Chloramphenicol versus ampicillin plus gentamicin for
community acquired very severe pneumonia among
children aged 2-59 months in low resource settings:
multicentre randomised controlled trial (SPEAR study)
Rai Asghar, professor,1 Salem Banajeh, professor,2 Josefina Egas, microbiologist,3
Patricia Hibberd, professor,4 Imran Iqbal, professor,5 Mary Katep-Bwalya, consultant,6
Zafarullah Kundi, FRCP professor,1 Paul Law, associate professor,7 William MacLeod, assistant
professor,8 Irene Maulen-Radovan, professor,9 Greta Mino, professor,10 Samir Saha, professor,11
Fernando Sempertegui, director,3 Jonathon Simon, director,8 Mathuram Santosham, professor,7
Sunit Singhi, professor,12 Donald M Thea, professor,8 Shamim Qazi, medical officer,13 for the SPEAR
(Severe Pneumonia Evaluation Antimicrobial Research) Study Group
1
Rawalpindi General Hospital,
Rawalpindi, Pakistan
2
Al-Sabeen Hospital, Sana’a,
Yemen
3
Corporacion Ecuatoriana de
Biotecnologia, Quito, Ecuador
4
Clinical Research Institute, New
England Medical Center Tufts
University, Boston, USA
5
Nishter Hospital, Multan,
Pakistan
6
University Teaching Hospital,
Lusaka, Zambia
7
Department of International
Health, Johns Hopkins Bloomberg
University, Baltimore, USA
8
Center for International Health
and Development, Boston
University School of Public Health,
Boston, MA 02118, USA
9
Instituto Nacional de Pediatria,
Division de Investigacíon, Mexico
City, Mexico
10
Children’s Hospital, Guayaquil,
Ecuador
11
Dhaka Shishu Hospital, Dhaka,
Bangladesh
12
Post Graduate Institute of
Medical Education and Research,
Chandigarh, India
13
Department of Child and
Adolescent Health and
Development, World Health
Organization, Geneva, Switzerland
Correspondence to: D M Thea
dthea@bu.edu
doi:10.1136/bmj.39421.435949.BE
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ABSTRACT
Objective To evaluate whether five days’ treatment with
injectable ampicillin plus gentamicin compared with
chloramphenicol reduces treatment failure in children
aged 2-59 months with community acquired very severe
pneumonia in low resource settings.
Design Open label randomised controlled trial.
Setting Inpatient wards within tertiary care hospitals in
Bangladesh, Ecuador, India, Mexico, Pakistan, Yemen,
and Zambia.
Participants Children aged 2-59 months with WHO
defined very severe pneumonia.
Intervention Chloramphenicol versus a combination of
ampicillin plus gentamicin.
Main outcome measures Primary outcome measure was
treatment failure at five days. Secondary outcomes were
treatment failure defined similarly among all participants
evaluated at 48 hours and at 10 and 21 days.
Results More children failed treatment with
chloramphenicol at day 5 (16% v 11%; relative risk 1.43,
95% confidence interval 1.03 to 1.97) and also by days 10
and 21. Overall, 112 bacterial isolates were obtained from
blood and lung aspirates in 110 children (11.5%), with the
most common organisms being Staphylococcus aureus
(n=47) and Streptococcus pneumoniae (n=22). In
subgroup analysis, bacteraemia with any organism
increased the risk of treatment failure at 21 days in the
chloramphenicol group (2.09, 1.41 to 3.10) but not in the
ampicillin plus gentamicin group (1.12, 0.59 to 2.13).
Similarly, isolation of S pneumoniae increased the risk of
treatment failure at day 21 (4.06, 2.73 to 6.03) and death
(5.80, 2.62 to 12.85) in the chloramphenicol group but not
in the ampicillin plus gentamicin group. No difference was
found in treatment failure for children with S aureus
bacteraemia in the two groups, but the power to detect a
difference in this subgroup analysis was low. Independent
predictors of treatment failure by multivariate analysis
were hypoxaemia (oxygen saturation <90%), receiving
chloramphenicol, being female, and poor immunisation
status.
Conclusion Injectable ampicillin plus gentamicin is
superior to injectable chloramphenicol for the treatment
of community acquired very severe pneumonia in children
aged 2-59 months in low resource settings.
Trial registration Current Controlled Trials
ISRCTN39543942.
