Ampicillin- gentamicin versus ceftriaxone- sulbactam in pediatric patients suffering from
severe and very severe community acquired pneumonia – A randomized controlled trial
Aparna Chandrasekaran
Arun Bansal
Department of Pediatrics
Postgraduate Institute of Medical Education and Research (PGIMER)
Chandigarh, 160012, India
Address for Correspondence:
Dr. Sunit C Singhi,
Professor and Head,
Department of Pediatrics,
Advanced Pediatric Center,
Postgraduate Institute of Medical Education and Research,
Chandigarh 160012, India.
Ph. 91-172-2755302, 91-9914208302
E-mail: sunit.singhi@gmail.com , dr_singhi@yahoo.com
ABSTRACT
Background: Although the WHO still recommends ampicillin/ benzyl penicillin for the
treatment of severe pneumonia, the use of cephalosporins, particularly ceftriaxone has become
common in community acquired pneumonia in children.
Objective: To compare the efficacy, safety and cost effectiveness of a combination of
Ceftriaxone–sulbactam versus Ampicillin-gentamicin in children with severe or very severe
community acquired pneumonia.
Methods:
Study design: Open label, prospective, randomized controlled trial. Setting: Pediatric emergency
service of a tertiary care teaching hospital of North India. Participants: Children between 3
months to 14 years with WHO defined severe or very severe pneumonia. Study Period: A period
of 12 months between December 2008 and December 2009. Intervention: Through computer
generated numbers, patients were randomized to group A (Ampicillin-50mg/kg QID IV and
gentamicin-7.5mg/kg OD IV) and group B (Ceftriaxone– sulbactam 50 mg/kg BD IV).
Antibiotics were made oral once respiratory distress settled. Patients were monitored 6th hourly
till the completion of 5 days of therapy. Supportive care including oxygen and oral antipyretics
were continued. Primary outcome measure: Number of treatment failures on day 6. Treatment
failure was defined as - any change or modification of antibiotics, new development (at any time
after enrollment) or persistence of respiratory distress beyond 5 days, development of
complications like septic shock, acute renal failure, meningitis and empyema, serious adverse
reactions, voluntary withdrawal or death.
Results: Out of 100 patients enrolled, 50 were in group A and 50 in group B. There were 9
treatment failures by day 6, of which 3 were in group A and 6 in group B (RR 0.5, 95% C.I.
0.14-1.72, p=0.48). The commonest cause of treatment failure was persistence of respiratory
distress (n=7). The mean intravenous antibiotic duration, time taken for recovery of tachypnoea,
lower chest wall indrawing and hypoxemia were comparable in both groups. Adverse events, the
commonest being phlebitis and diarrhea were found equally in both groups (p=0.66). The cost of
treatment of a 10 kg child was Rs.150.40 per day in group A, as compared to Rs.137.00 for
group B. However, number of injections required per day in group A was 5 against 2 in group B.
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Conclusion: There are no significant differences in the efficacy and safety of ampicillin –
gentamicin or ceftriaxone – sulbactam in community acquired pneumonia in children. However,
less frequent dosing and ease of administration make ceftriaxone – sulbactam a more convenient
alternative.
Key Words: Pneumonia, Ampicillin – gentamicin, Ceftriaxone – sulbactam.
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Introduction
Pneumonia kills more than 2 million children under 5 years of age each year, accounting
for 19% under-5 deaths worldwide, of which, 90% are from developing nations (1). The
commonest bacterial cause is Streptococcus pneumoniae (30–50%), followed by Haemophilus
influenzae type-b (10–30% of cases), Staphylococcus aureus and Klebsiella pneumonia (2),
although S. aureus emerged the commonest cause in a recent multicentre study in developing
nations (41%) (3).
Information on the bacterial etiology of pneumonia has been obtained through blood
cultures, despite its poor sensitivity – as low as 10% (4), although it varied upto 26.8%, if taken
prior to antibiotics (5). However, despite newer diagnostic modalities like nasopharyngeal
cultures, pneumolysin based PCR and rapid immunochromatogenic urinary antigen detection kits,
empiric antibiotic treatment in the ED is based largely on clinical factors, radiographic findings
and epidemiologic factors.
For severe pneumonia, the WHO recommends ampicillin/ benzyl penicillin or
chloramphenicol parenterally, while chloramphenicol is the recommended drug for very severe
pneumonia. In both cases, cloxacillin and gentamicin are added in case of non improvement (6).
