Clark 2006
Clark 2006
Clark 2006
The authors have indicated they have no financial relationships relevant to this article to disclose.
ABSTRACT
BACKGROUND. We reported previously that the use of cephalosporin among prema-
ture neonates increased the risk of subsequent fungal sepsis. As a result, we
www.pediatrics.org/cgi/doi/10.1542/
recommended that ampicillin and gentamicin be used as empiric coverage for peds.2005-0179
early-onset neonatal sepsis while culture results are awaited. doi:10.1542/peds.2005-0179
OBJECTIVES. To describe antibiotic use during the first 3 days after birth for neonates Key Words
antibiotics, neonate, mortality, sepsis
admitted to the NICU and to evaluate the outcomes for neonates treated with 2
Abbreviations
different antibiotic regimens. OR— odds ratio
CI— confidence interval
METHODS. We assembled a cohort of inborn neonates, from our deidentified admin-
Accepted for publication Mar 30, 2005
istrative database, who had documented exposure to ampicillin during the first 3
Address correspondence to Reese H. Clark,
days after birth. Infants treated concurrently with cefotaxime or gentamicin were MD, Pediatrix Medical Group, 1301 Concord
evaluated, to identify the factors that were associated independently with death Terrace, Sunrise, FL 33323-2825. E-mail:
reese㛭[email protected]
before discharge, with both univariate and multivariate analyses. PEDIATRICS (ISSN 0031 4005). Copyright © 2006
by the American Academy of Pediatrics
RESULTS. There were 128 914 neonates selected as the study cohort; 24 111 were
treated concurrently with ampicillin and cefotaxime and 104 803 were treated
concurrently with ampicillin and gentamicin. Logistic modeling showed that ne-
onates treated with ampicillin/cefotaxime were more likely to die (adjusted odds
ratio: 1.5; 95% confidence interval: 1.4 –1.7) and were less likely to be discharged
to home or foster care than were neonates treated with ampicillin/gentamicin.
This observation was true across all estimated gestational ages. Other factors that
were associated independently with death included immature gestational age,
need for assisted ventilation on the day of admission to the NICU, indications of
perinatal asphyxia or major congenital anomaly, and reported use of ampicillin/
cefotaxime.
CONCLUSIONS. For patients receiving ampicillin, the concurrent use of cefotaxime
during the first 3 days after birth either is a surrogate for an unrecognized factor
or is itself associated with an increased risk of death, compared with the concur-
rent use of gentamicin.
68 CLARK, et al
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TABLE 1 Population Characteristics and Outcomes
Variable Ampicillin/Cefotaxime Ampicillin/Gentamicin
No. 24 111 104 803
Maternal agea
Missing data, n (%) 4 (0.02) 46 (0.04)
Median (25th–75th percentile), y 28 (23–32) 27 (24–33)
Estimated gestational agea
Missing data, n (%) 2 (0.01) 7 (0.01)
Median (25th–75th percentile), wk 35 (31–38) 35 (32–38)
Birth weighta
Missing data, n (%) 61 (0.25) 220 (0.21)
Median (25th–75th percentile), kg 2.35 (1.5–3.2) 2.42 (1.7–3.2)
Apgar score at 1 min
Missing data, n (%) 116 (0.48) 625 (0.6)
Median (25th–75th percentile) 7 (5–8) 8 (6–8)
Apgar score at 5 min
Missing data, n (%) 118 (0.49) 633 (0.6)