INTRODUCTION
Pneumonia is a leading cause of death in under 5s in
low resource settings and accounts for about two
million deaths in this age group annually.1-3 The World
Health Organization recommends standard case management of pneumonia on the basis of disease severity.4
Very severe pneumonia—the most advanced form of
the disease—is defined as the presence of cough or
difficulty breathing, with clinical symptoms and signs
of pneumonia and any accompanying danger signs
(cyanosis, inability to drink, difficulty in waking, stridor
in a calm child)5 and carries the highest mortality.6 First
line treatment for this condition recommended by
WHO is injectable chloramphenicol followed by oral
chloramphenicol5 to treat for the common bacterial
pathogens that cause very severe pneumonia: Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus
aureus, and Gram negative bacteria such as Escherichia
coli and Klebsiella spp.7 8
Although chloramphenicol may have had some
advantages in the past, the increasing resistance of
bacteria, particularly H influenzae and S aureus, to this
antibiotic adds to the longstanding concerns that it is
bacteriostatic and associated with bone marrow
toxicity, particularly in malnourished children.9-14 An
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RESEARCH
RESEARCH
Bangladesh—Bangladesh Institute of Child Health, Dhaka Shishu Hospital, Dhaka
Ecuador—Dr Francisco de Icaza Bustamente Children’s Hospital, Guayaquil
India—Post Graduate Institute of Medical Research and Education, Chandigarh
Mexico—National Institute of Pediatrics, Mexico DF, Jaurez Hospital, Mexico City
Pakistan—Rawalpindi General Hospital, Rawalpindi, and Nishter Hospital, Multan
Yemen—Al-Sabeen Hospital, Sana’a University, Sana’a
Zambia—Department of Paediatrics and Child Health, University Teaching Hospital, Lusaka
alternative regimen already being used in some areas,
combined ampicillin and gentamicin, is bactericidal
and provides good coverage against H influenzae, S
pneumoniae, E coli, and Proteus mirabilis. The combination is synergistic and bactericidal against the common
Gram negative organisms associated with very severe
pneumonia, including E coli, Enterobacter spp, Klebsiella
spp, Proteus spp, Serratia spp, and Citrobacter spp.
Although in vitro penicillin resistance among S
pneumoniae has been reported,10 11 15 16 this has not
been clearly associated with worse clinical outcome
in pneumococcal pneumonia.17-21
Although the standard case management strategy
has successfully decreased pneumonia related
mortality,22 23 specific information about the efficacy
of chloramphenicol in very severe pneumonia is
sparse.24-27 In addition to concerns about increasing
resistance28 or adverse clinical outcomes,9 diminished
clinical response and increasing resistance to penicillin
and gentamicin among children with community
acquired severe bacteraemic pneumonia has been
seen in Congo29 and elsewhere.27 Only one published
study has directly compared the clinical efficacy of
ampicillin plus gentamicin with chloramphenicol in
young children with very severe pneumonia and found
no difference between the two regimens.28 The study
was, however, limited to one country and not powered
to detect less than a 10% difference between treatment
arms.
Given the lack of evidence on regimens other than
chloramphenicol, we carried out a multicentre study to
determine if injectable ampicillin plus gentamicin is
superior to injectable chloramphenicol for the treatment of community acquired very severe pneumonia
in children aged 2-59 months in seven developing
METHODS
Our primary hypothesis was that treatment failure at
five days among children aged 2-59 months with WHO
defined very severe pneumonia was greater for
parenteral chloramphenicol than it was for injectable
ampicillin plus gentamicin. The primary outcome was
treatment failure at five days. Secondary outcomes
were treatment failure defined similarly among all
participants evaluated at 48 hours and at 10 and
21 days.
This randomised, non-blinded efficacy study was
carried out at eight sites in seven countries: Dhaka,
Bangladesh; Guayaquil, Ecuador; Chandigarh, India;
Mexico City, Mexico; Multan and Rawalpindi, Pakistan; Sana’a, Yemen; and Lusaka, Zambia (box 1). A
consensus protocol was developed by investigators
from the study sites, WHO, Johns Hopkins University
Bloomberg School of Public Health, and the Center for
International Health and Development at Boston
University School of Public Health.
Study doctors and study nurses at each site were
trained on the study protocol and WHO case management for acute respiratory tract infections using WHO
training videos and exercises to ensure inter-rater
reliability among the study staff. The clinical investigator at each site oversaw and monitored the study
staff.