However, the increasing resistance H. influenzae and S. aureus to chloramphenicol added to its
bacteriostatic property and bone marrow toxicity, have made its use uncommon. Duke et al and
Asghar et al, clearly brought out the superiority of penicillin- gentamicin over chloramphenicol
(3, 7).
Recently, the treatment of pneumonia has been complicated by bacterial, particularly
pneumococcal resistance to penicillin. Around 20–40% of S pneumoniae isolates are nonsusceptible to penicillin (8). However, there is no evidence that in-vitro penicillin resistance of S.
pneumoniae translates into treatment failure (9). Despite this, for most non-susceptible strains, a
second-generation cephalosporin (cefuroxime) or a third-generation cephalosporin (cefotaxime
or ceftriaxone) is more effective than either ampicillin or penicillin, although a high dose of
amoxycillin (80 to 100 mg/kg per day) is the preferred in outpatients. The addition of a betalactamase inhibitor conveys no advantage, since the mechanism of resistance does not involve
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this enzyme (10). So there is a need to compare the efficacy of ceftriaxone and penicillin –
gentamicin in children with severe and very severe pneumonia.
Only one study in pediatrics has studied ceftriaxone in childhood pneumonia. A study by
Cetinkaya et al in Turkey compared a combination of penicillin G plus chloramphenicol versus
ceftriaxone in 97 children severe CAP and found no difference (11). However, the relevance of
this study today is questionable as chloramphenicol is rarely used nowadays. There are no direct
comparative studies between the combinations of ceftriaxone – sulbactam with ampicillin –
gentamicin in children suffering with severe and very severe pneumonia. In view of the above
consideration, the present study was undertaken.
Materials and methods
Design: An open label randomized comparison trial Setting: A busy pediatric emergency service
of a tertiary care teaching hospital of North India, from December 2008 to December 2009.
Participants: Children aged 3 months to 14 years with history of cough and difficulty in
breathing, with physical examination showing tachypnoea and presence of chest wall indrawing
and chest X-ray showing alveolar infiltrates, segmental or lobar consolidation were included in
the study. The following children were excluded i.
duration of illness more than 10 days,
ii.
known asthma, heart disease and HIV infection
iii.
empyema or pneumatoceles on chest radiograph
iv.
H/O prior hospitalization or injectable antibiotics for more than 24 hours
v.
clinical evidence of bacterial meningitis
Randomization and Allocation: The patients were randomized into two groups according to
computer generated random number blocks. By block randomization, confounding variables
were equally distributed among the two groups. The random number lots (labeled either A or B)
were kept within sealed envelopes, numbered from 1 to 100, which were opened only after the
patient’s enrollment. Group A received ampicillin and gentamicin IV, while group B received
ceftriaxone- sulbactam IV.
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Study intervention: Ceftriaxone–sulbactam (50 mg/kg BD IV) or ampicillin (50 mg/kg QID IV)
- gentamicin (7.5mg/kg OD IV) were given intravenously till respiratory distress (tachypnoea,
retractions and nasal flaring) settled. Subsequently, child was shifted to oral amoxycillin clavulanate in group A and oral cefixime in group B. Total duration of treatment was 7-10 days
depending upon the clinical response.
Monitoring of patients: Patients’ temperature (axillary), respiratory rate, chest wall retractions,
oxygen saturation (off oxygen), heart rate, pulses, capillary refill time, blood pressure, urine
output, sensorium and general well being were monitored 6th hourly till 5 completed days of
treatment and recorded in the case record form. Respiratory rate was counted manually for one
minute when the child was at rest. Heart rate and saturation were recorded with the help of pulse
oximeter. Any decision to change antibiotics, if indicated, was taken in consultation with the
investigator after careful consideration of the patient’s clinical status. The incidence and severity
of adverse events were also assessed by clinical evaluation and laboratory parameters.
Outcome measurement: All subjects were evaluated after 5 completed days of treatment.
Primary outcome was taken as number of treatment failures on day 6. Treatment failure was
defined as - any change or discontinuation of allocated antibiotic therapy as decided by the
treating physician, new development (at any time after enrollment) of inability to drink or
abnormal sleepiness, persistence of chest indrawing or tachypnoea beyond 48 hours of treatment,
development of complications like septic shock, acute renal failure, meningitis and empyema,
development of serious adverse reaction, voluntary withdrawal or death.
