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The authors have indicated they have no nancial relationships relevant to this article to disclose.
ABSTRACT
OBJECTIVE. In settings with limited assessment tools, we sought to determine whether
early clinical signs and symptoms and blood oxygen saturation would predict
amoxicillin treatment failure in children with severe pneumonia (as defined by the
World Health Organization).
METHODS. Data were from a previously reported, multinational trial of orally admin-
istered amoxicillin versus injectable penicillin for the treatment of World Health
Organization defined severe pneumonia in children 3 to 59 months of age. We
assessed all 857 participants assigned randomly to the experimental amoxicillin
arm. Six multivariate logistic regression models were created and evaluated for
their ability to predict failure after 48 hours of therapy. Regression models included vital signs, symptoms, and laboratory data collected at baseline and after 12
or 24 hours of observation. Oxygen saturation data were included in 3 models.
RESULTS. Clinical treatment failure occurred for 18% of children. Younger age,
increased initial respiratory rate, and baseline hypoxia predicted treatment failure
in all models. Data available after 24 hours improved the ability to predict failure
compared with data available at baseline or 12 hours. The inclusion of oximetry
data improved the predictive ability at baseline, 12 hours, and 24 hours. The ability
to predict failure after 12 hours of observation with oximetry data was similar to
the predictive ability after 24 hours without pulse oximetry data.
CONCLUSIONS. Assessment of clinical parameters at presentation and after 24 hours
improved the ability to predict clinical failure of oral amoxicillin therapy, compared with assessment at presentation alone or at presentation and after only 12
hours, for children with World Health Organization defined severe pneumonia.
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FU et al
www.pediatrics.org/cgi/doi/10.1542/
peds.2005-2673
doi:10.1542/peds.2005-2673
We attest to the fact that we, the authors,
are responsible for this research review. We
have all participated in the concept and
design of the manuscript, interpretation of
the articles reviewed, and drafting and
revising of the manuscript. We have all
approved the documents submitted.
Key Words
amoxicillin, pneumonia, hospitalization,
oximetry, child
Abbreviations
ARIacute respiratory infection
LCIlower chest wall indrawing
RSVrespiratory syncytial virus
WHOWorld Health Organization
CI condence interval
Accepted for publication Jul 11, 2006
Address correspondence to Linda Y. Fu, MD,
MSc, Department of General and Community
Pediatrics, George Washington University,
Childrens National Medical Center, 111
Michigan Ave, NW, Washington, DC 20010.
E-mail: lfu@cnmc.org
PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright 2006 by the
American Academy of Pediatrics
e1823
Statistical Analyses
The relationship of each predictor variable to oral amoxicillin treatment failure was examined in univariate analyses by using the 2 test (discrete data) or unpaired t test
(continuous data). A crude odds ratio with 95% confidence interval (CI) was calculated for the effect of each
predictor on the outcome by using logistic regression
modeling. All analyses were conducted with SAS 9.0
(SAS Institute, Cary, NC). Test levels for significance
were P .05.
To address our study question, 3 multivariate logistic
regression models were created. The first model used
data obtained at baseline only, the second used data
from baseline and from 12 hours after therapy initiation,
and the third used data from baseline and from 24 hours
after therapy initiation. A forward stepwise selection
process was used each time to choose variables to predict
failure. Pulse oximetry data were excluded from these
models. Three additional models were then created by
allowing pulse oximetry data to enter the selection process. All variables used in the development of regression
models were checked for colinearity; a Pearson correlation coefficient of 0.8 was considered highly colinear.
Because the range of Pearson correlation coefficients
was 0 to 0.73 for all pairings, no variable was excluded.
Because of a relatively high percentage of missing values
for the variables of immunization status (5%) and presence of RSV (11%), dummy variables were created in all
6 models for missing values for these 2 variables. Significance levels for entry and elimination in the stepwise
procedure were set at .1.
