Abstract
Background
Escherichia coli is a common cause of bloodstream infections (BSI) in infants and is associated with high mortality and morbidity among survivors. The clinical significance of antibiotic resistance and timing of appropriate antimicrobial therapy in this population is poorly understood.
Methods
We identified all infants with E. coli BSIs discharged from 77 neonatal intensive care units managed by the Pediatrix Medical Group in 2012. We used multivariable logistic regression to evaluate the association between 30-day mortality and ampicillin-resistant E. coli BSI, as well as the number of active empiric antimicrobial agents administered, controlling for gestational age, small-for-gestational age status, early- versus late-onset BSI, oxygen requirement, ventilator support, and inotropic support on the day of the first positive blood culture.
Results
We identified 258 episodes of E. coli BSI, including 123 (48%) ampicillin-resistant isolates. Unadjusted 30-day mortality did not significantly differ between infants with ampicillin-resistant vs. -susceptible E. coli BSI (11/123 [9%] vs. 7/135 [5%]; p=0.33; adjusted odds ratio=1.37 [95% confidence interval 0.39, 4.77]). Among ampicillin-resistant E. coli BSIs, 30-day mortality was not significantly lower for infants treated with at least one empiric antimicrobial active against ampicillin-resistant E. coli vs. infants receiving no active empiric agent (adjusted odds ratio=1.50 [0.07, 33.6]).
Conclusions
In this population of infants with E. coli BSI, ampicillin resistance was not associated with significantly increased mortality. Among the subset of infants with ampicillin-resistant E. coli, appropriate empirical antibiotic therapy was not associated with lower mortality.
Keywords: Escherichia coli, antimicrobial resistance, early-onset sepsis, late-onset sepsis, bacteremia
Escherichia coli is a frequent cause of early-onset bloodstream infection (BSI) among infants, accounting for 24% of all BSIs.1,2 Over the past two decades, E. coli has become the most common cause of early-onset BSI in premature infants and a frequent cause of late-onset BSI.3–5 In hospitalized infants, BSIs caused by E. coli are associated with higher mortality compared with those caused by gram-positive organisms.6
Several contemporary studies have reported increasing ampicillin resistance, ranging from 59–85% of E. coli isolates causing BSIs in infants.1–3,5,7–11 Higher mortality among infants with ampicillin-resistant E. coli BSI has been reported, but multiple confounders, primarily prematurity, were noted, and small sample sizes limited detailed analysis.8,11,12 Risk factors for antimicrobial-resistant E. coli BSI, clinical implications of infection with resistant organisms, and the impact of appropriate empiric antimicrobial therapy in infants with infection are poorly understood. Clinicians need this information to inform the balance between potential risk for excess morbidity and mortality associated with ineffective empiric antimicrobial therapy and the side effects of routine use of broad-spectrum empiric antimicrobial therapy.13
The aims of this study were to: 1) compare the clinical characteristics of infants with ampicillin-susceptible and -resistant E. coli BSIs; 2) compare the outcomes of infants with ampicillin-susceptible and -resistant E. coli BSIs; and 3) evaluate the impact of appropriate empiric antimicrobial therapy for infants with ampicillin-resistant E. coli BSIs.
METHODS
We identified all infants with E. coli BSI discharged from one of 77 U.S. neonatal intensive care units (NICUs) managed by the Pediatrix Medical Group in 2012. Data were obtained from an electronic medical record that prospectively captures information from notes generated by clinicians on all infants cared for by the Pediatrix Medical Group. Data are extracted, de-identified, and stored in the Pediatrix Clinical Data Warehouse. Information stored for infants on a daily basis includes maternal history, demographics, medications ordered, laboratory results, microbiology results, diagnoses, and procedures.14 Antimicrobial susceptibility data for microbiologic isolates are reported as the presence or absence of resistance to several common antibiotics. Comprehensive antimicrobial resistance patterns are not captured in the database.
