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The Pediatric Infectious Disease Journal • Volume 00, Number XX, XXX XXX www.pidj.com | 1
ISSN: 0891-3668/22/00XX-0000
DOI: 10.1097/INF.0000000000003503
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
O S
Accepted for publication February 9, 2022
From the *Pediatric Infectious Diseases Unit, Department of Pediatrics, Hospital
General Universitario Gregorio Marañón, Unidad de Investigación Materno-
Infantil Fundación Familia Alonso (UDIMIFFA), Instituto de Investigación
Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain; †CIBER en Enferme-
dades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid,
Spain; ‡Department of Pediatrics, Centro de Salud, Madrid, Spain; § Pedi-
atric Department, Hospital Universitario Quironsalud, Madrid, Spain; ¶
Department of Pediatrics, Hospital Universitario Niño Jesús, Madrid, Spain;
‖Department of Pediatrics, Hospital de Getafe, Madrid, Spain; **Department
of Pediatrics, Hospital de Torrejón, Madrid, Spain; ††Department of Pediat-
rics, Hospital Clinico San Carlos, Madrid, Spain; ‡‡Department of Pediatric
Infectious Diseases, Hospital Universitario Doce de Octubre, Madrid, Spain;
§§Department of Microbiology, Hospital General Universitario Gregorio
Marañón, CIBERES, Centro de Investigación Biomédica en Red de Enfer-
medades Respiratorias, Madrid, Spain; ¶¶Department of Pediatrics, Hospital
Infanta Sofía, Madrid, Spain; ‖‖ Department of Microbiology, Hospital de
Getafe, Madrid, Spain; ***Department of Microbiology, Hospital Univer-
sitario Niño Jesús, Madrid, Spain; †††Department of Microbiology, Hos-
pital Universitario La Paz, Madrid, Spain ‡‡‡Department of Microbiology,
Hospital Universitario 12 de Octubre, Madrid, Spain; and §§§Department of
Pediatric Infectious Diseases, Hospital Universitario La Paz, Madrid, Spain.
Dr. Aguilera-Alonso was funded by the Spanish Ministry of Health—Instituto
de Salud Carlos III (ISCIII) and cofunded by the European Union (FEDER)
[Contrato Río Hortega CM18/00100].
The authors have no funding or conflicts of interest to disclose.
Address for correspondence: David Aguilera-Alonso, MD, Hospital General
Universitario Gregorio Marañón, Servicio de Pediatría, Calle de O’Donnell,
28009 Madrid, Spain. E-mail: david.aguilera@salud.madrid.org.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions of
this article on the journal’s website (www.pidj.com)
Staphylococcus aureus Community-Acquired Pneumonia
in Children After 13-Valent Pneumococcal Vaccination
(2008–2018): Epidemiology, Clinical Characteristics
and Outcomes
David Aguilera-Alonso, MD,*† Silke Kirchschläger Nieto, MD,‡ María Fátima Ara Montojo, MD,§
Francisco José Sanz Santaeufemia, MD,¶ Jesús Saavedra-Lozano, PhD,*† Beatriz Soto, PhD,‖
María Belén Caminoa, MD,** Arantxa Berzosa, MD,†† Luis Prieto Tato, PhD,‡‡ Emilia Cercenado, BSc,§§
Alfredo Tagarro, PhD,¶¶ David Molina Arana, PhD,‖‖ Mercedes Alonso Sanz, BSc,*** María Pilar Romero
Gómez, BSc,†,††† Fernando Chaves Sánchez, PhD,‡‡‡ and Fernando Baquero-Artigao, MD†§§§
Background: The epidemiology of community-acquired pneumonia (CAP)
has changed, influenced by sociosanitary conditions and vaccination status.
We aimed to analyze the recent epidemiology of bacterial CAP in hospital-
ized children in a setting with high pneumococcal vaccination coverage and to
describe the clinical characteristics of pediatric Staphylococcus aureus CAP.
Methods: Children <17 years old hospitalized from 2008 to 2018 with bac-
terial CAP in 5 tertiary hospitals in Spain were included. Cases with pneu-
mococcal CAP were randomly selected as comparative group following a
case-control ratio of 2:1 with S. aureus CAP.
Results: A total of 313 bacterial CAP were diagnosed: Streptococcus
pneumoniae CAP (n = 236, 75.4%), Streptococcus pyogenes CAP (n = 43,
13.7%) and S. aureus CAP (n = 34, 10.9%). Throughout the study period,
the prevalence of S. pyogenes increased (annual percentage change: +16.1%
[95% CI: 1.7–32.4], P = 0.031), S. pneumoniae decreased (annual percent-
age change: –4.4% [95 CI: –8.8 to 0.2], P = 0.057) and S. aureus remained
stable. Nine isolates of S. aureus (26.5%) were methicillin-resistant. Sev-
enteen cases (50%) with S. aureus CAP had some pulmonary complication
and 21 (61.7%) required intensive care. S. pneumoniae CAP showed a trend
toward higher prevalence of pulmonary complications compared with S.
aureus CAP (69.1% vs. 50.0%, P = 0.060), including higher frequency of
pulmonary necrosis (32.4% vs. 5.9%, P = 0.003).
