ORIGINAL ARTICLE
Empiric Antibiotics for Serious Bacterial Infection
in Young Infants
Opportunities for Stewardship
Joseph B. Cantey, MD,* Eduardo Lopez-Medina, MD,† Sean Nguyen, PharmD,‡
Christopher Doern, PhD,§ and Carla Garcia, MD*
Objectives: To evaluate the causative agents of serious bacterial infection
(SBI) in young infants and the optimal approach to empiric antibiotic ther-
apy for infants with SBI.
Methods: From May 1, 2011, to December 1, 2013, pertinent clinical
data were collected on previously well infants 60 days or younger with
SBI as defined by a positive bacterial culture from a sterile site. Infants
were identified by prospective surveillance of admissions and daily review
of microbiology records.
Results: Two hundred sixty-five infants with SBI were identified. Mean
age was 32 days (SD ±16.6 days). Twenty-nine infants had meningitis, 66
had bacteremia (37 with concomitant urinary tract infection), and 170 had
urinary tract infection alone. No methicillin-resistant Staphylococcus
aureus, vancomycin-resistant Enterococcus sp., or penicillin-resistant
Streptococcus pneumoniae were identified. Four extended-spectrum
β-lactamase–producing gram-negative bacilli were seen. Empiric therapy
was ampicillin and gentamicin (n = 116, 44%) or third-generation cephalo-
sporin based (n = 149, 56%). Ampicillin and gentamicin, with third-
generation cephalosporins reserved for cases where meningitis is suspected,
would have provided effective coverage for 98.5% of infants and unnecessar-
ily broad therapy for 4.3%. Third-generation cephalosporins with ampicillin
would have been effective for 98.5% of infants and unnecessarily broad for
83.8%. Third-generation cephalosporin monotherapy was less effective than
either combination (P < 0.001). Fifty-seven percent of broad spectrum em-
piric therapy was continued despite culture results allowing de-escalation.
Conclusions: Ampicillin/gentamicin remains an effective empiric regi-
men for infants 60 days or younger with suspected SBI. Use of a third-
generation cephalosporin for suspected meningitis is appropriate, but cere-
brospinal fluid must be obtained promptly to guide appropriate therapy.
Key Words: antibiotic, stewardship, infant, serious bacterial infection
(Pediatr Emer Care 2015;31: 568–571)
I nfants 60 days or younger are at risk for serious bacterial
infection (SBI), and admission for empiric antibiotic therapy re-
mains a common cause of hospitalization in this age group.1 The
majority of these infants receive antibiotics, often ampicillin and
gentamicin for neonates (≤28 days) and a third-generation cephalo-
sporin with or without ampicillin for older infants.2–4 These agents
are selected based on the common causative agents of SBI in these
age groups, including group B Streptococcus (GBS), Escherichia
From the *Department of Pediatrics, University of Texas Southwestern Medical
Center, Dallas, TX; †Department of Pediatrics, Universidad del Valle and
Centro de Estudios en Infectologia Pediatrica, Cali, Colombia; and ‡Depart-
ment of Pharmacology, Children's Medical Center; §Department of Pathology,
University of Texas Southwestern Medical Center, Dallas, TX.
Disclosure: The authors declare no conflict of interest.
Reprints: Joseph B. Cantey, MD, Department of Pediatrics, University of Texas
Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-
9063 (e‐mail: joseph.cantey@utsouthwestern.edu).
This study was presented in part at the Pediatric Academic Society Annual
Meeting, April 28, 2012, to May 1, 2012, Boston, MA
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0749-5161
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
coli, and other gram-negative rods, Enterococcus sp., and Listeria
monocytogenes, among others.5 The epidemiology of SBI in young
infants continues to change, including an increasing prevalence of
ampicillin-resistant gram-negative rods and fewer GBS and Listeria
cases.6–10 As a result, some experts have called for a modification
of empiric therapy with an increased reliance on third-generation
cephalosporins.8,11 However, there is evidence that ampicillin-
and gentamicin-based regimens may be equally efficacious or
even superior to cephalosporin-based regimens.12,13 Additionally,
use of third-generation cephalosporins increase the risk for infec-
tion with resistant organisms both in the community14,15 and in
closed settings, such as neonatal intensive care units.16,17 As a re-
sult, the optimal approach to empiric therapy for infants with
suspected SBI remains uncertain. The objective of our study was
to evaluate the causative agents of SBI in infants 60 days or younger
and to identify the optimal strategy for empiric antibiotic therapy for
these infants.
