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Original Studies

Epidemiology and Antimicrobial Susceptibility of Invasive Bacterial Infections in Children—A Population-Based Study From Norway

Thaulow, Christian Magnus MD*,†; Lindemann, Paul Christoffer MD*,‡; Klingenberg, Claus PhD§,¶; Berild, Dag PhD; Salvesen Blix, Hege PhD**,††; Myklebust, Tor Åge PhD‡‡; Harthug, Stig PhD*,§§

Author Information
The Pediatric Infectious Disease Journal: May 2021 - Volume 40 - Issue 5 - p 403-410
doi: 10.1097/INF.0000000000003013

Abstract

Bacterial infections are one of the most frequently causes of death in children,1,2 and increasing antimicrobial resistance is a major health concern worldwide.3 Surveillance of epidemiology and antimicrobial susceptibility testing (AST) data for bacteria causing serious infections is of high importance,4 but data specific for children are often lacking, also in Norway.5 Specific antibiograms for children improve treatment quality,6 and pediatric surveillance programs are recommended.7,8

The distribution of the most frequent bacteria recovered in pediatric bloodstream infections varies in different countries and settings8–11 and with age.1,9 Studies comparing AST data in bacterial isolates from children versus adults are limited.8,12,13 A Canadian study reported lower rates of resistance to commonly used antibiotics in Escherichia coli and Staphylococcus aureus isolates from children than adults.12 A European study reported higher resistance rates to macrolides in pediatric Streptococcus pneumonia blood isolates than in adult isolates.8

Norway is a high-income country with low rates of antimicrobial resistance.5,14 Empirical recommendations for antibiotic regimen in children emphasize penicillin for pneumonia and gentamicin combined with penicillin or ampicillin for sepsis.15 However, adherence rate to the guideline varies.16,17

The aims of this study were to report the incidence of invasive bacterial infections, the distribution of causative pathogens and AST data, in Norwegian children compared with adults.

MATERIALS AND METHODS

Data Collection and Bacterial Isolates

This is an observational population-based study using prospectively collected data from the Norwegian Surveillance System for Antimicrobial Resistance (NORM) between 2013 and 2017. NORM was established in 2003 and collects clinically relevant AST data from different sites within defined time ranges for each bacterium. All 22 primary diagnostic laboratories and 11 reference laboratories in Norway participate in the collection. A specially designed web-based computer program (eNORM) is used for registration. The reporting of AST data is mandatory and is regulated by the National Regulation of Resistance Registry.18 All samples from both primary care and hospitals (including 22 pediatric centers) in entire Norway are covered by these laboratories. Thus, the expected national coverage is close to 100% within the defined time ranges of collection for each bacterium. Patients with more than 1 phenotypically identical isolate of the same species from the same site within 1 month are registered with only 1 isolate, but if the same isolate is observed in both blood and spinal fluid, they are registered as 2 isolates. Results from AST are interpreted in accordance with clinical breakpoints from EUCAST.19 Further details on testing are described in the NORM reports.5

We included all relevant systemic isolates from blood and cerebrospinal fluid (CSF) (see Table, Supplemental Digital Content 1, https://links.lww.com/INF/E245). NORM also collects isolates from urine, wounds, and the respiratory tract, but these are not registered in relation to systemic infections and were therefor not included in our study. Data on coagulase-negative staphylococci (CoNS) and Viridans group streptococci were not reported to NORM in the collection period and could not be included in our analyses, but these are also often defined as contaminants in pediatric blood culture studies.20 We excluded anaerobic isolates, as there were not a single isolate obtained in children, during a 12 months collection period. This can be explained by less frequently use of anaerobic blood culture bottles among children but also by less observations of anaerobe bacteria in children.21

Data on children (0–18 years), extracted from NORM, included birth month and year, county of residence, laboratory name, date of culture, name of antibiotic, and the minimum inhibitory concentration (MIC) value. We divided the children in 3 different age categories; infants (0–1 years of age, up to the month of turning 1 year); preschool children (1–6 years of age, from the first month after turning 1 year to the month of turning 6 years); schoolchildren (6–18 years of age, from the first month after turning 6 years to the month of turning 18 years). Additionally, we also report selected data separately for infants 0–3 months of age (up to the month of turning 3 months). The isolates from adults were separated from the year-specific NORM reports by subtracting the pediatric isolates from the total number of isolates presented in the reports.5 This was done separately for each bacteria-antibiotic combination so that all pediatric results were eliminated. In 41 pediatric Streptococcus agalactiae (GBS) isolates and in 1 S. aureus isolate, susceptibility data were missing. These isolates were included in the demographic overview for children but for comparison of resistance rates, they remained in the adult group because it was not possible to extract them.