Median (25th–75th percentile) 9 (8–9) 9 (8–9)
Day antibiotics started
Missing data, n (%) 0 0
Mean ⫾ SD 0.2 ⫾ 0.5 0.2 ⫾ 0.5
Fractional inspired oxygen on day of admission
Missing data, n (%) 1547 (6) 5328 (5)
Median (25th–75th percentile) 0.3 (0.2–0.6) 0.3 (0.2–0.5)
Duration of antibiotic therapy
Missing data, n (%) 1990 (8) 5962 (6)
Median (25th–75th percentile), d 3 (2–7) 3 (2–6)
Race, n (%)
Missing data 908 (3.8) 3806 (3.6)
Black 3920 (16.3) 16 455 (15.7)
Hispanic 3856 (16) 25 474 (24.3)
Other 1410 (5.8) 5270 (5.0)
White 14 017 (58.1) 53 798 (51.3)
Delivered through cesarean section, n (%) 11 799 (48.9) 50 991 (48.7)
Report of positive test for group B Streptococcus for patient’s mother, n (%) 3530 (14.6) 13 958 (13.3)
Any report of positive blood or cerebrospinal fluid culture during hospitalization, n (%) 1544 (6.4) 6296 (6)
Positive blood or cerebrospinal fluid culture in first 7 d, n (%) 542 (2.2) 2465 (2.4)
Most common bacteria associated with report of positive blood or cerebrospinal fluid culture (first 7 d), n (%)b
Coagulase-negative Staphylococcus 139 (0.58) 827 (0.79)
Group B Streptococcus 82 (0.34) 388 (0.37)
Gram-positive cocci 62 (0.26) 280 (0.27)
Escherichia coli 26 (0.11) 128 (0.12)
Staphylococcus species 15 (0.06) 69 (0.07)
Streptococcus viridians 22 (0.09) 66 (0.06)
Staphylococcus aureus 12 (0.05) 55 (0.05)
Enterococcus 8 (0.03) 48 (0.05)
Gram-negative rod 7 (0.03) 40 (0.04)
Degree of respiratory support on day of admission, n (%)a
Missing data 334 (1.4) 1252 (1.2)
Continuous positive airway pressure 2611 (10.8) 14 483 (13.8)
High-frequency ventilation 1729 (7.2) 4369 (4.2)
Hood oxygen 4207 (17.4) 21 711 (20.7)
Nasal cannula 1415 (5.9) 6147 (5.9)
Room air 7409 (30.7) 34 915 (33.3)
Ventilator 6406 (26.6) 21 926 (20.9)
Report of depression, n (%)a 2169 (9) 4936 (4.7)
Depression type, n (%)b
Asphyxia 81 (0.3) 131 (0.1)
Birth asphyxia 111 (0.5) 157 (0.1)
Depression at birth 440 (1.8) 866 (0.8)
Hypoxic-ischemic encephalopathy 206 (0.9) 224 (0.2)
Neonatal depression 160 (0.7) 334 (0.3)
Perinatal asphyxia 104 (0.4) 145 (0.1)
Perinatal depression 851 (3.5) 2061 (2)
Seizures occurring during the 7 d after birth 633 (2.6) 1514 (1.4)
cillin/gentamicin as your first line of treatment. The goal enced their use of ampicillin/cefotaxime rather than am-
of this informal survey was to determine what factors picillin/gentamicin. The main reasons indicated for the
might alter outcomes and to identify patient selection choice of cefotaxime over gentamicin as initial therapy
bias for the patients treated with ampicillin/cefotaxime. for sepsis were the potential nephrotoxic or ototoxic
effects of gentamicin, selective use of cefotaxime for
Analyses neonates with a history of neonatal depression and/or
perinatal asphyxia, and suspected or culture-proven
Univariate Analyses
Gram-negative organisms causing sepsis or meningitis.
We compared the 2 study populations by using both
These factors and those found in univariate analyses to
univariate and multivariate techniques. Continuous
differ between the 2 antibiotic groups were used to
variables (estimated gestational age and birth weight)
develop a logistic model that identified risk factors asso-
were evaluated with 2-tailed t tests. Categorical variables
ciated independently with death.