We identified all blood cultures positive for E. coli during the first 120 days of life. All positive cultures obtained within 21 days of each other were analyzed as single infectious episodes. We assumed the same antimicrobial resistance for all positive blood cultures obtained within a single BSI episode. We defined the duration of bacteremia as the difference between the day of the first and last positive blood cultures within a single episode. We defined an early-onset BSI as an initial positive blood culture within the first 3 postnatal days and a late-onset BSI as an initial positive blood culture after the first 3 postnatal days.
We defined empiric antimicrobial therapy as any antimicrobial administered on the day of the first positive blood culture for each episode of bacteremia. For ampicillin-resistant E. coli isolates, we categorized the number of effective empiric antimicrobials received on the day of first positive blood culture as none or ≥1. We considered the following antimicrobials effective empiric therapy against ampicillin-resistant E. coli: beta-lactam/lactamase inhibitor combinations, cephalosporins, anti-pseudomonal penicillins, aztreonam, carbapenems, aminoglycosides, fluoroquinolones, and trimethoprim/sulfamethoxazole. We defined inotropic support as exposure to any inotrope (dobutamine, dopamine, epinephrine, milrinone/amrinone, norepinephrine, or phenylephrine), supplemental oxygen requirement as any fraction of inspired oxygen >21%, and mechanical ventilation as any need for invasive mechanical ventilation on the day of the first positive blood culture for each episode of bacteremia. We categorized E. coli isolates as ampicillin-susceptible or ampicillin-resistant as reported by each site.
The primary outcome of our study was mortality within 30 days of the first positive blood culture. Secondary outcomes were duration of BSI, mortality within 7 days of the first positive blood culture, and mortality at hospital discharge. We used standard summary statistics including counts (percentages) and medians (interquartile ranges) to describe the categorical and continuous study variables, respectively. We compared study variables across groups using Wilcoxon rank sum and chi-square tests of association where appropriate. We used multivariable logistic regression to compare outcomes between ampicillin-susceptible and -resistant E. coli BSI. The following covariates were included in a full model: E. coli ampicillin-susceptible vs. -resistant, birth weight, male gender, gestational age (GA), small-for-gestational age status (SGA), early- vs. late-onset BSI, and inotropic, ventilator, or oxygen support on the day of the first positive culture. Reduced models were then constructed by removing pre-specified groups of covariates and comparing the reduced model to the full model using likelihood ratio tests. The most parsimonious model that fit the data well was retained and contained the following covariates in addition to ampicillin resistance: GA, SGA, early- vs. late-onset BSI, and inotropic, ventilator, or oxygen support on the day of the first positive culture. Lastly, we accounted for the clustering of data by fitting separate random intercepts for each NICU. We used standard graphing techniques and statistical tests to evaluate the assumptions of our models. To evaluate the impact of effective empiric antimicrobial therapy, 30-day mortality was compared between infants with ampicillin-resistant E. coli BSI receiving 0 or ≥1 empiric antimicrobial agents known to be effective against ampicillin-resistant isolates. Multivariable logistic regression was used to compare 30-day mortality for infants with ampicillin-resistant E. coli BSI receiving 0 versus ≥1 empiric antimicrobial agents active against ampicillin-resistant E. coli. Covariates incorporated into the model included: GA, SGA, early- vs. late-onset BSI, and inotropic, ventilator, or oxygen support on the day of the first positive culture. Finally, median duration of BSI for infants with ampicillin-resistant E. coli isolates receiving 0 versus ≥1 effective empiric antimicrobial agents was compared. We used Stata 13.0 (College Station, TX) to conduct all analyses and considered a p<0.05 statistically significant. The Duke University Health System Institutional Review Board determined that the study met the definition of research not involving human subjects and was, therefore, exempt.