Definitions, Analyses, and Statistics

All data and specifically the translation into susceptibility pattern were quality assured. We used the EUCAST clinical breakpoints corresponding to the year after data collection to define susceptibility into 3 categories: susceptible (S), intermediate resistant (I), or resistant (R). We used the old SIR definition since we used historical data and breakpoints. Nonsusceptibility (NS) rate was defined as isolates being I or R and was only used in relation to S. pneumoniae/penicillin, as this is a well-established method of describing susceptibility pattern for this combination.22 We used the nonmeningitis breakpoints for penicillin.19

Demographic data were described in numbers; age groups were described with corresponding percentages, and the different bacteria in children were described with corresponding risk ratio (RR) and 95% confidence intervals (CI) compared with adults. As an example, RR for E. coli was calculated as the rate of all E. coli isolates deriving from children divided by the rate of all isolates deriving from adults. The 95% CI were calculated by generating the natural log (Ln) of the RR and then the antilog of the upper and lower limits of the CI for Ln (RR).

As some bacteria were not sampled for 5 fully years, we estimated the total number by multiplying the number of isolates obtained for each bacterium with the factor needed to hypothetically get 5 complete years of registration data. These were used to describe distribution of bacteria and crude incidence of culture-confirmed bacterial infections based on census data from Statistics Norway.23 We also estimated the age-standardized incidence, using the European standard population as reference.24 We excluded Proteus spp., Enterobacter spp., and Pseudomonas aeruginosa from the incidence calculation because we regarded the collection period too short for these more rarely detected species. Both the distribution of isolates and the incidence rates were presented as figures and reported as percentages with corresponding 95% CI (distribution) and as number per 100,000 inhabitants in Norway (incidence).

All pediatric isolates were analyzed according to susceptibility for relevant antibiotics. For comparisons with adults, we included bacteria with more than 50 isolates, and we compared the proportion of isolates being R. The exception was S. pneumoniae where we compared the NS rate to penicillin. Resistance pattern were described in number and percentages with corresponding 95% CI. We also performed year-by-year sensitivity analyses comparing resistance rates in all bacteria-antibiotic combinations with at least 5 R isolates in total. For E. coli, S. aureus, and S. pneumoniae, we also compared resistance rates within our 3 defined pediatric age categories and for S. pneumoniae also the median MIC values for penicillin with corresponding interquartile range (IQR) between infants and older children.

For comparison of proportions, we based the statistical tests on 2-way frequency tables including the observed frequencies and the expected frequencies. The expected frequency in a 2-way frequency table is (row total × column total)/total number of observations. If any expected frequencies were <5, we used Fisher’s exact test and in all other cases we used a χ2 test. Comparison of MIC values was performed using a Mann-Whitney U test. We used Stata SE version 16.1 for analyses. A P value <0.05 was considered significant.

Ethics

The data were collected according to the National Regulation of Resistance Registry18 and were approved by the data protection official at Haukeland University Hospital (ID 1075).

RESULTS

Epidemiology

In total, 1173 isolates (1144 from blood, 29 from CSF) were included from children, compared with 27,735 isolates (27,621 from blood, 114 from CSF) from adults. Four percent of all blood culture isolates and 20.3% of all CSF isolates came from children (Table 1). Infants (0–12 months) accounted for 566 (48.2%) of the pediatric isolates, whereof 449 (79.3%) came from the age group 0–3 months. Of 181 GBS isolates, 175 (96.7%) came from infants 0–3 months of age. Estimated annual crude national incidence rate of invasive bacterial infections in children (excluding Proteus spp., Enterobacter spp., and Pseudomonas Aeruginosa) was 26.4 per 100,000 (95% CI: 23.6–29.5), corresponding to an age-standardized incidence rate of 26.2 per 100,000 (95% CI: 23.4–29.4). Incidence was strongly related to age, infants presenting with the highest rate, 274.4 per 100,000 (95% CI: 234.2–320.2) (Figure 1). Age-standardized incidence for S. aureus was 7.0 per 100,000 (95% CI: 5.6–8.7). Figure 2 show that E. coli and GBS dominated among infants (58.1%, 95% CI: 54.7–61.5), S. aureus and S. pneumoniae dominated among preschool children (40.7%, 95% CI: 35.3–46.2), and S. aureus dominated among schoolchildren (46.2%, 95% CI: 41.6–50.7). The Enterococcus faecalis/faecium ratio was 64/9 (7.1) in children and 2013/865 (2.3) in adults.