Sample size: The efficacy of ampicillin – gentamicin combination was expected to be around
70%. The sample size was calculated assuming 20% difference in efficacy between the two
groups with a standard deviation of 10%. To achieve 80% power, 40 patients were needed in
each group. Assuming 80% compliance, 50 patients were recruited in each group.
Ethical issues: The study was an effort to find out the more efficacious and safe antibiotic in
children with community acquired pneumonia. Both groups of antibiotics are time tested in
children, with negligible adverse events. All the same, voluntary written informed consent was
obtained for each subject. Refusal to participate in the study had no bearing on the child’s
treatment. Patients were free to withdraw from the study at any stage. Confidentiality of data
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obtained was maintained. There was no financial gain to anybody out of the study. Clearance
was obtained from the institutional ethical committee.
Statistical analysis: Descriptive statistics (Mean and standard deviation/ standard error) were
used for the continuous variables and these were compared using independent t test. The number
along with percentage was presented for categorical variables and these were compared using chi
square test. Percentage of treatment failures in both treatment groups on day 6 was compared
using chi square test and relative risk was calculated. In addition, Kaplan - Meier analysis was
performed to compare the time taken for treatment in both groups as well as time taken for
resolution of tachypnoea, chest indrawing and hypoxaemia. For non parametric variables, Mann
Whitney U test was used. P value < 0.05 was taken as significant.
Results and observations
The baseline variables of all 100 children were comparable (Table 1). There was a male
preponderance in both groups. Since the study included only children with severe and very
severe pneumonia, all children had tachypnoea and lower chest retractions at admission. Signs
and symptoms of very severe pneumonia, such as inability to drink, central cyanosis, convulsions,
WHO – defined severe malnutrition and abnormal sleepiness were distributed equally in both
groups: 16 in group A and 16 in group B, although cyanosis at admission was significantly more
in group B (Table 1).
All children were febrile at admission. Heart rate and systolic blood pressures at
admission were also comparable (p = 0.69 and 0.29 respectively) (Table 2). None of the 100
children had shock at admission, although 2 were dehydrated. Infants enrolled under group A
had a median respiratory rate of 60 breaths/minute at presentation (IQR 56-67) in contrast to
66/minute in group B (IQR 60-70), although the difference was not significant (p=0.06). The
median respiratory rate in children ≥ 12 months age was 52/minute in both groups (p=0.87)
(Table 2).
Of the total 100 patients, 9 had treatment failure on day 6, of which 3 belonged to group
A and 6 to group B (RR 0.5, 95% CI 0.14-1.72, p=0.48). The causes of treatment failure included
persistence of respiratory distress (n=7) followed by development of septic shock (n=4).There
were no voluntary withdrawals, serious adverse drug reactions or deaths. When children with
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very severe pneumonia were analyzed separately, there was a greater risk of treatment failure in
children treated with ceftriaxone – sulbactam, as against children treated with ampicillin
gentamicin (RR 4.53; 95% CI 0.77 – 28.60, p=0.16).
The mean duration of intravenous antibiotic was 4.27 days (SD ± 1.39) in group A, as
against 4.61 (SD ±1.29) days in group B (p = 0.29), although this difference was not significant
(Table 3). The mean time for fever clearance, which was defined as the time taken for
temperature to fall below 37.50C and remain so for 48 hours was 36 hours in the ampicillin group
as against 34 hours in the ceftriaxone group ( p = 0.74). Tachypnoea settled faster in the
ceftriaxone group, but the time taken for resolution of hypoxaemia and lower chest indrawing
was longer as compared with the ampicillin group (Table 3). The time taken for normalization of
tachypnoea was comparable in either group (p=0.96). However, at any particular point of
observation, more children treated under group B had hypoxaemia compared to group A (p =
0.09), and this observation was found to be nearing significance (Figures 1 and 2).
Adverse events were reported in 16 children in the ampicillin - gentamicin group as
against 19 in the ceftriaxone - sulbactam group, the commonest being phlebitis and diarrhea
accounting for 12 ADRs in each group. None had any serious ADRs such as hypotension,
anaphylaxis, seizures, hearing deficit or death.