METHODS
From May 1, 2011, to December 1, 2013, study investigators
reviewed admission records at Children's Medical Center (CMC)
Dallas daily to identify previously well infants 60 days or younger
evaluated for SBI. Microbiology laboratory records were reviewed
daily by the clinical microbiologist and study investigators. Infants
with a pathogen isolated from a sterile site (blood, urine, cerebro-
spinal fluid [CSF], or peritoneal fluid) were included in the study.
Infants born before 32 weeks gestation, or who had previous sur-
geries other than circumcision, previous admission(s), or chronic
medical conditions were excluded from analysis.
Urine cultures were considered positive if they yielded
greater than 5  104 colony-forming units of a single pathogen.18
Blood, CSF, or peritoneal fluid cultures were considered positive
if they yielded a known pathogen. Viridans group Streptococcus,
coagulase-negative Staphylococcus, and cutaneous gram-positive
rods, such as Corynebacterium or Bacillus, were considered con-
taminants. Blood cultures were processed using the BacT-Alert
system (Becton-Dickinson, Franklin Lakes, NJ); urine and CSF
cultures were processed using appropriate agar media (Remel,
Lenexa, KS).
Review of the electronic medical records for each infant in-
cluded demographic, clinical, and outcome data. Antibiotic regi-
mens were collected, including empiric therapy, defined as
initiation before culture results were available; and definitive ther-
apy, defined as antibiotic(s) used to complete therapy once culture
results were finalized. Dose, dosing interval, and days of antibiotic
therapy were recorded. Empiric therapy was considered effective
if it had in vitro activity against the identified pathogen(s) and dis-
tributed to the infected compartment. For example, for ampicillin-
resistant, gentamicin-susceptible, ceftriaxone-susceptible E. coli
causing urinary tract infection (UTI), a third-generation cephalo-
sporin would be effective coverage but unnecessarily broad relative
to ampicillin/gentamicin. However, for the same isolate causing
Pediatric Emergency Care • Volume 31, Number 8, August 2015
Pediatric Emergency Care • Volume 31, Number 8, August 2015 Empiric Therapy for SBI in Young Infants

meningitis, a third-generation cephalosporin would be considered

necessary because gentamicin does not penetrate well into CSF. TABLE 2. Pathogens and Types of Serious Bacterial Infection
Identified in Infants ≤ 60 Days of Age (N = 265)
De-escalation of therapy was evaluated for infants who received
broad-spectrum therapy and subsequently received narrow spec-
Serious Bacterial
trum therapy based on the infected compartment(s) and bacterial
Infection N (%) Pathogens (N)
susceptibilities. If third-generation cephalosporin therapy was con-
tinued for suspected meningitis, but CSF was not obtained, then Meningitis alone 9 (3.4%) Escherichia coli (3)
the de-escalation of a third-generation cephalosporin was consid- GBS (3)
ered unevaluable. Infants with suspected meningitis included those Enterococcus faecalis (2)
with abnormal CSF profiles (>15 white blood cell/mm3, protein Salmonella sp. (1)
>100 mg/dL, or glucose <35 mg/dL) or neurologic signs at presen- Meningitis with 18 (6.8%) Escherichia coli (7)
tation, including lethargy, seizures, or apnea.19 Antibiotic days were bacteremia GBS (7)
calculated using days of therapy, meaning the number of calendar
days that an infant received a specific antibiotic. For example, 2 days Streptococcus bovis (2)