TABLE 1. - Bacterial Isolates From the Norwegian Surveillance System for Antimicrobial Drug Resistance (NORM) 2013–2017—Total Number, Main Bacterial Pathogens in Children (0–18 Years) and Relative Risk Ratio (RR) in Children to Adults
Blood CSF
All, n 28 403 143
Children n (% of all) 1144 (4.0) 29 (20.3)
Age groups (n, % of pediatric isolates)
 0–1 566 (49.5) 9 (31.0)
 1–6 233 (20.4) 12 (41.4)
 6–18 342 (29.9) 8 (27.6)
 Unknown 3 (0.3)
Microbes, n (RR to adults, 95% CI)
 0–1 yrs
  All Gram-positive bacteria 382 (1.38, 1.31–1.47)
   S. aureus 119 (0.98, 0.84–1.15)
   S. agalactiae 175 (9.93, 8.63–11.42) 3 (5.43, 1.68–17.5)
   S. pneumoniae 35 (0.65, 0.47–0.90) 5 (0.75, 0.42–1.37)
   Enterococcus spp.* 42 (0.70, 0.52–0.94)
   S. pyogenes 11 (0.60, 0.33–1.08) 0 (n/a)
  All Gram-negative bacteria 184 (0.63, 0.56–0.71)
   E. coli 131 (0.70, 0.60–0.81)
   Klebsiella spp.* 38 (0.47, 0.35–0.64)
   H. influenzae 9 (1.08, 0.56–2.08) 0 (n/a)
   N. meningitidis 3 (2.49, 0.78–7.93) 1 (0.84, 0.13–5.69)
   Others 3 (0.16, 0.04–0.62)
 1–6 yrs
  All Gram-positive bacteria 171 (1.50, 1.39–1.62)
   S. aureus 45 (0.90, 0.69–1.17)
   S. pneumoniae 65 (2.93, 2.38–3.62) 8 (0.90, 0.60–1.37)
   S. pyogenes 46 (6.01, 4.65–7.93) 0 (n/a)
   S. agalactiae 0 (0.07, 0.00–1.09) 0 (n/a)
   Enterococcus spp.* 15 (0.56, 0.34–0.91)
  All Gram-negative bacteria 63 (0.53, 0.43–0.65)
   E.coli 28 (0.36, 0.25–0.51)
   Klebsiella spp.* 14 (0.42, 0.25–0.70)
   H. influenzae 12 (3.49, 1.99–6.10) 4 (4.75, 1.67–13.47)
   N. meningitidis 4 (8.03, 2.94–21.95) 1 (0.84, 0.13–5.69)
   Others 5 (1.08, 0.45–2.59)
 6–18 yrs
  All Gram-positive bacteria 261 (1.57, 1.48–1.67)
   S. aureus 165 (2.26, 2.02–2.53)
   S. pneumoniae 36 (1.11, 0.82–1.52) 2 (0.34, 0.10–1.13)
   S. pyogenes 35 (3.17, 2.30–4.37) 1 (38.33, 1.68–875.03)
   S. agalactiae 6 (0.56, 0.25–1.25) 0 (n/a)
   Enterococcus spp.* 19 (0.48, 0.31–0.75)
  All Gram-negative bacteria 85 (0.46, 0.38–0.55)
   E. coli 53 (0.47, 0.36–0.60)
   Klebsiella spp.* 18 (0.37, 0.24–0.58)
   H. influenzae 7 (1.40, 0.67–2.92) 2 (3.56, 0.90–14.07)
   N. meningitidis 1 (1.38, 0.19–9.92) 3 (2.85, 1.04–7.84)
   Others 1 (0.15, 0.02–1.05) -
*All age groups: E. faecalis (64), E. faecium (9), Enterococcus spp. (3), K. pneumoniae (54), K. oxytoca (13), Klebsiella spp. (3).
†All age groups: Proteus spp. (2), Enterobacter spp. (2), P. aeruginosa (5).