Conclusions: The incidence of S. aureus CAP in children remained sta-
ble, whereas the prevalence of pneumococcal CAP decreased and S. pyo-
genes CAP increased. Patients with S. aureus presented a high frequency
of severe outcomes, but a lower risk of pulmonary complications than
patients with S. pneumoniae.
Key Words: pneumonia, community-acquired pneumonia, Staphylococcus
aureus, Streptococcus pneumoniae, Streptococcus pyogenes
(Pediatr Infect Dis J 2022;00:00–00)
Community-acquired pneumonia (CAP) is one of the leading
causes of morbidity and mortality in children under 5 years
old worldwide.1 The epidemiology of CAP diers remarkably
according to the country and is influenced by social and health care
conditions and vaccination status. Traditionally, Streptococcus
pneumoniae has been the most common causative microorganism
in childhood CAP. The advent of pneumococcal vaccination modi-
fied the spectrum of vaccine-preventable respiratory bacteria, lead-
ing to a decrease in the incidence of S. pneumoniae CAP, mostly
because of a reduction in the incidence of serotypes included in the
7-, 10- and 13-valent pneumococcal conjugate vaccines (PCV).2,3
Additionally, a relative increase seems to have occurred in the
prevalence of other bacteria, such as Streptococcus pyogenes and
Staphylococcus aureus, thus diminishing the relevance of S. pneu-
moniae.4–7
Recognition and management of S. aureus CAP in children
is challenging. Most national guidelines on pediatric CAP do not
recommend routine empirical coverage of S. aureus.8,9 Moreover,
methicillin-resistant S. aureus (MRSA) further increases the risk
of inadequate empirical therapy. Consequently, surveillance of
S. aureus CAP, including changes in resistance patterns, is very
important. However, few data have been reported to date on the
epidemiology and characteristics of S. aureus CAP in children after
the implementation of PCV.
The aims of this study were to analyze the recent epidemi-
ology of bacterial CAP in hospitalized children in a setting with
high PCV coverage, focusing on the clinical characteristics and
outcomes of pediatric S. aureus CAP.
MATERIALS AND METHODS
We performed a retrospective, multicenter, observational,
cross-sectional, case-control study. The study population comprised
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Aguilera-Alonso et al
children younger than 17 years of age who were hospitalized with
bacterial CAP in 5 tertiary hospitals in Spain between January 1,
2008, and December 31, 2018.
Definitions
Bacterial CAP was defined as cases with radiographic evi-
dence of pneumonia and a microbiologically confirmed bacterial
infection. The radiographic criteria were the presence of consolidation
(a lung opacity with or without air bronchograms), other infiltrate
(alveolar or interstitial densities) or pleural eusion. Chest radiogra-
phy findings were interpreted by a radiologist. Pneumonia was con-
sidered to be community-acquired if onset of symptoms/signs was
outside the hospital or during the first 48 hours after admission, in
contrast with the definition of hospital-acquired pneumonia.10,11
Microbiologic confirmation of bacterial CAP was defined as
detection of S. pneumoniae, S. pyogenes or S. aureus in blood cul-
ture, pleural eusion or bronchoalveolar lavage after culture or by
polymerase chain reaction (PCR) in a sterile fluid. Other bacteria
(eg, Mycoplasma pneumoniae, Chlamydia pneumoniae and
Legionella spp.) were not considered in this definition because of their
atypical manifestations. Patients were recruited from the databases of
the microbiology laboratories included in the study. Antibiotic treat-
ment was judged to be adequate based on the in vitro susceptibility of
the organism isolated and the degree of lung penetration.
The hospitals included in the study had 226, 120, 112, 76 and
32 pediatric beds, with 8800, 2400, 7800, 2800 and 1200 annual pedi-
atric admissions during the study period, respectively. Samples were
obtained at the physicians’ discretion and the hospital laboratories per-
formed cultures of respiratory samples and blood, including antimi-
crobial susceptibility testing of the organisms isolated using standard
techniques. Minimum inhibitory concentration breakpoints were inter-
preted following the recommendations of the European Committee on
Antimicrobial Susceptibility Testing (EUCAST) in place at the time.12
The characteristics of S. aureus CAP, including demographic
information, medical history, chest imaging results and clinical data,
were systematically collected from the medical chart using standard-
ized definitions and data collection instruments. We used pneumococ-
cal CAP, the most common bacterial CAP detected in children, as the
comparison group. We randomly selected cases with pneumococcal
CAP following a case-control ratio of 2:1. The information collected
from S. pneumoniae cases was the same as that collected from S. aureus
CAP cases. The study data were collected using the REDCap electronic
data capture tools hosted at Gregorio Marañón University Hospital.
Statistics
Continuous variables are expressed as medians and inter-
quartile ranges (IQR), since the data were non-normally distrib-
uted, and categorical variables are expressed as absolute values and
percentages. Dierences between categorical data were evaluated
using the χ2 or Fisher Exact test, and dierences between continu-
ous variables were assessed using the Kruskal-Wallis test. To char-
acterize trends, the annual percentage change (APC) was estimated
with its corresponding 95% confidence interval (CI). We applied the
joinpoint modeling percent change calculation to our monthly data
by using log-transformed data. For all analyses, a 2-tailed P value
<0.05 was considered statistically significant. STATA software ver-
sion 17 (StataCorp., College Station, TX: StataCorp LLC) and Join-
point Regression software version 4.9.0.0 (Statistical Methodology
and Applications Branch, Surveillance Research Program, National
Cancer Institute) were used for the statistical analysis.