The final regression models included study site as a
random effect. Random-effects modeling was performed
by using the SAS macro program Glimmix (available at:
http://ftp.sas.com). The predictive abilities of the 6 models generated were compared by using receiver operating
characteristic curve areas and likelihood ratios. The Hosmer-Lemeshow goodness-of-fit test was used to determine the fit of the models to the data.
FU et al
RESULTS
Study Group
A total of 857 children (50.4% of 1702 patients enrolled
in the study) who were assigned randomly to the amoxicillin arm of the clinical trial represented the present
study sample. We identified 23 children in the trial with
treatment failure for reasons other than failure to exhibit improvement or worsening pneumonia (8 children
received another antibiotic, 4 had newly diagnosed comorbid conditions, 2 had newly diagnosed conditions
and received another antibiotic, and 9 withdrew from
the study voluntarily or left against medical advice).
Two investigators (Drs Fu and Fox) independently reclassified these cases according to our definitions of
treatment success and failure and agreed on 22 of 23
cases. Inter-rater agreement was high ( 0.93; 95%
CI: 0.80 1.00). Of the 23 cases in question, 3 were
reclassified as treatment success, 8 were reclassified as
treatment failure, and 12 were excluded from analysis
because they were not classifiable with the information
available (Fig 1). After reclassification, the rate of treatment failure was 18% (152 of 843 cases), which was
very similar to the percentage obtained in the amoxicillin arm of the clinical trial (19%). Among all of the
patients classified as experiencing treatment failure, the
condition of 13% had worsened, compared with baseline, whereas that of the rest had not changed.
According to univariate analysis, age was a strong
predictor of treatment failure (P .001) (Table 1). The
FIGURE 1
Reclassication of treatment outcomes. a No children in
the amoxicillin arm died during the clinical trial.
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TABLE 1 Odds of Amoxicillin Treatment Failure According to Patient History and Signs and Symptoms
at Baseline and 12 and 24 Hours After Study Enrollment
Variable
Proportion or Mean
Treatment Failure
(n 152)
Treatment Success
(n 691)
57.2
23.0
19.7
13.8
16.6
31.2
28.6
40.2
7.8
8.7
3.60 (2.305.63)
1.59 (0.952.66)
1.00
1.90 (1.113.26)
2.09 (1.253.49)
4.0
18.4
77.6
1.3
0.4 1.4
28.4
18.8
17.5
63.8
0.7
0.6 1.4
24.4
0.20 (0.090.44)
0.87 (0.551.37)
1.00
1.82 (0.359.44)
1.07 (0.951.21)a
1.23 (0.811.87)
32.9
60.5
6.6
37.5 0.9
15.8
23.4
67.8
8.9
37.6 0.9
8.1
1.93 (0.924.05)
1.20 (0.592.43)
1.00
0.87 (0.711.07)c
2.12 (1.273.54)
6 13
6 11
1.01 (0.941.09)e
0.4 1.0
44.1
0.7 4.9
0.6 0.9
40.7
0.1 3.0
1.27 (1.051.54)c
1.15 (0.811.64)
1.14 (1.081.19)f
6 13
11 12
1.18 (1.091.28)e
0.5 1.1
44.4
0.1 4.0
0.9 1.0
37.5
1.1 3.2
1.52 (1.251.85)c
1.33 (0.931.90)
1.20 (1.111.32)f
b If the child was 12 months of age, then very fast respiratory rate was 70 beats per minute, fast was 50 beats per minute, and not fast was
50 beats per minute. If the child was 12 months of age, then very fast was 60 beats per minute, fast was 40 beats per minute, and not fast
was 40 beats per minute.
c Odds ratio and 95% CI reported for an increase in temperature of 1C.
d Hypoxia was dened as oxygen saturation in room air of 90% at sea level or 88% at elevation (in Columbia and Mexico).
e Odds ratio and 95% CI reported for an increase in respiratory rate of 5 breaths per minute.
f Odds ratio and 95% CI reported for a decrease in blood oxygen saturation of 1%.