of cefotaxime and 2 days of ampicillin would equal 4 days of ther- Salmonella sp. (1)
apy. To determine whether empiric antibiotic selection was similar Streptococcus pneumoniae (1)
between infants with proven SBI and those in whom SBI was ex- Meningitis with UTI 2 (0.8%) Escherichia coli (1)
cluded, we evaluated the empiric antibiotics administered to infants GBS (1)
with ruled-out SBI in a one-to-one manner. The infant with the Bacteremia alone 29 (10.9%) GBS (18)*
next-highest medical record number who otherwise met inclusion Escherichia coli (4)
criteria but had sterile cultures was evaluated for this purpose. Enterococcus faecalis (2)
Descriptive comparisons were performed using mean and Streptococcus pneumoniae (2)
standard deviation, or median and interquartile range for data
Pasteurella sp. (1)
not normally distributed. Statistical comparisons were performed
using χ2 testing with a 2-tailed significance threshold of P less Streptococcus pyogenes (1)
than 0.05. This study was approved by the institutional review Staphylococcus aureus (1)
board at the University of Texas Southwestern Medical Center Bacteremia with UTI 37 (14%) Escherichia coli (35)
with a waiver of informed consent (study 042011-072). Enterobacter sp. (2)
UTI alone 171 (64.5%) Escherichia coli (131)*
Enterococcus faecalis (16)
RESULTS Klebsiella pneumoniae (13)
During the study period, 265 infants with SBI were identi- Enterobacter sp. (4)
fied. Their demographic and clinical features are summarized in Citrobacter sp. (2)
Table 1. Infants were admitted through the CMC emergency de- GBS (1)
partment (ED, 89%) or via the ED of another facility (11%).
Morganella morgagni (1)
Twenty-nine infants (11%) had meningitis, 66 infants (25%) had
Enterococcus fergusonii (1)
Serratia marcesens (1)
TABLE 1. Demographic and Clinical Features of Infants With Proteus mirabilis (1)
Serious Bacterial Infection (N = 265)
No methicillin-resistant Staphylococcus aureus, vancomycin-resistant
Enterococcus, or penicillin-resistant Pneumococcus.
Age, mean (SD), d 32 (16.6)
*One infant with GBS bacteremia and concomitant E. coli UTI.
Male, N (%) 174 (65.7%)
Gestational age, mean (SD), weeks 38.8 (1.9)
Birth weight, mean (SD), g 3326 (550)
Vaginal delivery, N (%) 207 (78.1%) bacteremia (27 with concomitant UTI), and 170 infants (64%)
Maternal age, mean (SD), y 26.8 (6.1) had UTI alone (Table 2). E. coli and GBS were the predominant path-
Maternal parity, median (IQR) 2 (1 – 3)
ogens, and there were no differences between the pathogens causing
SBI in neonates versus older infants (29-60 days, P = 0.23). No
Empiric antibiotic therapy, N (%)
methicillin-resistant Staphylococcus aureus, vancomycin-resistant
Ampicillin and gentamicin 116 (43.8%) Enterococcus sp., or penicillin-resistant Streptococcus pneumoniae
Third-generation cephalosporin monotherapy 72 (27.2%) were seen. There were 4 extended-spectrum β-lactamase–producing
Third-generation cephalosporin and ampicillin 65 (24.5%) gram-negative bacilli seen. Antibiotic therapy was initiated before
Third-generation cephalosporin and vancomycin 12 (4.5%) CSF was obtained in 30% of the infants (80/265). Thirty-seven in-
Serious bacterial infection, N (%) fants had CSF obtained a median of 2 days after antibiotic initia-
Meningitis (±bacteremia or UTI) 29 (10.9%) tion, and 84% (31/37) had normal CSF findings. The remaining
Bacteremia (±UTI) 66 (24.9%) 43 infants did not undergo lumbar puncture.