Ethical Approvals
The study was approved by the Clinical Research Ethics
Committee at Hospital La Paz (study code PI-3352). The STROBE
statement for reporting observational studies was followed.13
RESULTS
Epidemiology of Bacterial CAP
From 2008 to 2018, a total of 313 episodes of bacterial
CAP were diagnosed in children at the study centers (median age,
18 months; 95% CI: 6–30 months). The most common causative
microorganism was S. pneumoniae (236 cases; 75.4%), followed
by S. pyogenes (43 cases; 13.7%) and S. aureus (34 cases; 10.9%).
Patients with S. aureus CAP were younger (median age 9 months,
95% CI: 6–31 months) than patients with S. pneumoniae CAP
(median age 18 months, 95% CI: 6–34 months) and S. pyogenes
CAP (median age: 18 months, 95% CI: 6–21 months) (P = 0.047).
The prevalence of S. pyogenes increased during the study
period (APC: +16.1% [95% CI: 1.7–32.4], P = 0.031), from
7.0% in 2008 to 26.9% in 2018. The prevalence of S. pneumo-
niae decreased (APC: –4.4% [95% CI: –8.8 to 0.2], P = 0.057),
from 88.4% in 2008 to 65.4% in 2018 (Fig.1). The prevalence of
S. aureus remained stable (APC: +6.1% [95% CI: –11.4 to 27.1],
P = 0.474), peaking in 2017.
The annual rate of hospitalized children with CAP decreased
from 2008 to 2013 (APC: –18.2% [95% CI: –32.6 to –0.7], P =
0.044) and then remained stable (Fig.2). This decrease was mainly
due to the decline in S. pneumoniae CAP from 2008 to 2011 (APC:
–31.6% [95% CI: –54.8 to 3.5], P = 0.066). Of note, there was an
increase in the annual rate of S. pyogenes CAP from 2013 to 2018
(APC: +56.2% [95% CI: 10.4–121], P = 0.020). The annual rate of
S. aureus CAP remained stable (average of 1.3 cases/10,000 admis-
sions/year).
S. aureus CAP
Table 1 shows the characteristics of the 34 patients with S.
aureus CAP. Twenty (58.8%) were males and 11 (32.4%) had a rel-
evant chronic medical condition. S. aureus was isolated in pleural
fluid in 18 cases (52.9%), blood culture in 17 (50.0%), bronchoalveo-
lar lavage in 1 (2.9%) and in both blood culture and pleural fluid in 2
cases. In 9 cases (26.4%), S. aureus was detected by PCR in pleural
fluid (positive culture in only 2/9). The number of cases was similar
in autumn, spring and winter (11, 10 and 9 cases, respectively), com-
pared with a lower number of cases in summer (4 cases).
The median hospital stay was 14 days (IQR: 9–21 days).
Seven patients (20.6%) had begun antibiotic therapy for CAP
before admission, with 5/7 cases (71.4%) not receiving appropriate
therapy according to the antimicrobial susceptibility of S. aureus.
The most common antibiotic used after S. aureus was identified
and its antibiotic susceptibility known (see Figure, Supplemental
Digital Content 1; http://links.lww.com/INF/E687) was cloxacil-
lin (14 cases), followed by clindamycin (9 cases) and vancomycin
(9 cases). Twenty-one patients (61.8%) received a single antibiotic
as definitive treatment, 10 (29.4%) received a combination of 2
antibiotics, most commonly with toxin-inhibitor antibiotics (clin-
damycin in 7 cases and linezolid in 2 cases) and 3 (8.8%) received
3 antibiotics. Twenty-seven patients (79.4%) completed their treat-
ment as outpatients with oral antibiotics (median duration, 10.5
days; IQR: 8–18 days). The median total duration of antibiotic ther-
apy was 22 days (IQR: 12–33 days). The most common outpatient
oral antibiotic (see Figure, Supplemental Digital Content 1, http://
links.lww.com/INF/E687) was amoxicillin-clavulanate (9 cases),
followed by cloxacillin (5 cases) and cefuroxime (4 cases). Twenty-
six of these patients (96.3%) received a single antibiotic.
Diagnostic testing for viruses was performed in a respira-
tory specimen in 20 cases of S. aureus CAP (58.8%), with detec-
tion of virus in 9 cases (45.0%). The most common virus was res-
piratory syncytial virus (4 cases), followed by influenza (2 cases),
rhinovirus (2 cases) and parainfluenza (1 case). The presence of
Panton-Valentine leukocidin genes (lukS-PV and lukF-PV) was
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The Pediatric Infectious Disease Journal • Volume 00, Number XX, XXX XXX
© 2022 Wolters Kluwer Health, Inc. All rights reserved. www.pidj.com | 3
Pediatric Staphylococcus aureus Pneumonia
evaluated using PCR in 9 patients. Results were positive in 5/9
cases (55.6%) (positive in 33.3% [2/6] methicillin-susceptible
S. aureus [MSSA] vs. 100% [3/3] MRSA, P = 0.058).
Methicillin-resistant S. aureus CAP
Of the 34 cases of S. aureus CAP, 25 (73.5%) were caused
by MSSA and 9 (26.5%) by MRSA. Figure (Supplemental Digital
Content 2, http://links.lww.com/INF/E687) shows the distribution
of MRSA throughout the study period. The prevalence of MRSA
remained stable (APC: –0.2% [95% CI: –14.3 to 16.1], P = 0.973).