FU et al
Baseline Data
(n 842)
Baseline and
12-h Data
(n 842)
Baseline and
24-h Data
(n 838)
Baseline Data
With Pulse
Oximetry
(n 838)
Baseline and
12-h Data With
Pulse Oximetry
(n 833)
Baseline and
24-h Data With
Pulse Oximetry
(n 832)
3.65 (2.255.93)
1.74 (1.022.98)
1.00
4.01 (2.456.57)
1.91 (1.113.30)
1.00
4.48 (2.627.67)
2.07 (1.153.70)
1.00
3.60 (2.225.85)
1.74 (1.022.98)
1.00
3.89 (2.236.81)
1.87 (1.023.45)
1.00
3.90 (2.326.57)
1.79 (1.013.19)
1.00
3.90 (1.768.65)
1.68 (0.803.51)
1.00
6.89 (2.8816.46)
2.29 (1.074.91)
1.00
12.20 (4.7831.19)
2.86 (1.276.43)
1.00
3.60 (1.627.98)
1.56 (0.753.24)
1.00
2.37 (1.204.68)
6.34 (2.4516.44)
2.08 (0.914.76)
1.00
3.99 (1.798.90)
1.15 (1.042.85)
11.16 (4.5127.64)
2.57 (1.175.60)
1.00
3.83 (1.828.09)
1.16 (1.061.26)
1.28 (1.031.41)
1.32 (1.201.45)
1.17 (1.101.24)
1.20 (1.091.32)
0.67 (0.630.72)
1.80 (1.262.55)
1.97 (1.412.74)
2.19 (1.223.93)
0.73 (0.680.77)
0.68 (0.630.73)
0.69 (0.650.74)
0.72 (0.670.77)
2.05 (1.173.61)
0.76 (0.710.80)
b If the child was 12 months of age, then very fast respiratory rate was 70 beats per minute, fast was 50 beats per minute, and not fast was 50 beats per minute. If the child was 12 months
of age, then very fast was 60 beats per minute, fast was 40 beats per minute, and not fast was 40 beats per minute.
was dened as oxygen saturation in room air of 90% at sea level or 88% at elevation (in Columbia and Mexico).
d Odds ratio and 95% CI reported for an increase in respiratory rate of 5 breaths per minute.
e Odds ratio and 95% CI reported for a decrease in blood oxygen saturation of 1%.
f Odds ratio and 95% CI reported for an increase in temperature of 1C.
c Hypoxia
TABLE 3 Abilities of Logistic Regression Models to Predict Amoxicillin Treatment Failure (n 828)
Logistic Regression Model
Likelihood
Ratio
Degrees of
Freedom
Predictive
Abilitya
Pb
105.3
86.6
85.2
62.9
51.8
50.9
8
8
7
5
5
4
1
2 (tie)
2 (tie)
4
5 (tie)
5 (tie)
.001
.23
.001
.001
.35
a Predictive
bP
ability was best for the regression model ranked 1 and worst for the models ranked 5.
value for comparison with the next highest ranking regression model.
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When we compared this model with the one that included 24 hours of data without pulse oximetry information, again we found that treatment failure was predicted more accurately with pulse oximetry data than
without such data (P .001) (Table 3).
In all 3 regression models that included pulse oximetry variables, baseline hypoxia increased the odds of
treatment failure twofold to fourfold, and each 1% decrease in oxygen saturation over 12 or 24 hours was
associated with 20% increased odds of treatment failure (Table 2). Variables related to pulse oximetry were
such strong predictors of treatment failure that there was
no difference in predictive ability between the model
that used data collected after 12 hours of therapy and
included pulse oximetry information and the model that
used data collected after 24 hours of therapy and excluded pulse oximetry information (P .24) (Table 3).
All 6 logistic regression models fit the data well, according to the Hosmer-Lemeshow goodness-of-fit test (P
.52.99).