RESULTS
Infant Characteristics
We identified 267 episodes of E. coli BSI in 267 infants. No episodes of recurrent E. coli BSI were identified. We excluded 9 episodes of extended spectrum beta-lactamase producing E. coli BSI from further analysis. Ampicillin resistance was noted for 123/258 (48%) remaining isolates. Early-onset BSI accounted for 109/258 (42%) cases. The proportion of ampicillin-resistant isolates did not significantly differ between early-onset and late-onset BSI (53/109 [49%] vs. 70/149 [47%], p=0.80). The median GA (29 weeks [interquartile range; 24, 34] vs. 28 weeks [26, 34], p=0.67) and birth weight (1220 g [690, 2470] vs. 1140 g [810, 2080], p=0.48) did not significantly differ between infants with ampicillin-resistant and -susceptible E. coli BSI, respectively (Table 1). The median postnatal age on the date of first positive blood culture was similar between infants with ampicillin-resistant and -susceptible infections: 4 days (0, 12) vs. 6 (0, 13), p=0.57. More infants with ampicillin-resistant E. coli BSI were exposed to antenatal antibiotics: 80/123 (65%) vs. 65/135 (48%), p=0.008. The proportion of infants receiving at least one active empiric antimicrobial agent was not significantly different between those with ampicillin-resistant and -susceptible E. coli BSI: 100/123 (81%) vs. 104/135 (77%), p=0.45. Among the 135 episodes of ampicillin-susceptible E. coli BSI, the most commonly administered antibiotics on the day of first positive culture were gentamicin (61%), ampicillin (46%), vancomycin (19%), cefotaxime (10%), piperacillin-tazobactam (9%), and nafcillin (6%). For the 123 episodes of ampicillin-resistant E. coli BSI, the most commonly administered antibiotics on the day of first positive culture were gentamicin (67%), ampicillin (47%), vancomycin (22%), cefotaxime (15%), piperacillin-tazobactam (8%), and ceftazidime (4%).
TABLE 1.
Demographics
| Ampicillin-susceptible E. coli N=135 (%) |
Ampicillin-resistant E. coli N=123 (%) |
||
|---|---|---|---|
| Gestational age, weeks | |||
| ≤25 | 32 (24) | 45 (37) | |
| 26–28 | 37 (28) | 16 (13) | |
| 29–32 | 27 (20) | 21 (17) | |
| 33–36 | 16 (12) | 15 (12) | |
| ≥37 | 21 (16) | 26 (21) | |
| Birth weight, g | |||
| <1000 | 51 (38) | 54 (44) | |
| 1000–1499 | 32 (24) | 17 (14) | |
| 1500–2499 | 24 (18) | 23 (19) | |
| 2500–3499 | 14 (10) | 24 (20) | |
| ≥3500 | 14 (10) | 5 (4) | |
| Race/ethnicity | |||
| White | 52 (39) | 42 (35) | |
| African American | 44 (33) | 39 (32) | |
| Hispanic | 28 (21) | 33 (27) | |
| Other | 10 (8) | 7 (6) | |
| Male | 79 (59) | 71 (58) | |
| 5-minute APGAR | |||
| 0–3 | 8 (6) | 10 (9) | |
| 4–6 | 31 (24) | 34 (29) | |
| 7–10 | 88 (69) | 73 (62) | |
| Cesarean section | 62 (47) | 58 (48) | |
| Antenatal antibiotic exposure | 65 (48) | 80 (65) | |
| Early-onset BSI | 56 (42) | 53 (43) | |
| Mechanical ventilation on day of culture | 66 (52) | 55 (47) | |
| Inotrope support on day of culture | 14 (10) | 20 (16) | |
| Supplemental oxygen on day of culture | 70 (52) | 68 (55) | |
Outcomes
Unadjusted 30-day mortality was similar for infants with ampicillin-resistant (11/123 [9%]) and ampicillin-susceptible isolates (7/135 [5%], p=0.33). On adjusted analysis, there was no significant difference in odds of death at 30 days for infants with ampicillin-resistant versus ampicillin-susceptible E. coli BSI (odds ratio [OR]=1.37 [0.39, 4.77]). Additionally, no significant difference in death at 7 days or hospital discharge was noted (Table 2). Median duration of E. coli BSI was similar for infants with ampicillin-resistant (1 day [range; 1, 10]) and ampicillin-susceptible isolates (1 day [1, 6], p=0.43).