However, in 2017, there was a peak of 10 cases of S. aureus CAP,
of which 5 (50.0%) were MRSA. Table1 shows the comparison of
the characteristics between MRSA and MSSA CAP. Compared with
MSSA, patients with MRSA were more frequently male (88.9% vs.
48.0%, P = 0.033) and more frequently had a relevant chronic medical
condition (66.7% vs. 20.0%, P = 0.010). Additionally, the empirical
antibiotic on admission was not active against the bacterial isolate in a
higher proportion of cases (64.0% vs. 22.2, P = 0.031), with a higher
FIGURE 1. Prevalence of bacterial community-acquired pneumonia throughout the study period.
FIGURE 2. Annual rate of children hospitalized with bacterial community-acquired pneumonia.
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Aguilera-Alonso et al
delay in days until adequate antibiotic therapy was given (median of 3
days [IQR: 1–4] vs. 0 days [0–2], P = 0.033). However, the length of
stay and the frequency of pediatric intensive care unit (PICU) admis-
sion or hospital readmissions were not significantly dierent.
Figure 3 shows the overall proportion of S. aureus isolates
resistant to various antibiotics and according to methicillin suscepti-
bility. Data on antibiotic susceptibility were not available for all iso-
lates. None of the isolates were resistant to rifampicin, vancomycin
or linezolid. Notably, 12.5% of the isolates (4/32) were clindamycin-
resistant, which increased to 22.2% (2/9) in the case of MRSA (P =
0.298). Furthermore, 14.3% (4/28) of the isolates were levofloxacin-
resistant, increasing to 44.4% (4/9) in the case of MRSA (P = 0.002).
Clinical Severity in Children With S. aureus CAP
A total of 17 children (50.0%) had a pulmonary complica-
tion, including pleural eusion in 16 (47.1%), pulmonary necrosis
TABLE 1. Clinical Characteristics of Children Hospitalized With Bacterial Community-acquired Pneumonia
According to the Etiology
S. aureus CAP
(N = 34) MSSA CAP
(N = 25) MRSA CAP
(N = 9) P (MSSA vs.
MRSA CAP) S. pneumoniae
CAP (N = 68)
P (S. aureus
vs. S.
pneumoniae
CAP)
Demographics
Gender (male) 20/34 (58.8%) 12/25 (48.0%) 8/9 (88.9%) 0.033 32/68 (47.1%) 0.263
Age at diagnosis (years) 0.7 (0.5–2.6) 1.0 (0.5–2.1) 0.6 (0.2–3.6) 0.470 2.9 (1.7–4.6) <0.001
Born abroad 2/34 (5.9%) 1/25 (4.0%) 1/9 (11.1%) 0.437 5/68 (7.4%) 0.782
Foreign parents 11/26 (42.3%) 6/18 (33.3%) 5/8 (62.5%) 0.165 13/52 (25.0%) 0.118
Medical chronic condition 11/34 (32.4%) 5/25 (20.0%) 6/9 (66.7%) 0.010 21/68 (30.9%) 0.880
Hospitalized during previous 6 months 8/34 (23.5%) 4/25 (16.0%) 4/9 (44.4%) 0.085 9/68 (13.2%) 0.188
Travel abroad during previous
6 months 3/34 (8.8%) 2/25 (8.0%) 1/9 (11.1%) 0.778 4/56 (7.1%) 0.773
Antibiotic therapy
Antibiotic before admission 7/34 (20.6%) 5/25 (20.0%) 2/9 (22.2%) 0.888 7/68 (10.3%) 0.150
Adequate empirical antibiotic 18/34 (52.9%) 16/25 (64.0%) 2/9 (22.2%) 0.031 67/68 (98.5%) <0.001
Delay of adequate antibiotic (days) 0.5 (0.0–3.0) 0.0 (0.0–2.0) 3.0 (1.0–4.0) 0.033 0.0 (0.0–0.0) <0.001
Duration of active antibiotic during
the admission (days) 12.0 (9.0–21.0) 11.5 (6.5–19.0) 12.0 (10.0–22.0) 0.570 11.0 (5.0–21.0) 0.538
Total duration of active antibiotic (days) 22.0 (12.0–33.0) 21.0 (12.0–34.0) 23.0 (15.0–27.0) 0.969 14.0 (10.0–29.0) 0.037
Blood test