DISCUSSION
Our study has 2 main findings. First, information obtained after at least 12 hours but ideally 24 hours of
patient observation provides more valuable information
than baseline assessments alone for predicting which
children with severe pneumonia are likely to experience
failure of oral amoxicillin therapy. Second, assessments
of blood oxygen saturation at baseline and saturation
trends over time improve the ability to predict which
children will experience failure of oral therapy. Specifically, if pulse oximetry is available, then the ability to
predict treatment failure with data from baseline and
from 12 hours after initiation of therapy is almost identical to the predictive ability obtained with data from
baseline and from 24 hours without the benefit of pulse
oximetry. Having 24 hours to observe a child with access
to pulse oximetry provides the best predictive ability for
treatment failure.
These findings extend the observations of the recently
published trial that demonstrated equivalence between
injectable penicillin and orally administered amoxicillin
for the treatment of severe pneumonia in children.8 The
original trial established the equivalence of oral and
parenteral therapy in a facility setting, without affirming
the safety of home oral therapy. Our study suggests that
an identifiable subset of children presenting with severe
pneumonia may need to be hospitalized for optimally
safe care if treated with oral therapy. Hospitalization
provides patients with monitoring by trained professionals, as well as the opportunity to receive ancillary therapies as appropriate. Patient observation has been cited
as one of the most common methods through which
health care providers acquire information on which to
base decisions.18 One fifth of all children in our study
received supplemental oxygen at least once during the
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FU et al
tions, there will be even more inducements for widespread distribution of pulse oximeters.
Our study has several limitations. To make the results
of our study readily applicable to practitioners internationally, we used the WHO ARI algorithm as the basis for
our definition of treatment failure. Because of the minimal resources needed to follow the guidelines, the WHO
ARI algorithm is the accepted method for diagnosing
pneumonia in much of the world. Use of empiric antibiotic therapy based on these guidelines has been estimated to reduce mortality rates in the developing world
by 27%.7 However, the WHO definition of pneumonia
has a significant false-positive rate and misclassified 35%
of well children as having pneumonia in one study.11
Patients with ARI attributable to pathologic processes
not expected to be responsive to amoxicillin were likely
included as cases of antibiotic failure in our study. At the
Durban and Zambia study sites, the adult seroprevalence
of HIV was as high as 30%. Children from those sites
who experienced failure of therapy were at greater risk
of having pneumonia caused by Pneumocystis jiroveci, because amoxicillin is ineffective against that organism.
Overall, 67% of the children in our study were afebrile
at the time of study enrollment; some of those children
with failure of antibiotic therapy were likely suffering
from reactive airway disease rather than pneumonia,
despite our baseline exclusion of children with known
asthma or positive responses to bronchodilator therapy.
Our study identified children infected with the 2 most
common pathogens causing community-acquired pneumonia. Twenty-seven percent of the children had Streptococcus pneumoniae isolated from their nasopharynx, and
20% had Haemophilus influenzae. Negative culture results
were not a risk factor for treatment failure. It is likely
that a higher percentage of children in the study had
bacterial lung infections, because the percentage of children with ARI symptoms and positive lung aspirate cultures ranged from 21% to 74% in other studies.2 Because of the diagnostic ambiguity inherent in using the
WHO definition of severe pneumonia for determination of treatment failure, the conclusions of our study
and the original trial may not be directly applicable to
settings in which more-precise methods of diagnosing
bacterial pneumonia, such as bacterial culture and radiography, are routine.
Additional study is necessary to translate our findings
into simple practical guidelines for individual-level patient care in developing countries. We found incrementally increasing value of 12-hour and 24-hour patient
data over baseline data alone, as well as benefits of
knowing blood oxygen saturation at all time points, for
predicting amoxicillin treatment failure. Future treatment guidelines will need to balance the maximization
of predictive ability with practicality. Although the techniques for assessing clinical status in this trial were the
same as the methods promoted by the WHO for care at
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