When the cost of treatment of a 10 kg child was considered, cost of therapy per day for
ampicillin- gentamicin works out to be Rs.150.40 in comparison to Rs.137.00 for ceftriaxone –
sulbactam. The number of injections required in per day, would be 5 in group A, against only 2
in group B. This difference has an important bearing on the rate of hospital acquired infections,
burden on hospital staff and indirect costs involved.
Discussion
The present study has shown that there is no significant difference between the two
groups in terms of efficacy and safety, although there was a trend towards more treatment
failures on day 6 of treatment (6 out of 9 failures were in group B) and slower improvement in
hypoxaemia in ceftriaxone treated children.
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In the present study, 94% of children who received ampicillin-gentamicin and 88% of
those given ceftriaxone-sulbactam responded to treatment on day 6. In a similar study by
Cetinkaya et al from Turkey which compared penicillin plus chloramphenicol (group I) versus
ceftriaxone (group II), at the end of ten days of treatment, 84.7% of the children treated under
group I and 80.4% of those under group II responded (p> 0.05) (11).
Interestingly, there was a relatively higher risk (RR 4.53; 95% CI 0.77 to 28.60) of
treatment failure in the children with very severe pneumonia treated with ceftriaxone –
sulbactam (p = 0.16). This observation comes as a surprise as literature recommends a third
generation cephalosporin (eg., ceftriaxone) in the treatment of very severe pneumonia (12). This
finding opens avenues for more research on the therapy of very severe pneumonia in developing
nations, since most trials from this part of the world have focused on severe pneumonia. If more
evidence supports the use of penicillins over ceftriaxone in very severe pneumonia, the existing
guidelines could be stepped down.
The investigators of the SPEAR study believed that
Staphylococcal infections could be treated effectively with ampicillin and gentamicin, without
the addition of a penicillinase resistant antibiotic like cloxacillin, due to the anti – staphylococcal
action of gentamicin (3). Although we excluded children with clearcut pneumatocoeles and
empyema, this property possibly conferred a better efficacy to the ampicillin – gentamicin group
over the ceftriaxone – sulbactam group.
Cetinkaya et al, demonstrated that the total cost of treating a child ≤ 24 months for 10
days was 50 US dollars with penicillin G and chloramphenicol versus 80 US dollars for
ceftriaxone monotherapy (11). Surprisingly, ceftriaxone – sulbactam proved cheaper than
ampicillin – gentamicin in the present study, due to the additional cost of intravenous infusion set
required for administering gentamicin.
A recent study in Pakistan has claimed to show that high – dose oral amoxycillin (80-90
mg/kg/day) is found to be equally efficacious as parenteral ampicillin for severe pneumonia (13).
But since the cases were not radiologically confirmed, there might have been recruitment of
children with non-pneumonic illnesses. In addition, very severe pneumonia does not figure in
their study population, which, by definition, includes children who would be unable to accept
orally. Interestingly, the mean duration of recovery in a European trial on oral antibiotics in
pneumonia was 9 days (14), whereas the present study demonstrated that the mean time taken for
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stopping intravenous therapy was only 4.27 days (SD ± 1.39) and 4.61 days (SD ± 1.29) in group
A and B respectively. So, the overall costs and duration of sickness are clearly lesser with
parenteral therapy.
The present study had some definite strengths - high rates of compliance to medication
and availability of 100% follow up of all subjects on day 6. This enhances the confidence in
outcomes and minimizes classification error associated with an intention to treat analysis.
Further, there were no serious adverse effects to any of the drugs. The trial has established the
efficacy of a well proven therapy of pneumonia and has reinforced that older drugs are still
equally effective if not superior to newer therapies.
Nonetheless, the study is not devoid of limitations. First, the study could not be
blinded due to the completely different dosing schedules of both the study medications and since
it was considered unethical to administer placebo injections to tackle differences in schedules.
Secondly, despite best efforts to avoid enrolment of children with wheeze, it has to be accepted
that some children did have viral pneumonia. But even the WHO recommends the use of
antibiotics in such children because mixed viral and bacterial infections are common in children
from both developed and developing countries.
This was the first randomized controlled study to compare intravenous ampicillin –
gentamicin and ceftriaxone – sulbactam in children with severe and very severe pneumonia.