(eg, race and gender) were evaluated with 2-tailed 2
tests. Nonparametric continuous data were assessed with
Kruskal-Wallis analysis of variance. Multivariate Analyses
After making the initial observation that mortality After univariate analyses, we used multivariate logistic
risk seemed unequal, we evaluated potential selection regression to identify factors associated independently
bias immediately. Using the Pediatrix internal E-mail with death before discharge. In the logistic regression
system, we circulated a survey to clinicians affiliated analysis, we incorporated the variables (Table 1) found
with Pediatrix, to try to determine what factors influ- in univariate analyses to be significantly different for the
70 CLARK, et al
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TABLE 2 Diagnoses Made in First 21 Days for Which the Rate defined 3 types of sites of care, ie, low-use sites, where
Reported for the Ampicillin/Cefotaxime Group Was >1.5 ampicillin/cefotaxime was used for ⱕ30% of the pa-
or <0.5 Times That Reported for the tients cared for; moderate-use sites, where ampicillin/
Ampicillin/Gentamicin Group cefotaxime was used for 31% to 59% of the patients
Variable n (%) Relative cared for; and high-use sites, where ampicillin/cefo-
Rate taxime was used for ⱖ60% of the patients cared for.
Ampicillin/ Ampicillin/
Cefotaxime Gentamicin Cases with missing values for any of the independent
Liver dysfunction 96 (0.398) 158 (0.151) 2.6
variables were excluded from the analyses. The number
Renal failure 237 (0.983) 394 (0.376) 2.6 of patients evaluated in the logistic model is listed with
Cardiac arrest 154 (0.639) 287 (0.274) 2.3 the results in Table 3.
Coagulopathy 310 (1.286) 609 (0.581) 2.2
Disseminated intravascular coagulation 131 (0.543) 269 (0.257) 2.1 RESULTS
Renal dysfunction 189 (0.784) 399 (0.381) 2.1
Alkalosis 35 (0.145) 81 (0.077) 1.9
Between January 1, 1996, and June 1, 2004, care was
Hydrocephalus (posthemorrhagic) 118 (0.489) 271 (0.259) 1.9 provided by clinicians affiliated with Pediatrix Medical
Pulmonary hemorrhage 344 (1.427) 800 (0.763) 1.9 Group to 227 711 neonates, of whom 192 989 (85%)
Perinatal depression 848 (3.517) 2061 (1.967) 1.8 were born at the site where neonatal intensive care was
Intraventricular hemorrhage (grade IV) 257 (1.066) 673 (0.642) 1.7 provided. The other 34 722 neonates (15%) were trans-
Perforated bowel 85 (0.353) 218 (0.208) 1.7
Tachycardia 107 (0.444) 270 (0.258) 1.7
ported for care or their care represented a subsequent
Hypertension 269 (1.116) 718 (0.685) 1.6 admission.
Hypovolemia 616 (2.555) 1669 (1.593) 1.6 We identified 1 338 980 reports of 409 different med-
Intracranial hemorrhage 129 (0.535) 357 (0.341) 1.6 ications during the time period from January 1996
Intraventricular hemorrhage (grade III) 311 (1.29) 831 (0.793) 1.6 through June 2004. For these data, an antibiotic course
Patent ductus arteriosus (ligation) 352 (1.46) 957 (0.913) 1.6
Seizures (during first 21 d) 737 (3.057) 1947 (1.858) 1.6
could be represented as a single report with start and
Congestive heart failure 45 (0.187) 128 (0.122) 1.5 stop dates or as sequential reports that represented each
Hyperkalemia 423 (1.754) 1221 (1.165) 1.5 day of antibiotic administration. There were a total of
Necrotizing enterocolitis (surgical) 82 (0.34) 280 (0.267) 1.3 172 930 reports of ampicillin use, with 161 049 (93.1%)
Necrotizing enterocolitis (medical) 97 (0.402) 867 (0.827) 0.5 reported in the first 3 days after birth. There were
156 384 reports of gentamicin use, 130 616 (83.5%) of
which occurred in the first 3 days after birth; 54 255
2 groups (P ⬍ .1). Variables were entered into the model reports of cefotaxime use, 34 168 (63.0%) of which
with a stepwise selection method (for entry and reten- occurred in the first 3 days after birth; and 9965 reports
tion, P ⬍ .1). Maternal age, birth weight, and gestational of tobramycin use, 2716 (27%) of which occurred in the
age were entered into the model as continuous variables. first 3 days after birth. Reports of these 4 antibiotics were
The need for assisted ventilation on the day of admission made for a total of 159 636 unique patients derived from
to the NICU, a report suggesting perinatal asphyxia (see the medications table, which included outborn patients.