UTI alone 170 (64.2%) Empiric antibiotic regimens for infants were either ampicillin/
Length of stay, median (IQR), d 3 (2 – 9)
gentamicin (n = 116; 44%) or third-generation cephalosporin-based
(n = 149; 56%). The selection of empiric antibiotics was similar to
Intensive care unit admission, N (%) 37 (14%)
265 matched infants without SBI (43% ampicillin/gentamicin,
Infectious diseases consultation, N (%) 56 (19.6%) 57% third-generation cephalosporin-based, P = 0.69). For 126 in-
Deaths, N (%) 3 (1.1%) fants 28 days or younger with SBI, ampicillin/gentamicin was
IQR indicates interquartile range. used more frequently (n = 98; 78%); for the 139 infants older than
28 day, empiric therapy was predominantly third-generation

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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Cantey et al
cephalosporin-based (n = 121; 87%). Twelve infants (5%) re-
ceived vancomycin. When meningitis was not suspected,
ampicillin/gentamicin and third-generation cephalosporin-based
regimens were effective empiric coverage for 96% and 97% of in-
fants, respectively (P = 0.78). Based on the identified pathogens
and infected compartments, the hypothetical efficacy of 3 ap-
proaches to empiric antibiotic regimens is shown in Table 3.
Based on in vitro susceptibilities and infected compartment(s),
67% of third-generation cephalosporin use and 12 of 12 (100%)
courses of vancomycin were unnecessarily broad relative to
ampicillin/gentamicin. Fifty-seven percent of third-generation
cephalosporin courses were continued despite susceptibility results
which would have allowed a de-escalation of therapy, resulting in
511 extra days of therapy with third-generation cephalosporins.
Another 12% of continued third-generation cephalosporin use
could not be de-escalated because meningitis was suspected, but
CSF was not obtained or was obtained after antibiotic therapy
was initiated.
DISCUSSION
Suspected SBI is one of the most common causes of ED eval-
uation and hospital admission in infants younger than 60 days. The
optimal empiric antibiotic regimen for these infants remains a sub-
ject of debate. Third-generation cephalosporins have been associ-
ated with adverse outcomes, most notably an association with
increased resistance.15,17 However, empiric therapy for infants with
suspected SBI must ensure that at least 1 antibiotic is active against
the likely causative pathogens.20 Therefore, empiric antibiotic ther-
apy must be continuously updated based on local resistance
patterns.11 In our cohort of infants, either the combination of ampi-
cillin and gentamicin or ampicillin with a third-generation cephalo-
sporin would have provided effective coverage to greater than 98%
of infants in the absence of meningitis. However, there would have
been significantly more unnecessary cephalosporin use if third-
generation cephalosporins were used empirically for all infants with
suspected SBI (83.8%) as opposed to only those with suspected
meningitis (4.2%, P < 0.001). There were 4 Enterobacteriaceae iso-
lates that were resistant to both ampicillin and gentamicin and sus-
ceptible to third-generation cephalosporins; however, there were
TABLE 3. In Vitro Efficacy of 3 Different Approaches to Empiric Antibiotic Therapy, Based on Pathogens Identified in Infant Cohort
(N = 265)
Ampicillin/Gentamicin;
Ampicillin/Third-Generation
Cephalosporin Reserved
for Suspected Meningitis†
Infants who would receive 225
ampicillin/gentamicin
Infants who would receive 40
third-generation cephalosporins
Effective therapy, N (%) 261‡ (98.5%)
Unnecessarily broad, N (%) 11 (4.2%)*
*Cerebrospinal fluid with >15 white blood cell/mm3, >120 mg/dL protein, or <35 mg/dL glucose, or seizures, apnea, or lethargy at presentation.
†
4 Enterobacteriaceae resistant to both ampicillin and gentamicin.
‡
4 extended-spectrum β-lactamase–producing Enterobacteriaceae.
§
20 Enterococcus faecalis infections, intrinsically resistant to cephalosporins.
||
P value < 0.001 compared to other 2 regimens.
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Pediatric Emergency Care • Volume 31, Number 8, August 2015
also 4 isolates that produced extended-spectrum β-lactamases
and were resistant to third-generation cephalosporins and ampicil-
lin, but susceptible to gentamicin. Ampicillin and gentamicin are
an effective combination for empiric therapy for SBI, and third-
generation cephalosporins should be reserved for cases where
meningitis is suspected.
Third-generation cephalosporin monotherapy would have
been a less efficacious regimen for the infants in our cohort. Only
91% of infants would have received effective therapy compared to
98.5% with either ampicillin/gentamicin or ampicillin/third-
generation cephalosporin (P < 0.001 for both comparisons). This
difference is because of the 20 Enterococcus faecalis isolates
(7.5% of identified pathogens), which are intrinsically resistant
to cephalosporins. Without the addition of ampicillin, empiric
third-generation cephalosporin monotherapy was inferior to com-
bination regimens for suspected SBI.