C-reactive protein at admission (mg/dl) 12.1 (2.5–22.3) 14.2 (2.5–24.0) 11.1 (2.9–18.6) 0.711 35.9 (24.9–211.1) <0.001
Highest PCR (mg/dL) 17.5 (6.9–28.8) 21.3 (6.0–29.5) 14.0 (10.2–17.6) 0.777 35.9 (25.9–230.5) <0.001
PCT at admission (ng/mL) 1.5 (0.6–3.2) 3.1 (0.9–3.2) 0.5 (0.4–0.9) 0.020 6.6 (2.6–14.0) <0.001
Highest PCT (ng/mL) 2.6 (0.8–4.1) 3.2 (0.9–4.4) 1.0 (0.7–3.1) 0.322 4.0 (1.9–13.5) 0.033
Leukocytes count at admission (x109/L) 16.9 (12.0–19.3) 17.0 (11.8–19.3) 16.8 (13.0–18.1) 0.891 16.7 (12.0–24.8) 0.537
Neutrophils count at admission (x109/L) 9.1 (7.7–15.2) 9.4 (6.7–15.3) 9.1 (8.3–11.7) 0.746 13.4 (8.1–19.5) 0.068
Highest neutrophils count (x109/L) 12.8 (8.9–1.8) 13.1 (8.4–18.7) 12.8 (9.1–18.4) 0.891 15.4 (10.1–23.3) 0.116
Support
PICU admission 21/34 (61.8%) 15/25 (60.0%) 6/9 (66.7%) 0.724 41/68 (60.3%) 0.886
Duration of PICU admission 5.0 (2.0–10.0) 4.0 (2.0–10.0) 6.5 (2.0–15.0) 0.695 5.5 (3.5–10.5) 0.432
Oxygen therapy 30/34 (88.2%) 21/25 (84.0%) 9/9 (100.0%) 0.201 55/68 (80.9%) 0.348
Duration of oxygen therapy (days) 7.5 (3.0–10.0) 7.5 (3.0–10.0) 7.5 (4.5–11.5) 0.472 6.5 (3.0–11.0) 0.926
Invasive mechanical ventilation 3/34 (8.8%) 3/25 (12.0%) 0/9 (0.0%) 0.276 3/68 (4.4%) 0.372
Duration of invasive mechanical
ventilation (days) 4.0 (1.0–12.0) 4.0 (1.0–12.0) – – 3.0 (2.0–4.0) 0.658
Noninvasive mechanical ventilation 10/34 (29.4%) 8/25 (32.0%) 2/9 (22.2%) 0.581 7/68 (10.3%) 0.015
Duration of noninvasive mechanical
ventilation (days) 5.0 (1.0–5.0) 5.0 (1.0–5.0) 4.0 (2.0–6.0) 0.585 11.0 (4.0–12.0) 0.060
Virus
Respiratory virus diagnostic test 20/34 (58.8%) 15/25 (60.0%) 5/9 (55.6%) 0.816 27/68 (39.7%) 0.068
Virus coinfection 9/20 (45.0%) 6/15 (40.0%) 3/5 (60.0%) 0.436 5/27 (18.5%) 0.050
Influenza detected 2/20 (10.0%) 1/15 (6.6%) 1/5 (20.0%) 0.389 3/27 (11.1%) 0.903
RSV detected 4/20 (20.0%) 3/15 (20.0%) 1/5 (20.0%) 1.000 2/27 (7.4%) 0.201
Complications
Lung complications 17/34 (50.0%) 13/25 (52.0%) 4/9 (44.4%) 0.697 47/68 (69.1%) 0.060
Pleural effusion 16/34 (47.1%) 12/25 (48.0%) 4/9 (44.4%) 0.855 44/68 (64.7%) 0.088
Pulmonary necrosis 2/34 (5.9%) 1/25 (4.0%) 1/9 (11.1%) 0.437 22/68 (32.4%) 0.003
Lung abscess 0/34 (0.0%) 0/25 (0.0%) 0/9 (0.0%) – 2/68 (2.9%) 0.313
Pneumothorax 1/34 (2.9%) 1/25 (4.0%) 0/9 (0.0%) 0.543 11/68 (16.2%) 0.050
Pleural drainage 15/34 (44.1%) 12/25 (48.0%) 3/9 (33.3%) 0.447 39/68 (57.4%) 0.207
Intrapleural fibrinolytics 9/15 (60.0%) 7/12 (58.3%) 2/3 (66.7%) 0.792 23/38 (60.5%) 0.972
Videothoracoscopy 3/34 (8.8%) 3/25 (12.0%) 0/9 (0.0%) 0.276 10/68 (14.7%) 0.401
Panton-Valentine leukocidin 5/9 (55.6%) 2/6 (33.3%) 3/3 (100%) 0.058 – –
Outcome
Days of admission 14.0 (9.0–21.0) 13.0 (9.0–18.0) 16.0 (13.0–27.0) 0.291 12.0 (5.5–23.0) 0.341
30-day mortality 0/34 (0.0%) 0/25 (0.0%) 0/9 (0.0%) – 2/68 (2.9%) 0.313
30-day readmission 3/34 (8.8%) 1/25 (4.0%) 2/9 (22.2%) 0.098 4/68 (5.9%) 0.580
CRP indicates C-reactive protein; PCT, procalcitonin; PICU, pediatric intensive care unit; RSV, respiratory syncytial virus.
Significant (<0.05) or almost significant (0.05) P-values are shown in bold.
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The Pediatric Infectious Disease Journal • Volume 00, Number XX, XXX XXX
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Pediatric Staphylococcus aureus Pneumonia
in 2 (5.9%), pneumatoceles in 1 (2.9%) and pneumothorax in 1
(2.9%).