list in Table 1) or a report of a major anomaly (see partial We then matched these reports to our inborn demo-
list of most common anomalies in Table 1), and the graphic data set.
reported use of ampicillin/cefotaxime were entered into For the inborn neonates (n ⫽ 192 989) and the pa-
the model as dichotomous (“yes/no” or “present/ab- tients with reported use of 1 of the 4 antibiotics (ampi-
sent”) categorical variables. The site of care (the hospital cillin, cefotaxime, gentamicin, and tobramycin) in the
where the patient was treated) was evaluated as a cate- first 3 days after birth (n ⫽ 159 636), there were 135 095
gorical variable in the logistic model. In addition, we matches. Of these matches, 128 914 neonates were se-
lected for the study cohort as a result of their antibiotic initial therapy for sepsis were the potential nephrotoxic
use; 24 111 were treated concurrently with ampicillin or ototoxic effects of gentamicin, selective use of cefo-
and cefotaxime, and 104 803 were treated concurrently taxime for neonates with a history of neonatal depres-
with ampicillin and gentamicin. These 2 strategies were sion and/or perinatal asphyxia, and suspected or cul-
the most commonly reported strategies for the empiric ture-proven Gram-negative organisms causing sepsis or
treatment of neonates considered at risk for neonatal meningitis. Two clinicians raised concerns about the po-
sepsis. tential interaction between gentamicin and magnesium,
There was significant site variation in the reported use causing hypotonia and respiratory depression.
of ampicillin/cefotaxime and ampicillin/gentamicin (Fig Univariate analyses showed that neonates treated
1A). Twenty-five (15%) of the 165 sites that reported with ampicillin/cefotaxime were slightly more imma-
data on ⬎100 patients used ampicillin/cefotaxime for ture, had lower birth weights, were reported more often
⬎50% of their patients. In addition to site variation, to be white and less often to be Hispanic, were reported
there were differences in the relative use of these 2 more often to require mechanical ventilation on the day
treatment approaches over time, with a decrease in the of admission, and were reported more often to have
overall use of ampicillin/cefotaxime between 1996 and perinatal and/or neonatal depression (interestingly,
2004 (Fig 1B). there were no significant differences in Apgar scores),
A survey was sent via an internal E-mail system, compared with neonates who were treated with ampi-
which we estimated reached ⬃200 clinicians, on the cillin/gentamicin (Table 1). Diagnoses made before 21
basis of review of the message history. One hundred days of age were examined in an attempt to identify a
twenty-one clinicians affiliated with Pediatrix responded pattern of potential adverse events. There was no differ-
to this survey, which was circulated to determine the ence in the patterns of the most common (top 10) diag-
factors that influenced their use of ampicillin/cefotaxime noses (Table 1). In addition, reports of major anomalies
rather than ampicillin/gentamicin. Forty-six (38%) re- and positive blood and/or cerebrospinal fluid cultures
ported some use of cefotaxime for treatment of neonates were similar. We did find a group of relatively rare
and 4 reported routine use of cefotaxime for treatment (⬍5% of the total sample) diagnoses that occurred at
of neonates admitted to their NICU. The main reasons different rates (the rate reported for the ampicillin/cefo-
indicated for the choice of cefotaxime over gentamicin as taxime group was ⱖ1.5 or ⱕ0.5 times that reported for
72 CLARK, et al
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the ampicillin/gentamicin group) for the 2 treatment We anticipated that most of the antibiotics adminis-
groups (Table 2). We have provided these descriptive tered during the first 3 days after birth would be pre-
data for informational purposes only; we did not attempt scribed for neonates who were identified as being “at risk
to correct for the effects of gestational age and birth for sepsis” and that mortality rates for these neonates
weight on the relative rates of occurrence of these would be low and similar, independent of the empiric
events. antibiotics used. We found that most antibiotic use was
Neonates treated with ampicillin/cefotaxime were for neonates at risk for sepsis and that overall mortality
more likely to die and were less likely to be discharged to rates were low. Consequently, it was surprising to find
home or foster care than were neonates treated with that mortality rates for ampicillin-treated neonates were
ampicillin/gentamicin (Table 1). These findings were higher when ampicillin was combined with cefotaxime,
true across all estimated gestational ages. Factors that compared with gentamicin.