Based on the findings of the present study, it can be concluded that there are no significant
differences in the efficacy and safety of ampicillin – gentamicin or ceftriaxone – sulbactam in
community acquired pneumonia in children. Ampicillin – gentamicin, despite being in use for
many years now, continues to be safer and effective in childhood pneumonia. Nevertheless, less
frequent dosing and ease of administration make ceftriaxone – sulbactam a more convenient
alternative. Although there is no reason to believe that other general hospitals and tertiary centres
in developing countries admit a different population of children with pneumonia, more studies
comparing these two parenteral antibiotic combinations are necessary, notably due to different
antibiotic resistant patterns, immunization rates and co-existence of other diseases like
malnutrition.
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Flow of patients enrolled in the study
Total number screened (n=158)
Excluded (n=58)
Not meeting inclusion criteria (n=28)
Meeting exclusion criteria (n=20)
Declined consent (n=10)
Randomised (n=100)
Randomized to ampicillingentamicin (n=50)
At 5
completed
days of
treatment
Randomized to ceftriaxonesulbactam (n=50)
At 5
completed
days of
treatment
Lost to follow up (n=0)
Lost to follow up (n=0)
Failed treatment (n=3)
Failed treatment (n=6)
andomized to ampicillingentamicin (n=50)
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Table 1: Baseline characteristics of children aged 3 months – 14 years with severe and very
severe pneumonia
Characteristic
Gender (male)
Median age (months)
No. of infants
Median age of
infants(months)
Breastfeeding*
Complete immunization
status
Malnutrition$
Antibiotic use in previous
Ampicillin-gentamicin
Ceftriaxone-sulbactam
(n= 50)
(n= 50)
33(66)
35(70)
0.87
12(7-21.75)
11 (5-24)
0.38
21(42)
27(54)
0.55
7(5-10)
6(3-7)
0.12
24 /39 (61.5)
21/38 (55.3)
0.74
44 (88)
44 (88)
0.44
21(42)
24(48)
0.55
2 (4)
3 (6)
0.46
50 (100)
50 (100)
-
1 (2)
-
p value
24 hours
H/o difficult breathing
Symptoms/ Signs of very severe pneumonia$$
Abnormally sleepy
0 (0)
Inability to drink
16 (32)
13 (26)
0.66
Convulsion
0 (0)
1(2)
1.0
Severe malnutrition
1(2)
2(4)
Data are n (%), n/number with data available (%), or median (IQR) unless otherwise indicated.
*Denominators for breastfeeding are the number of children under 24 months of age.
$
Malnutrition was defined as weight < 80 percent of expected for age. $$One child might have
more than one criteria for very severe pneumonia.
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Table 2: Physical examination findings at admission
Physical parameter
Ampicillin-gentamicin
Ceftriaxone-sulbactam
Median (IQR)
Median (IQR)
131 (120-148)
131 (120-145)
0.69
90 (86-98)
92 (90-100)
0.29
2 (4)
0 (0)
0.47
Signs of shock
0
0
-
Lower chest indrawing
50
50
1.0
24 (48)
32 (64)
0.16
Infants (3-11)
60 (56-67)
66 (60-70)
0.06
Children (≥12 mths - <5 yrs)
52 (44-58)
52 (44-56)
0.87
Heart rate (bpm)
Systolic blood pressure (mm
p value
Hg)
Dehydration
Hypoxemia (Spo2≤ 92%)
Respiratory rate / min
Table 3: Secondary efficacy analysis
Outcome
Ampicillin-gentamicin Ceftriaxone-sulbactam p value
I.v. Antibiotic duration* (days)
Fever clearance time (hours)
Improvement of respiration rate (hours)
Improvement of chest indrawing (hours)
Improvement in hypoxemia (hours)
(n=50)
(n=50)
Mean(SD)
Mean(SD)
4.27 (1.39)
4.61 (1.29)
0.29
33.8 (37.7)
0.74
63.4 (33.3)
0.67
55.9 (28.9)
0.29
53.3 (40.9)
0.24
36.36 (37.3)
66.12 (32.5)
50.64 (20.8)
44.04 (36.8)
*Number of children who improved on study medication
Groups are compared with independent t test
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Figure 1: Time to normalization of respiratory rate in both groups compared using
Kaplan-Meier analysis (p = 0.96)
Figure 2: Time to recovery of hypoxaemia (SpO2 ≥ 93%) compared
using Kaplan-Meier analysis (p = 0.09)
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ACKNOWLEDGEMENTS:
We are thankful to Prof. Dr. Sunit C Singhi, Head, Department of pediatrics, PGIMER,
Chandigarh, India, for motivating us towards the successful completion of this study.
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