Twenty-one patients (61.7%) were admitted to the PICU,
requiring noninvasive mechanical ventilation in 10 cases (29.4%)
and invasive mechanical ventilation in 3 (8.8%). Table2 compares
patients admitted with those not admitted to the PICU. Patients
admitted to the PICU were younger (median age: 6 months vs. 2.1
years, P = 0.045) and less frequently had relevant chronic clinical
conditions (19.0% vs. 53.8%, P = 0.035). They more frequently
had pleural eusion (61.9% vs. 23.1%, P = 0.028) and a higher
maximum level of C-reactive protein (median: 22.9 vs. 6.4 mg/dL,
P = 0.004). There were no dierences in severity according to
methicillin susceptibility (Table 1). None of the patients with
S. aureus CAP died.
Comparison With S. pneumoniae CAP
A total of 68 patients with S. pneumoniae CAP were ran-
domly selected and compared with the 34 cases with S. aureus
CAP (Table 1). The patients with S. aureus CAP were younger
(median age: 8.4 vs. 34.8 months, P < 0.001), with more frequent
detection of a concomitant virus (45.0% [9/20] vs. 18.5% [5/27],
P = 0.050). Although patients with S. pneumoniae CAP more fre-
quently received adequate empirical antibiotic therapy (98.5% vs.
50.0%, P < 0.001), a trend toward higher prevalence of pulmonary
complications was observed (69.1% vs. 50.0%, P = 0.060), includ-
ing a higher prevalence of pulmonary necrosis (32.4% vs. 5.9%,
P = 0.003). Furthermore, patients with S. pneumoniae CAP had
higher acute phase reactant values (C-reactive protein and procalci-
tonin), although they received antibiotics for shorter periods.
DISCUSSION
We evaluated the epidemiology of bacterial CAP in chil-
dren hospitalized after implementation of PCV13, showing a
global decrease in bacterial CAP, mainly associated with a reduc-
tion in S. pneumoniae CAP. However, the annual rate of S. pyo-
genes CAP increased after 2013, representing 26.9% of bacterial
CAP in 2018. S. aureus CAP, including MRSA isolates, remained
stable throughout the 11-year period. Globally, one-third of cases of
S. aureus CAP were MRSA, with a high prevalence of resistance
to clindamycin. Children with S. aureus CAP were younger than
those with other causes of bacterial CAP. Patients with S. aureus
CAP had a high prevalence of complications, although morbidity
was even higher in patients with S. pneumoniae CAP.
PCV7 was implemented in the Community of Madrid
(Spain) in 2006 as part of the publicly funded immunization
program. In 2010, it was replaced by PCV13 but was later tem-
porarily excluded in 2012. From 2012 to 2015, the vaccine was
available privately for purchase by parents. PCV13 was eventu-
ally reintroduced as a publicly funded vaccine in 2015. During the
free universal vaccination period, pneumococcal vaccine cover-
age reached 95% and dropped to 67%–82% during the nonfunded
years.2 This study shows a decrease in the annual rate of CAP cases
hospitalized from 2008 to 2013 owing mainly to the decline in S.
pneumoniae CAP. This annual rate remained stable. The decreased
incidence of S. pneumoniae CAP has also been reported, mostly
because of a reduction in the frequency of those serotypes included
in the PCV.2,3,14 Of note, the incidence of S. pyogenes increased after
2013. An increment in the frequency of invasive diseases caused by
S. pyogenes, including pneumonia, has been reported in several coun-
tries.6,15–17 In a study conducted in France on the epidemiology of com-
munity-acquired pleural empyema, the frequency of pneumococcal
infection declined from 79.1% in 2009 to 36.4% in 2017 (P < 0.001),
with S. pyogenes being the leading cause in the later years of the study
period (2015–2017, 45.5%).4 Because of the stable prevalence of S.
aureus CAP, recent updates to guidelines recommend maintaining
aminopenicillins as first-line treatment for most cases of CAP, since
they remain highly active against S. pyogenes and S. pneumoniae.8,9,18
The prevalence of MRSA among children with S. aureus
CAP in our study (26.5%) was comparable to that seen in childhood
CAP in various European countries,4,6,7 but lower than reported
in other studies performed in countries with a higher burden of
MRSA.19–22 A recent study describing the epidemiology of Spanish
children colonized by S. aureus reported a prevalence of MRSA of
4.4% among S. aureus isolates.23 Considering only invasive isolates
(blood and cerebrospinal fluid), data from the European Centre for
FIGURE 3. Antibiotic resistance among Staphylococcus aureus isolates according to methicillin susceptibility. Antibiotic
susceptibility was not available for all isolates. The number of isolates evaluated for each antibiotic is shown in parentheses
(MSSA/MRSA). MRSA indicates methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus.
Copyright © 2022 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
The Pediatric Infectious Disease Journal • Volume 00, Number XX, XXX XXX
6 | www.pidj.com © 2022 Wolters Kluwer Health, Inc. All rights reserved.
Aguilera-Alonso et al
Disease Prevention and Control (ECDC, EARS-Net)24 show that
the prevalence of MRSA in children with 0–4 years and 5–18 years
of age in 2019 in Spain was 12% and 15.7%, respectively. Despite
the low prevalence of MRSA among children in Spain, S. aureus
isolates from patients with CAP were associated with a higher
prevalence of methicillin resistance. A similar prevalence of methi-
cillin resistance among S. aureus CAP in adults in our setting was
recently reported.25
Another relevant finding in our study is the prevalence of
clindamycin resistance in MRSA (22.2%), which was much higher
than in MSSA (8.7%). This dierence has also been described in
isolates from children colonized with S. aureus in Spain (26%
vs. 16.9%).23 Such a high prevalence calls into question the suit-
ability of clindamycin as empirical treatment of children with
suspected MRSA CAP in our region, as recommended by several
guidelines.8,18,26 Alternatives include vancomycin, linezolid and
trimethoprim-sulfamethoxazole.