were found to be associated independently with death After making the initial observation that mortality
included an immature gestational age, the need for as- risk seemed unequal, we evaluated potential selection
sisted ventilation on the day of admission to the NICU, a bias immediately. Although the majority of sites used
report suggesting perinatal asphyxia or a report of a predominantly ampicillin and gentamicin concurrently,
major anomaly, and the reported use of ampicillin/cefo- 15% of the 165 sites that reported data for ⬎100 patients
taxime (Table 3). Entering site of care into the model as administered ampicillin and cefotaxime concurrently for
either a categorical variable or a group variable (low-, ⬎50% of their patients. On the basis of these data, we
moderate-, or high-use sites, as defined above) did not circulated a survey to clinicians affiliated with Pediatrix,
alter these results. to determine their primary reasons for choosing cefo-
When we limited regression model development to taxime over gentamicin. This survey demonstrated 2
neonates with an estimated gestational age of ⱖ37 potential confounding factors driven by selection bias.
weeks and a birth weight of ⬎2 kg, the same variables Clinicians reported selective use of ampicillin/cefo-
were found to be important, except that birth weight, taxime for neonates who had a history suggesting Gram-
rather than gestational age, was retained in the logistic negative sepsis or a report of perinatal/neonatal depres-
regression model. The calculated odds ratios (ORs) were sion/asphyxia.
similar in the 2 analyses (Table 3). To evaluate the ORs These findings led us to evaluate the impact of several
within specific gestational-age groups, the final model important confounding variables on our observation of
was analyzed within gestational-age groups; these re- increased mortality rates. These variables included all of
sults are reported graphically (Fig 2). the items listed in Table 1. We expected that logistic
regression analysis that included these variables would
DISCUSSION allow us to exclude antibiotic choice (ampicillin/cefo-
We found that antibiotics were the most common med- taxime versus ampicillin/gentamicin) as an associated
ications reported in the NICU and that most antibiotic risk factor. Our results, however, did not permit this
use was initiated during the first 3 days after birth. In our exclusion (Table 3 and Fig 2). Consequently, we are
study cohort, only 2% had a report of a positive culture compelled to report that the use of ampicillin/cefotaxime
during the first 7 days after birth and ⬍1% had a report (in the NICU) during the first 3 days after birth may be
of group B Streptococcus, Escherichia coli, or other known associated with an increased risk of death (adjusted OR:
serious neonatal pathogens. Most patients (98%) did not 1.5; 95% confidence interval [CI]: 1.4 –1.7), compared
have culture-proven sepsis. with the use of ampicillin/gentamicin.
FIGURE 2
Adjusted OR (based on final model) within gestational-age
groups (logistic regression [odds of death] adjusted for need for
assisted ventilation, anomalies, birth depression, and estimated
gestational age [EGA] within each estimated gestational-age
group).
74 CLARK, et al
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Empiric Use of Ampicillin and Cefotaxime, Compared With Ampicillin and
Gentamicin, for Neonates at Risk for Sepsis Is Associated With an Increased Risk
of Neonatal Death
Reese H. Clark, Barry T. Bloom, Alan R. Spitzer and Dale R. Gerstmann
Pediatrics 2006;117;67
DOI: 10.1542/peds.2005-0179
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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2006 by the American Academy of Pediatrics. All rights reserved. Print ISSN:
.