TABLE 2.
Mortality by antimicrobial resistance pattern
| Ampicillin-susceptible E. coli N=135 (%) |
Ampicillin-resistant E. coli N=123 (%) |
Adjusted odds ratio* (95% CI) |
|
|---|---|---|---|
| Death within 30 days of culture | 7 (5) | 11 (9) | 1.37 (0.39, 4.77) |
| Death within 7 days of culture | 6 (4) | 8 (7) | 1.25 (0.35, 4.39) |
| Death at hospital discharge | 8 (7) | 16 (15) | 1.74 (0.65, 4.67) |
Odds of death for infection with ampicillin-resistant vs. -susceptible E. coli. Covariates included: gestational age, small-for-gestational age status, early- vs. late-onset BSI, and inotropic, ventilator, or oxygen support on the day first positive culture obtained.
CI, confidence interval.
Among ampicillin-resistant E. coli isolates, unadjusted odds of death at 30 days was not significantly lower for infants treated with ≥1 active empiric antimicrobial agent (10/100 [10%]) versus those receiving no active empiric antimicrobial agent (1/23 [4%], p=0.69). On adjusted analysis, odds of death at 30 days were similar for infants receiving ≥1 versus no active empiric antimicrobial therapy (OR=1.50 [0.07, 33.6]). Median duration of BSI was similar among infants with ampicillin-resistant E. coli BSI treated with ≥1 effective empiric antimicrobial agent (1 day [range; 1, 10]) versus those receiving no active empiric antimicrobial agent (1 day [1, 2], p=0.24).
DISCUSSION
This study compares clinical characteristics and outcomes of infants with ampicillin-susceptible and -resistant E. coli BSIs. It is among the largest studies of E. coli BSIs in infants reporting antimicrobial resistance data and the impact of effective empiric antimicrobial therapy among resistant isolates. Compared with previous reports, the prevalence of ampicillin resistance in this study was lower: 46% vs. 59–85%. Cases of BSI caused by ESBL-producing isolates were infrequent (3%) in this cohort.
Clinical factors associated with increased risk of antimicrobial resistant E. coli BSI are poorly defined. In this study, only antenatal antibiotic exposure was associated with ampicillin-resistant E. coli BSI (p=0.008). These findings are consistent with prior studies of both early- and late-onset sepsis.5,15,16 The strength of this association may be exaggerated, however, as these analyses lack a control group and cannot account for ampicillin-susceptible isolates eradicated with antenatal antibiotics.17 Notably, the only case-control study evaluating this association showed no significant difference in risk of antimicrobial-resistant infection, demonstrating an overall protective effect of intrapartum antimicrobial prophylaxis.7
We found no significant increase in unadjusted or adjusted 30-day mortality for infants with ampicillin-resistant E. coli BSI. Notably, birth weight and GA were similar among infants with ampicillin-resistant and -susceptible BSI in this study. These findings are in contrast to prior reports of E. coli BSI that identified trends toward increased mortality among infants infected with ampicillin-resistant isolates.8,11 In previous reports, ampicillin resistance was significantly more common in premature infants. Our results are consistent with those previously reported in a study of late-onset sepsis that controlled for prematurity,5 but our analysis also includes data from 114 episodes of early-onset BSI.
Among infants with ampicillin-resistant E. coli BSI, no significant association between mortality and the number of active empiric antimicrobial agents administered was noted. This study is among the first to evaluate the impact of empiric antimicrobial therapy for infants with ampicillin-resistant E. coli BSI. The adequacy of empiric antimicrobial regimens must be continually reevaluated as the emergence of more extensively drug-resistant organisms is observed. The number of extensively drug-resistant E. coli isolates in this study was small, and results may not be applicable to centers reporting higher rates of extensive drug resistance.12,18
To date, our study represents the largest series of E. coli BSIs in infants reporting antimicrobial resistance data and associated outcomes. Strengths of the study include a large sample size obtained from a wide variety of NICUs in the U.S., incorporation of both early- and late-onset BSI cases, and evaluation of the impact of empiric antimicrobial therapy not previously reported.
