
who developed nosocomially acquired bacteremia. The isolate in lane 4 was
obtained from a 4-year-old with cerebral palsy as a sequela of neonatal meningitis.
She had multiple previous admissions and had received antibiotics for recurrent
aspiration pneumonia. Both isolates (lanes 3 and 4) were susceptible only
to vancomycin. There were no genetic differences detected for the isolates
depicted in lanes 5 and 6. The isolate in lane 5 was obtained from a 14-year-old
boy transferred to UCCH for osteomyelitis of the right calcaneus bone. He
had no known risk factors for MRSA acquisition. The organism was recovered
from blood and pus obtained from aspiration of the bone and was resistant
only to methicillin. The isolate in lane 6 was obtained from a 6-year-old
boy with pyomyositis of the left gluteus maximus muscle who was hospitalized
6 months later. He too had no known risk factors for MRSA acquisition. His
isolate was obtained from aspiration of the gluteal abscess (infected hematoma)
with an identical antibiotic susceptibility pattern to the isolate in lane
5. The isolate in lane 7 was distinct. It was obtained from a newborn with
nosocomially acquired bacteremia. Although this was a limited sampling, the
finding of 4 distinct patterns among the MRSA isolates suggests that a single
clone was not responsible for disease at UCCH.
We have found an increase in the prevalence of community-acquired MRSA
among hospitalized children in a tertiary care pediatric hospital. Our retrospective
chart review of pediatric patients suggests a change in the epidemiology of
MRSA. The isolation of MRSA is no longer limited to those patients at risk
for nosocomial infection or with other predisposing factors. Several anecdotal
and abstract reports of community-acquired MRSA infections in both adults
and children who had no identified risk factors support our findings.24- 32
Three recent reports documented that community-acquired or outpatient MRSA
infections may be increasing among adults,9,17,31
although it was unclear whether the isolates were obtained from patients with
identified risk factors. Moreover, a similar increase in community-acquired
MRSA in children has been reported from a second university hospital in Chicago.32 Together with our findings, these isolated reports
support the notion that MRSA infections are no longer confined to patients
with previously ascertained risk factors.
This study was a retrospective chart review from a single institution
with relatively small sample sizes and few isolates available for molecular
studies. To fully define the extent of the problem of MRSA infections in children
without identified risk, further population-based studies are warranted. For
example, it is uncertain whether the increased prevalence of community-acquired
MRSA infection we documented is limited to the children we studied in an inner-city
university hospital. While there was no documentation of MRSA risk factors
such as intravenous drug abuse among the children or their families, the information
we obtained was by retrospective chart review. Thus, it is possible that a
community-based study would reveal risk factors not recognized in this study
or, possibly, reveal as-yet-unknown risk factors.
We observed a difference in age distribution among children with community-acquired
MRSA isolates in the 2 time periods. The increase in community-acquired MRSA
among toddlers might be explained, for example, by changes in day care usage
or rates of transmission. We also observed an increase in the percentage of
MRSA isolates associated with clinical disease in 1993-1995 compared with
1988-1990. The reasons for this are also unclear. These observations underscore
the need for further investigation and for population-based studies.
Although our study was not designed to examine the prevalence or importance
of MRSA in children with CF, the data indicate that MRSA has emerged as a
clinical problem in this patient population. A retrospective review of sputum
and throat S aureus isolates obtained from 452 patients
with CF in 1986 found that S aureus was isolated
in 212 (47%) of the patients, but only 14 (3%) had MRSA.33
All the MRSA isolates were considered to be colonizing since none of the patients
received treatment for MRSA, and MRSA colonization, per se, did not appear
to affect the course of pulmonary disease. The authors of that study warned,
however, of the potential for MRSA to become a pathogen in children with CF.
No children with CF were hospitalized and treated for pulmonary exacerbations
associated with MRSA or MSSA in 1988-1990. However, all 4 children with CF
who were hospitalized and treated for pulmonary exacerbations associated with
isolation of S aureus in 1993-1995 had an MRSA isolate.
This observation is of obvious concern and suggests that MRSA may be an important
pathogen for children with CF.
The community-acquired MRSA isolates obtained from children without
identified risk differed from those obtained from children with identified
risk and from nosocomially acquired isolates with respect to their susceptibility
to other antibiotics. In the isolates obtained from children without identified
risk, resistance was usually limited to methicillin. In contrast, multidrug
resistance characterized most nosocomially acquired MRSA strains and most
community-acquired MRSA strains isolated from children with identified risk.
A similar observation was reported in studies of community-acquired MRSA isolates
among adult intravenous drug abusers compared with nosocomially acquired MRSA
isolates.16,34 Two smaller studies
of community-acquired MRSA isolates obtained from children with no identified
risk have also found that the isolates tended to be susceptible to non–β-lactam
Only a few isolates were available for PFGE studies. Notably, the PFGE
patterns for the isolates obtained from 2 children without identified risk
differed from those obtained from 5 children with nosocomially acquired disease.
This result suggests that the community-acquired isolates obtained from children
without identified risk may have important differences when contrasted with
nosocomially acquired MRSA isolates.
Data regarding antimicrobial susceptibility among our isolates reinforce
this notion. Although several mechanisms identified to date have accounted
for decreased methicillin susceptibility or actual resistance among S aureus clinical isolates, the best-studied mechanism
of methicillin resistance in S aureus is related
to the presence of the mecA gene. The mecA gene was present in all the isolates we examined. It encodes a
novel penicillin binding protein (PBP) called PBP2′ or PBP2a36 and is often acquired with a larger DNA fragment
called the mec region. Presumably because multiple insertion sequences are
present in this mec region, transposons mediating resistance to quinolones,
clindamycin, erythromycin, trimethoprim, and gentamicin have been identified
in MRSA strains. Thus, MRSA isolates have tended to become multiply resistant.
However, the majority of the community-acquired isolates obtained from
our patients without identified risk were not multiply resistant. Notably,
we have found a similar phenotype (presence of the mecA gene but susceptibility to non–β-lactam antibiotics) among
a small sampling of MRSA isolates obtained from ambulatory children without
predisposing risks in another ongoing study.35
Thus, currently, at UCCH, we now consider clindamycin or other alternative
therapies for initial antimicrobial treatment for severely ill children, while
awaiting identification and susceptibility testing of the infecting bacterium.
Because the community-acquired isolates obtained from children without identified
risk were usually susceptible to clindamycin, we have not yet encouraged empiric
use of vancomycin.