FIGURE 1.
FIGURE 1.:
Estimated incidence rate for different age groups of invasive bacterial infections confirmed by isolates from blood/CSF in Norway. Vertical line represents the 95% CI around the point estimate for each category. The number of isolates is estimated based on sampling from the Norwegian Surveillance System for Antimicrobial resistance (NORM) 2013–2017. Bacteria included as follows: S. aureus, S. pneumoniae, S. pyogenes, S. agalactiae, Enterococcus spp., E. coli, Klebsiella spp., H. influenza, and N. meningitides. CI indicates confidence intervals; CSF, cerebrospinal fluid.
FIGURE 2.
FIGURE 2.:
Distribution of (A) bacterial species and (B) Gram-negative/Gram-positive bacteria in blood/CSF isolates in Norway for different age groups; adults (n = 44 000), 0–1 years (n = 834), 1–6 years (n = 327), 6–18 years (n = 477). The number of isolates is estimated based on sampling from the Norwegian Surveillance System for Antimicrobial resistance (NORM) 2013–2017. CSF indicates cerebrospinal fluid.

Resistance Rates

Figure 3 highlights differences between children and adults. For a detailed description of resistance pattern in children compared with adults, see Table (Supplementary Digital Content 2, https://links.lww.com/INF/E246). For year-by-year resistance rates and susceptibility pattern in pediatric isolates not included for comparison, see Table (Supplementary Digital Content 3, https://links.lww.com/INF/E247).

FIGURE 3.
FIGURE 3.:
Comparison of susceptibility pattern between invasive (blood/CSF) isolates from Norwegian children (0–18 years) and adults, (a) Gram-positive bacteria and (b) Gram-negative bacteria. 95% CI are shown as the vertical line on the column. Data are based on sampling from the Norwegian Surveillance System for Antimicrobial Resistance (NORM), 2013–2017. Penicillin NS indicates Pencillin nonsusceptible; SXT, Trimethoprim-sulfamethoxazol; Gentamicin Hi, high-level gentamicin resistance; TZP, Piperacillin-tazobactam; CSF, cerebrospinal fluid.

Compared with S. pneumoniae isolates from adults (N = 2674), we observed higher NS rates in isolates from children (N = 151) to penicillin, 11.9% versus 5.8%, P < 0.01. Two of the S. pneumoniae isolates from children were R, and 16 were I. All S. pneumoniae isolates from children that were collected from the CSF were S (MIC ≤ 0.06) to penicillin. Compared with S. pneumoniae isolates from adults, we also revealed higher resistance rates in isolates from children to erythromycin (11.3% vs. 4.9%, P < 0.01), clindamycin (9.3% vs. 3.6%, P < 0.001), and trimethoprim/sulfamethoxazole (17.9% vs. 6.4%, P < 0.001). Of the 18 isolates expressing NS to penicillin, 6 were resistant to all the antibiotics mentioned above, 5 were resistant to only erythromycin and clindamycin, and 3 isolates were resistant to only trimethoprim/sulfamethoxazole. None of the pediatric S. pneumoniae isolates were R to cefotaxime, but 4 (2.6%) were I.

Compared with GBS isolates from adults (N = 895), we observed higher resistance rates in isolates from children (N = 143) to erythromycin (29.4% vs. 17.1%, P < 0.001) and clindamycin (25.2% vs. 11.6%, P < 0.001). In S. aureus isolates from children, we observed only 1 MRSA positive case (0.3%) of 330 isolates. Compared with E. coli isolates from adults (N = 9073), we observed lower rates of ESBL production in isolates from children (N = 212), 2.4% versus 6.1%, P < 0.05. All 5 ESBL isolates in children were S to piperacillin-tazobactam and meropenem. Compared with E. coli isolates from adults, we also observed lower resistance rates to ciprofloxacin in isolates from children, 7.5% versus 13.0%, P < 0.05.