Regarding clinical outcomes, several studies have compared
the severity of CAP caused by the most common bacterial agents
in childhood CAP.7,27–31 Bacteremic pneumonia caused by S. aureus
and S. pyogenes in children in the United States was characterized
by higher morbidity, with a higher frequency of hospitalization,
PICU admission and mechanical ventilation than in children with
S. pneumoniae.28 Other studies in children and adults have shown
similar results.25,30,30 A Spanish study showed results similar to ours,
with comparable outcomes among children with S. pneumoniae and
S. aureus CAP, whereas S. pyogenes was associated with a higher
risk for complications.7 This higher morbidity associated with
S. pyogenes CAP than with S. pneumoniae CAP was also reported
in Israel.31 In our study, it is noteworthy that patients with S. aureus
TABLE 2. Clinical Characteristics of Children Hospitalized With Staphylococcus aureus Community-acquired
Pneumonia According to the Admission to the Pediatric Intensive Care Unit
Total N = 34 No PICU N = 25 PICU N = 9 P
Demographics
Gender (male) 20/34 (58.8%) 6/13 (46.2%) 14/21 (66.7%) 0.238
Age at diagnosis (years) 0.7 (0.5–2.6) 2.1 (1.0–3.6) 0.5 (0.4–1.1) 0.045
Born abroad 2/34 (5.9%) 1/13 (7.7%) 1/21 (4.8%) 0.724
Foreign parents 11/26 (42.3%) 2/11 (18.2%) 9/15 (60.0%) 0.033
Underlying disease 11/34 (32.4%) 7/13 (53.8%) 4/21 (19.0%) 0.035
Hospitalized during previous 6 months 8/34 (23.5%) 3/13 (23.1%) 5/21 (23.8%) 0.961
Travel abroad during previous 6 months 3/34 (8.8%) 0/13 (0.0%) 3/21 (14.3%) 0.154
Antibiotic therapy
Antibiotic before admission 7/34 (20.6%) 3/13 (23.1%) 4/21 (19.0%) 0.778
Adequate empirical antibiotic 17/33 (51.5%) 5/13 (38.5%) 12/20 (60.0%) 0.486
Delay of adequate antibiotic (days) 0.5 (0.0–3.0) 1.0 (0.0–4.0) 0.0 (0.0–2.0) 0.203
Duration of active antibiotic during the admission (days) 12.0 (9.0–21.0) 9.5 (5.0–18.0) 12.0 (11.0–21.0) 0.124
Total duration of active antibiotic (days) 22.0 (12.0–33.0) 19.0 (11.0–30.0) 23.0 (12.0–35.0) 0.263
Blood test
CRP on admission (mg/dl) 12.1 (2.5–22.3) 5.1 (1.7–17.5) 19.7 (3.6–22.9) 0.127
Highest CRP (mg/dL) 17.5 (6.9–28.8) 6.4 (3.8–13.9) 22.9 (14.0–30.3) 0.004
PCT at admission (ng/mL) 1.5 (0.6–3.2) 0.9 (0.9–3.2) 2.0 (0.5–3.1) 0.841
Highest PCT (ng/mL) 2.6 (0.8–4.1) 1.6 (0.9–3.2) 3.1 (0.7–5.5) 0.760
Leukocytes count at admission (x109) 16.9 (12.0–19.3) 16.5 (11.8–19.2) 17.0 (13.6–19.4) 0.547
Neutrophils count at admission (x109) 9.1 (7.7–15.2) 8.8 (7.7–11.7) 10.7 (7.4–16.3) 0.713
Highest neutrophils count (x109) 12.8 (8.9–18.5) 9.9 (7.9–15.5) 13.6 (11.1–18.7) 0.156
Support
Oxygen therapy 30/34 (88.2%) 10/13 (76.9%) 20/21 (95.2%) 0.107
Duration of oxygen therapy (days) 7.5 (3.0–10.0) 3.0 (1.0–10.0) 8.0 (3.0–12.0) 0.117
Invasive mechanical ventilation 3/34 (8.8%) 0/13 (0.0%) 3/21 (14.3%) 0.154
Duration of invasive mechanical ventilation (days) 4.0 (1.0–12.0) 4.0 (1.0–12.0)
Noninvasive mechanical ventilation 10/34 (29.4%) 1/13 (7.7%) 9/21 (42.9%) 0.029
Duration of noninvasive mechanical ventilation (days) 5.0 (1.0–5.0) 1.0 (1.0–1.0) 5.0 (2.0–5.0) 0.203
Virus
Virus respiratory diagnostic test 20/34 (58.8%) 8/13 (61.5%) 12/21 (57.1%) 0.800
Virus coinfection 9/34 (26.5%) 2/13 (15.4%) 7/21 (33.3%) 0.249
Influenza detected 2/2 (100.0%) 1/1 (100.0%) 1/1 (100.0%) 1.000
RSV detected 4/34 (11.8%) 1/13 (7.7%) 3/21 (14.3%) 0.562
Complications
Lung complications 17/34 (50.0%) 3/13 (23.1%) 14/21 (66.7%) 0.013
Pleural effusion 16/34 (47.1%) 3/13 (23.1%) 13/21 (61.9%) 0.028
Pulmonary necrosis 2/34 (5.9%) 1/13 (7.7%) 1/21 (4.8%) 0.720
Lung abscess 0/34 (0.0%) 0/13 (0.0%) 0/21 (0.0%) 1.000
Pneumothorax 1/34 (2.9%) 1/13 (7.7%) 0/21 (0.0%) 0.206
Pleural drainage 15/34 (44.1%) 3/13 (23.1%) 12/21 (57.1%) 0.052
Intrapleural fibrinolytics 9/15 (60.0%) 0/3 (0.0%) 9/12 (75.0%) 0.018
Videothoracoscopy 3/34 (8.8%) 2/13 (15.4%) 1/21 (4.8%) 0.290
Panton-Valentine leukocidin 5/9 (55.6%) 1/1 (100%) 4/8 (100%) 0.340
Methicillin resistance 9/25 (36.0%) 12/25 (48.0%) 6/9 (66.7%) 0.724
Outcome
Days of admission 14.0 (9.0–21.0) 11.0 (6.0–16.0) 15.0 (13.0–21.0) 0.092
30-days mortality 0/34 (0.0%) 0/13 (0.0%) 0/21 (0.0%) 1.000
