ESBL-producing organisms are increasingly common worldwide, and represent an emerging infectious threat. 2,3,8
Our study documents a marked increase in both the proportion of ESBL producers and the incidence of primary ESBL infection over the 5 year study period, indicating ESBL-producing organisms may be an emerging problem in US pediatric institutions. Similar to adult studies and other pediatric studies, 10,11,15
most children from whom ESBL-producing organisms were isolated had chronic medical issues and recurrent infection. Unique to this study was the identification of ESBL-producing isolates from young infants evaluated in outpatient settings. We found a comparatively low prevalence of ESBL-producing E. coli
spp. when compared to adult studies in the US and to pediatric studies outside the US.7,11,16,17
Rates of ESBL production among isolates from children at our institution between 2003 and 2007 were low, but similar to those reported by SENTRY investigators for US pediatric institutions in 2004. 2
Among Gram-negative organisms isolated from children in the SENTRY study, 1.9% of E. coli
and 1.1–3.2% of Klebsiella
spp. were ESBL producers, compared to 0.87% and 1.3% respectively in our study. A recent French study also reported relatively low rates of ESBL-production among Enterobacteriaceae (not including K. pneumoniae
) at 1.4%. 17
High rates of ESBL production have been reported for organisms isolated from high-risk settings in the US and internationally. ICU surveillance in the US reported the prevalence of resistant K. pneumoniae
isolates at 20.6% in 2003, 7
and two recent studies reported the prevalence of ESBL-producing organisms in pediatric bloodstream infections in the US and Korea 10,11
to be between 7–17.9% for E. coli
and 18–52.9% for Klebsiella
The overall proportion of isolates producing ESBLs at our institution more than doubled in the final 30 months. Additionally, the incidence of a primary ESBL infection was 2.2 times greater when compared to the first 2 ½ years. As primary infection often led to recurrence in our chronically ill children, it seems likely that the burden of ESBL-producing pathogens in pediatrics will continue to increase. Prospective studies in a variety of settings are needed in order to implement adequate control strategies.
As has been seen in adults, 18
urine was the most common site of isolation of ESBL-producing organisms in our study. In 3 cases of UTI, the urinary infection preceded or was concurrent with a more invasive infection with the same organism. Notably, two of these secondary invasive infections occurred 2 months (liver abscess) and 11 months (bloodstream infection) later, indicating probable ongoing colonization. Although the isolation of a colonizing organism in our cohort did not predict subsequent infection, these data suggest that a history of infection with a resistant Gram-negative organism, including a urine isolate, should be considered in the choice of initial therapy for subsequent infections. Unfortunately, as shown in this and other studies, 7,9,19
high levels of resistance to multiple classes of antibiotics are common in ESBL producers, and thus initial empiric therapy with a carbapenem may be necessary.
Most children in our study had chronic medical conditions, anatomic abnormalities or frequent hospital admissions. While all but one child had been hospitalized during the year before their primary ESBL infection, most (13/16) had been hospitalized for less than 48 hours when the culture was obtained. Only three of these children had been hospitalized in the last 30 days, defining 10/16 (63%) of our primary infections as community-onset. 12
Chronic medical conditions, frequent hospital admissions and antibiotic exposure are described as risk factors for long-term ESBL colonization and community-onset infection in adults, 15,20–22
and our affected pediatric patients had similar characteristics. An understanding of which children are likely to be colonized with ESBL-producing organisms is crucial to the choice of effective initial therapy for infection.
A disturbing finding in our study was the isolation of ESBL-producing organisms from four young infants presenting to the emergency department or outpatient clinic. Two of the infants had a history of prematurity, and had spent time in a NICU following birth, although both had uncomplicated stays of approximately 2 weeks. A number of studies have examined ESBL-producing organisms in the NICU, including risk factors for colonization and infection. 19,23–26
Reported risk factors include very low birth weight, antibiotic exposure, as well as length of NICU stay. Mean length of stay prior to colonization can be as short as 9 days 24,26
and may explain the colonization of the two NICU graduates in our study. A third infant, however, born at term and with no significant prior hospitalization, had a life-threatening infection with ESBL producing E. coli
at 4.5 months of age. While studies have been published documenting methicillin-resistant S. aureus
(MRSA) infection in the normal newborn nursery, 27–29
as well as mother-to-child transmission of MRSA, 30–32
no data exists on infection with ESBL-producing organisms in healthy newborns. Other studies have not reported the isolation of ESBL-producing organisms from infants in the outpatient setting, and their presence in this population is a substantial concern. In particular, due to the high morbidity and mortality associated with Gram-negative sepsis in young infants and the reliance on ampicillin and 3rd
generation cephalosporins for initial therapy in outpatient settings, the emergence of ESBLs poses a significant threat.
A fourth infant in our study was a recent adoptee from Africa found to have a UTI caused by an ESBL-producing E. coli
. Recent studies from Africa have reported on the presence of ESBL-producing Enterobacteriaceae, 33–36
and have shown particularly high rates of resistance in Klebsiella
spp. The child in our study had been adopted from an orphanage in Ethiopia; a single study from that region reported ESBL rates among Klebsiella
spp. in Ethiopia at 33.3%. 37
Rates of ESBL-production among E. coli
in Ethiopia are unknown. As drug resistance among Gram-negative pathogens rises throughout the world, further studies will be needed to assess the risk of colonization among internationally adopted children.
No child with ESBL infection in our study died. While factors associated with mortality were not specifically examined here, we can hypothesize that our low mortality rate may be related to the overall low number of ESBL-producing pathogens at our institution, and the preponderance of urinary tract as opposed to invasive isolates. It is possible that there are other differences in the virulence of our isolates or in our patient population that could explain this low mortality, but this is outside the scope of the current study
Our study has several limitations. Overall rates and incidence of ESBL-producing organisms at our institution were low, and our results may not be applicable to medical centers and regions with higher rates. The classification of isolates as infecting or colonizing was made retrospectively; we did not distinguish between infection and colonization in our overall data analysis in order to capture all ESBL isolates in our pediatric patient population. Our pharmacy database query was limited to inpatient antibiotics prescribed within the IH system and outpatient prescriptions could not be documented, potentially falsely decreasing the proportion of patients with a history of prior antibiotic exposure. Finally, this is a descriptive, retrospective study without a control group, therefore we cannot define risk factors or associations here. Children in our study, however, did have many characteristics associated with resistant infection in reports from adults. 3,15,18
Gram-negative infection is a significant problem in pediatrics, and as resistance increases among these pathogens, treatment will become more difficult. The limited pipeline of new antibiotics is particularly an issue for children as safety, pharmacokinetic data and FDA approval typically lag years behind that for adults. Future studies will need to better address the role that colonization plays in pediatric infection, the role of prior antibiotic therapy, and the role of increasing infection rates in adult hospitals, particularly as it relates to maternal transfer of ESBL-producing organisms to newborn infants. Continued surveillance and an understanding of those factors associated with infection and colonization is essential to develop containment strategies that prevent these organisms becoming a common problem in pediatric hospitals and the community.