Resistance rates within the children group are shown in Table (Supplemental Digital Content 4, https://links.lww.com/INF/E248). For S. pneumoniae, NS rate to penicillin was 5.0% (95% CI: 0.6–16.9) in isolates from infants, 13.7% (95% CI: 6.8–23.8) from preschool children and 15.8% (95% CI: 6.0–31.3) from schoolchildren. The median penicillin MIC value for S. pneumoniae were lower in infants (0.016, IQR: 0.016) than in older children (0.032, IQR: 0.016), P < 0.01. For E. coli, resistance rate to gentamicin was 11.3% (95% CI: 4.3–23.0) in schoolchildren.

DISCUSSION

To our knowledge, this is the first study from the Nordic countries describing national epidemiology and susceptibility pattern in pediatric invasive bacterial isolates.

The estimated annual incidence of invasive bacterial infections in Norway (age 0–18, 26.2/100,000) was very similar to data on blood culture proven sepsis in Switzerland (age 0–16, 25.1/100,000).1 However, the annual incidence for infants was somewhat higher in our study (274.4/100,000) compared with the Swiss study (231.3/100,000). This could mirror that the latter only included isolates associated with clinical proven sepsis (by SIRS criteria). On the other hand, a substantial proportion of isolates (such as CoNS) were not included in our estimation. CoNS are often regarded as contamination but may cause infections in immunosuppressed children.25

Age stratified distribution of pathogens from children were in the same range as in a large Swiss study.1 The E. faecalis/faecium ratio was high (7.1) in our study compared with a European point-prevalence survey (1.9).8 Given that E. faecium mostly causes nosocomial infections,26 this finding is supported by the somewhat lower rate of nosocomial infections among children in Norwegian hospitals (19.8%) compared with the average rates reported in a selection of European countries (27.6%).16,27

In our study, the incidence of invasive bacterial infections was lower in children (except infants) than in adults. Antibiotic administration before first blood culture could stop bacteria from growing. A study in Norwegian children revealed that any microbiologic testing was missing in 23% of children before start of antibiotic treatment for any indications.16 In children, blood culture procedures are more challenging than in most adults, which may lead to antibiotic administration without a corresponding blood culture. Especially during transport to hospital (when circumstances is challenging), this is relevant. A recently published study reported that multiple blood cultures with age adjusted volume before antibiotics increased the chance of pathogen isolation in children.28 Regarding pattern of antibiotic use, reports from Norwegian hospitals show that children use less broad-spectrum antibiotics compared with the entire population.5,16 This is relevant since detection of pathogen is more difficult if broad-spectrum antibiotics are administrated before blood culture is obtained.

Empirical antibiotic guidelines for pediatric sepsis in Norway (gentamicin plus penicillin/ampicillin) are based on low resistance rates, a long treatment tradition favoring this regimen and by a limited number of studies.25,29,30 In neonates, this regimen is applied worldwide but for older children most guidelines emphasizes broad-spectrum antibiotics such as third-generation cephalosporins or piperazillin-tacobactam.31,32 Based on the results in our study and as part of this discussion, we have compared 4 different empirical antibiotic regimens for pediatric sepsis in our population (Figure 4). On one side, one should aim for antibiotics categorized as access in the acknowledged WHO AWaRe classification system to slow down resistance,3 but one should neither underestimate the morbidity and mortality rate of sepsis for the individual patient.2 Clinical studies in children comparing the established antibiotic regimen with a third-generation cephalosporin or piperacillin-tazobactam are warranted.

FIGURE 4.
FIGURE 4.:
Alternative antibiotic empirical regimes for pediatric/neonatal sepsis in Norway and their expected effect on the most common bacteria. Resistance rates are based on national collected data on children (0–18 years) from blood/CSF 2013–2017. ¤Access and Watch antibiotics are defined by the WHO. #If resistance rate for a certain bacteria/antibiotic combination was not available, the most appropriate category was evaluated based on resistance rates for similar antibiotics and/or available literature. §Breakpoints for this figure are based on the 2020 version of EUCAST cutoff limits. CSF indicates cerebrospinal fluid; EUCAST, European Committee on Antimicrobial Susceptibility Testing.