De-escalating therapy once culture results are available is a
core principle of antibiotic stewardship.21 Empiric broad-spectrum
therapy is reasonable in an infant with signs of sepsis or significant
clinical instability, or when meningitis is suspected. However, de-
escalation to narrow spectrum therapy should be performed as soon
as susceptibilities of the bacterial isolate are finalized. In 57% of
cases, providers continued third-generation cephalosporin-based
therapy when narrower-spectrum options were available. The fail-
ure to de-escalate therapy accounted for 511 additional antibiotic
days with a third-generation cephalosporin in this cohort. Evaluat-
ing the appropriateness of continued third-generation cephalosporin
therapy is difficult in situations where it is being administered for
concerns of meningitis, but CSF is either not obtained or obtained
after the initiation of antibiotic treatment. A substantial fraction
(12%) of cephalosporin use in this study was not able to be evalu-
ated. If meningitis is not suspected, then broadening therapy to en-
sure penetration into the CSF is unnecessary.22 If antibiotics are
being broadened because of a suspicion for meningitis, then
obtaining CSF for analysis before the initiation of antibiotics is im-
perative, and will allow clinicians to optimize the empiric antibiotic
regimen and to de-escalate therapy when meningitis is excluded.
As other investigators have noted, an institution's empiric
therapy for SBI in early infancy must be driven by a careful anal-
ysis of their local epidemiology.8,10,11,23 The low prevalence of
Empiric Therapy
Third-Generation Third-Generation
Cephalosporin Cephalosporin
With Ampicillin Monotherapy
0 0
265 265
261§ (98.5%) 241§,|| (90.9%)*
222 (83.8%) 222 (83.8%)
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Pediatric Emergency Care • Volume 31, Number 8, August 2015
methicillin-resistant Staphylococcus aureus, penicillin-resistant
Pneumococcus, and vancomycin-resistant Enterococcus seen in
our cohort may not apply in other geographic locations. Every in-
stitution should strive to work with their clinical microbiology lab-
oratory to perform their own surveillance of antibiotic resistance
and maintain an updated antibiogram to optimize their empiric an-
tibiotic therapy for specific clinical scenarios.21,24
All infants in the study cohort were admitted through an ED,
and in most cases, the initial evaluation and selection of empiric
therapy is performed by emergency medicine providers. As a re-
sult, emergency medicine physicians are in a unique position to
be good antibiotic stewards for infants with suspected SBI.
Ostrowsky et al25 demonstrated that ED providers, working closely
with the antibiotic stewardship program, can use antibiotic al-
gorithms to improve prescribing for patients with pneumonia.
Suspected SBI in infancy is a frequent cause of ED visits that
provides a similar opportunity for antibiotic stewardship.
Our study has several limitations beyond those inherent to
chart reviews. First, our cohort included only infants hospitalized
at CMC. We did not collect information on all infants evaluated
for SBI who had sterile cultures and therefore cannot extrapolate
our results to all young infants evaluated for SBI at CMC, but it
is likely that the empiric therapy administered to infants with ster-
ile cultures is similar to those with positive cultures. Finally, our
findings apply only to our geographic area and may not be gener-
alizable to other regions where local resistance patterns and epide-
miology may be different.
In conclusion, ampicillin/gentamicin remains an effective,
narrow-spectrum combination for empiric therapy if meningitis
is excluded. A third-generation cephalosporin with ampicillin is
appropriate if meningitis is suspected. Emergency medicine pro-
viders play a primary role in antibiotic stewardship for suspected
SBI, including determining optimal therapy for their center and
obtaining timely CSF analysis in cases of suspected meningitis.
Empiric therapy must be re-evaluated and de-escalated once
susceptibilities are available. Institutions should monitor their
clinical isolates and maintain an antibiogram that is updated annu-
ally to guide any necessary changes in empiric therapy for SBI in
early infancy.
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