30-days readmission 3/34 (8.8%) 1/13 (7.7%) 2/21 (9.5%) 0.850
CRP indicates C-reactive protein; PCT, procalcitonin; PICU, pediatric intensive care unit; RSV, respiratory syncytial virus.
Significant (<0.05) P-values are shown in bold.
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The Pediatric Infectious Disease Journal • Volume 00, Number XX, XXX XXX
© 2022 Wolters Kluwer Health, Inc. All rights reserved. www.pidj.com | 7
Pediatric Staphylococcus aureus Pneumonia
CAP, which mainly aect infants, were younger than those with
CAP caused by other bacteria. This finding was also highlighted in
other, similar studies, which report a higher prevalence of S. aureus
CAP in infants.20,22,32
S. aureus bacteremia is a leading cause of mortality. In a
study carried out in the United States on S. aureus bloodstream
infections in children, 8/394 (2%) patients died because of S.
aureus bacteremia, 5 of whom (62.5%) had pneumonia.33 Despite
the fact that none of the patients with S. aureus CAP died in our
study, other studies evaluating the outcome of pediatric S. aureus
CAP have reported a mortality of 0.9–4.9%.21,22,29,34 A 12-year-old
girl living in our region during the study period died suddenly at
home; the autopsy revealed the cause of death to be multiple organ
failure after MRSA bilateral abscess pneumonia.35 If she had been
hospitalized, the mortality rate of S. aureus CAP in our study would
have been 2.9%.
We found that disease severity in patients with MRSA was
not significantly greater than in those with MSSA CAP. Methicil-
lin resistance in S. aureus infection has traditionally been consid-
ered a risk factor for adverse outcomes and is probably associated,
at least in part, with a delay in the start of active antibiotic therapy.
A study that included 394 episodes of S. aureus bloodstream infec-
tions in children showed that methicillin resistance was associated
with a higher risk of complications (aOR 3.31; 95% CI: 1.60–6.85).33
However, in another study including 152 children with invasive
community-acquired S. aureus infections, MRSA was not associ-
ated with a severe outcome.37 Additionally, other studies focusing on
pediatric S. aureus CAP did not show higher morbidity in children
with MRSA.21,22,27 A recent large, prospective study evaluating 552
children with S. aureus bacteremia found that whereas developing
necrotizing pneumonia increased mortality, the isolation of MRSA
did not.34 Several factors, such as previous MRSA infection or colo-
nization, recurrent skin infections and long-term hemodialysis have
been associated with MRSA CAP in adults.30,38 We found that chil-
dren with MRSA were more frequently male and more frequently
had relevant chronic clinical conditions than those with MSSA.
Our study has several limitations. First, its retrospective
design limits the evaluation of factors not routinely considered,
including molecular analysis of the isolates (eg, sequence type of S.
aureus strains or toxin genes) and days of antibiotic therapy before
admission. Second, our data can be extrapolated only to populations
with a similar epidemiology and comparable vaccination coverage.
Finally, S. pneumoniae serotypes were not routinely collected. As
a strength, our study is one of the largest cohorts of children with
bacterial CAP in the post-PCV era. In addition, the patients were
included over a long period of time, with a focus on S. aureus CAP.
In conclusion, the incidence of S. aureus CAP in children
remained stable in our study, whereas that of S. pneumoniae CAP
decreased and that of S. pyogenes CAP increased. The prevalence of
severe outcomes was high in patients with S. aureus, although the
risk of pulmonary complications was lower than in patients with S.
pneumoniae. The relevant prevalence of clindamycin resistance in
S. aureus CAP, especially in that caused by MRSA, should be moni-
tored closely. Clinical guidelines should be updated if necessary.
ACKNOWLEDGMENTS
We are grateful to Thomas O’Boyle for writing assistance,
and to the Unidad de Investigación Materno-Infantil Fundación
Familia Alonso (UDIMIFFA) for its support.
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