There are several limitations to this analysis. Details regarding antenatal antimicrobial exposure, including the specific agent administered, indication, timing, dosing, or duration of exposure, were not captured within this dataset, thus limiting the ability to evaluate a potential association between exposure and risk of infection with antimicrobial-resistant E. coli. Previous studies demonstrated the importance of considering these aspects of antenatal antimicrobial exposure.7,16,19 Comprehensive antimicrobial resistance profiles were not captured within the dataset. Ampicillin resistance secondary to narrow spectrum beta-lactamases does not reliably predict resistance to first-generation cephalosporins. In our analysis, first-generation cephalosporins were considered effective empiric antimicrobial therapy for ampicillin-resistant E. coli, potentially diminishing our ability to detect differences between infants receiving zero and at least one active empiric antimicrobial agent. Additionally, this dataset did not capture doses of empiric antimicrobials or administration schedules. Suboptimal prescribing of these agents may limit our ability to discern differences in outcomes based upon choice of empiric antimicrobial alone. Our outcome analyses incorporated the confounders of prematurity and severity of illness at the onset of BSI, but it is possible additional contributors to infant mortality were not included in this dataset or the multivariable regression model of this retrospective study. Despite a relatively large sample size, mortality was an infrequent occurrence; thus, our study may not have been adequately powered to detect important differences in the outcomes associated with resistant infections or inadequate empiric antimicrobial therapy.
In conclusion, ampicillin resistance was not associated with significantly increased mortality in this cohort of infants with E. coli BSI. Among infants with ampicillin-resistant E. coli BSI, empiric treatment with an antimicrobial active against resistant E. coli was not associated with decreased mortality. Changes in the epidemiology of BSI and increasing antimicrobial resistance represent important areas of concern in the management of this significant cause of infant morbidity and mortality. Continued monitoring of antimicrobial resistance patterns and further prospective studies are needed to better evaluate risk factors for infection with drug-resistant E. coli and the optimal empiric antimicrobial strategy to employ in this important clinical entity.
Acknowledgments
Source of funding and conflicts of interest: This research was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) under award number UM1AI104681. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Dr. Ericson receives support from the National Institute of Child Health and Human Development of the NIH under award number 5T32HD060558. Dr. Fowler receives salary support for research from the NIH (K24-AI093969, 2R01-AI068804, and NO1-AI90023); he also served as chair of V710 Scientific Advisory Committee (Merck), has received grant support from Cerexa, Pfizer, Advanced Liquid Logic, MedImmune, and Cubist (grant pending), has been a paid consultant for Merck, Astellas, Affinium, Theravance, Bayer, Cubist, Cerexa, Durata, Pfizer, NovaDigm, Novartis, Medicines Company, Biosynexus, MedImmune, and Inimex, and has received honoraria from Merck, Astellas, Cubist, Pfizer, Theravance, and Novartis. Dr. Benjamin receives support from the United States government for his work in pediatric and neonatal clinical pharmacology (1R01HD057956-05, 1K24HD058735-05, UL1TR001117, and NICHD contract HHSN275201000003I) and the nonprofit organization Thrasher Research Fund for his work in neonatal candidiasis (www.thrasherresearch.org); he also receives research support from industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). Dr. Hornik receives salary support for research from the National Center for Advancing Translational Sciences of the NIH (UL1TR001117). Dr. Smith receives salary support for research from the NIH and the National Center for Advancing Translational Sciences of the NIH (HHSN267200700051C, HHSN275201000003I, and UL1TR001117); he also receives research support from industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp).
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