The high burden of S. aureus bacteremia among schoolchildren in our study is in line with observations from otherwise healthy Swiss children (10–16 years).1 In comparison with the annual incidence of S. aureus bacteremia reported in our study (7.0/100,000), other high-income countries have reported incidences from 3.7 to 14.4/100,000.1,33 Fatality of invasive S. aureus infections in children is considerable, 4.7% in Australia/New Zealand.33 Thus, adequately covering of S. aureus should be high priority in empirical guidelines. Many invasive S. aureus infections present with typical infection-sites such as bone and soft-tissue, but a notable proportion (36%33) presents with no or less typical organ-specific symptoms. Gentamicin resistance was low in S. aureus isolates in our population, but there is a lack of evidence using this drug as monotherapy for other than Enterobacterales.34 Thus, the empirical sepsis regimen in Norway could be problematic. To continue using antibiotics listed as access in the WHO AWaRe classification system,35 we speculate whether gentamicin combined with a narrow-spectrum β-lactamase stable penicillin (such as cloxacillin) could be suitable for initial treatment of suspected sepsis in schoolchildren. Another option is to use a first-generation cephalosporin.

We could not find other studies reporting higher NS rate to penicillin in invasive S. pneumoniae isolates from children than adults, but a Canadian study from 2012 (including both blood and respiratory tract isolates) observed that a higher proportion of isolates from children than adults had MIC values >1.0 mg/L.12 Opposite to our results, one study observed higher NS rates in infants (20.6%) compared with older children (10.6%).8 Our observation of more resistance in isolates from children to both erythromycin, clindamycin, and trimethoprim/sulfamethoxazole is not mirrored in other comparative studies.8,12 Particularly striking was the high resistance rate (17.9%) to trimethoprim/sulfamethoxazole, reflected by high use of this agent in Norwegian children.36 The 13 valent pneumococcal conjugate vaccine was introduced in the Norwegian children vaccine program in 2011. A population-based study reported an increase in nonsusceptible clones in invasive pneumococcal disease that was mainly nonvaccine serotypes imported to Norway from 2011 to 2016.22 Susceptibility pattern in these serotypes corresponded to our observation.

Despite the high NS rate in S. pneumoniae isolates, we argue that penicillin should continue as first-line empirical drug in severe pneumonia because most isolates were intermediate resistant, and relevant alternatives have even higher odds of treatment failure or an unfavorable ecologic profile. However, one should aim for high-dose exposure (up to 50 mg/kg every 4 hours).37 For the future, serotype independent vaccines may help combat invasive pneumococcal infections.38

Our observation of lower ESBL rates in E. coli isolates from children than from adults is comparable with studies from North America,12,39 and the lower resistance rate to ciprofloxacin is even more dominant in other reports.8,12 In Canada, gentamicin resistance in isolates from children was reported lower than in adults,12 while a European study reported the opposite.8 The high resistance rates in E. coli isolates from schoolchildren to multiple antibiotic classes observed in our study is of concern, but it corresponds to other observations of increasing E. coli resistance during childhood.8,40 Despite the latter, our study supports that gentamicin continues as an appropriate drug for Enterobacterales for most children in our population.

In this large study, we used national prospectively collected data from a high-quality register using identical methods in all data collection. In contrast to another study that used the entire population as reference group,8 we have compared resistance rates in 2 homogenous groups of children and adults. The lack of clinical data is a limitation when interpreting the results of the study. We acknowledge that studies with focus on the connection between microbiologic findings and clinical parameters are needed. Unfortunately, we could not include all microbes with fully registration periods. We compensated by calculating an estimated number of total isolates, but we excluded bacteria that were not collected ≥50% of the entire period (2013–2017) from the incidence calculation. The 41 GBS isolates from children that had to remain in the adult group has to be considered when interpreting the resistance rates. Finally, we had to use breakpoints corresponding to the year of the different NORM reports because we did not have MIC values available for the adult population. However, we also analyzed all isolates from children in accordance with the 2020 breakpoints from EUCAST and we revealed different resistance rate in only 4 bacteria/antibiotic combinations and in total only 8 single isolates were added or subtracted in the R category, see Table (Supplemental Digital Content 5, https://links.lww.com/INF/E249).

ACKNOWLEDGMENTS

We want to thank Gunnar Skov Simonsen and the rest of the group managing the NORM registry for support and hand-over of data.

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Keywords:

antimicrobial resistance; pediatric antibiotic stewardship; invasive infections; pediatric sepsis; bacterial isolates

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