Enrolment
Box 2 shows the criteria for study inclusion and
exclusion. We informed families about the purpose
and background of the study, the study procedures,
risks, payments, and confidentiality. They were told
that they could withdraw their child from the study at
any time and that he or she would continue to receive
standard medical care provided to children with
similar illness in the participating hospital. They were
told that during admission to hospital their child would
be assessed every six hours or more often if needed, for
any change in their condition until there was an
improvement in breathing difficulty and satisfactory
oxygen levels when breathing room air. They were told
about the need for follow-up and when and where to
Table 1 | Enrolment by study site
Site
Dates of study accrual
183 (19.1)
Aug 2000 to Apr 2004
Dhaka, Bangladesh
203 (21.2)
Sep 2000 to Nov 2003
Guayaquil, Ecuador
46 (4.8)
Apr 2003 to Mar 2004
Lusaka, Zambia
23 (2.4)
Apr 2001 to Nov 2001
40 (4.2)
Sep 2000 to Nov 2003
Mexico City, Mexico
page 2 of 13
No (%) of children enrolled
Chandigarh, India
Multan, Pakistan
154 (16.1)
Oct 2000 to Jun 2003
Rawalpindi, Pakistan
156 (16.3)
Dec 2000 to Mar 2004
Sana’a, Yemen
153 (16.0)
Nov 2000 to Apr 2004
Total
958 (100)
Aug 2000 to Apr 2004
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countries. We chose ampicillin because of its greater
activity against H influenzae and some Gram negative
enteric bacilli, such as E coli and P mirabilis.
Box 1: Study sites
RESEARCH
Inclusion criteria
Age 2 to 59 months
History of cough or difficulty breathing, or both
WHO defined very severe pneumonia30
Central cyanosis or inability to drink
Caregiver willingness to consent
Exclusion criteria
Wheezing, with a history of three or more attacks, or
known asthma
Known heart disease
Duration of present illness more than 10 days
History of serious adverse reaction to any of the study
drugs
Previous enrolment in the study
Admission to hospital for more than 24 hours within past
seven days
Documented evidence of injectable antibiotic treatment
for more than 24 hours before enrolment
Stridor
Known renal failure or not passed urine during past six
hours
Evidence of cerebral malaria
Evidence of bacterial meningitis
Clinical jaundice
Residence of patient in an area where follow-up was not
possible
Empyema or presence of pneumatocoeles on chest
radiograph
bring the child back to the hospital after discharge to see
if they were still infected.
Randomisation
WHO prepared lists for randomisation using permuted blocks of variable length (6-8-10), with block
sizes presented in random order. Separate randomisation lists were prepared for each site according to
nutrition status of the children (severely malnourished,
defined by WHO as oedema or severe wasting=weight
for height <70% (−3 z score) or severe stunting=height
for age <85% (−3 z score) versus not severely
malnourished, as assessed during the baseline examination), and individual patient assignments were
placed in opaque sealed envelopes. After each patient
was selected for study, the next envelope in order of
study numbers (that is, in numerical sequence) was
opened to determine the treatment assignment: thus
the investigator could not know the order of randomisation and was unable to predict the next assignment.
Before opening each envelope the doctor in charge
signed and dated the opening flap of the envelope. The
card inside, with the patient’s treatment assignment,
and the signed envelope were attached to the patient’s
study file. To prevent tampering with the
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randomisation process, envelopes were checked to
ensure that the assignment could not be seen before the
envelope was opened. During site visits the presence of
the signature, date, and time notification was evaluated
and compared with the date and time of randomisation
recorded in the medical record.
Baseline assessment
When children were admitted to the hospital we took a
standardised baseline history and carried out a physical
examination, laboratory evaluations, and chest radiography. Blood was obtained by venepuncture for
complete blood count, malaria smear, blood glucose
levels, and bacterial culture. Lumbar puncture was
done on participants with clinical signs suggestive of
bacterial meningitis, and we examined cerebrospinal
fluid for total leucocyte count, differential leucocyte
count, biochemistry, and bacterial culture by Gram
stain.
Case management protocol
Children received the first dose of antibiotics within
two hours of enrolment. Those randomised to the
ampicillin plus gentamicin arm received ampicillin
200 mg/kg/d in four doses every six hours, and
gentamicin 7.5 mg/kg/d as in a single daily dose.
Children randomised to the chloramphenicol arm
received 75 mg/kg/d given in three doses every eight
hours. Study drugs were procured for all sites from the
International Dispensary Association, Amsterdam,
Holland. Oxygen was delivered at a rate of 1-2 l/min
by nasal cannula for children with oxygen saturations
less than or equal to 90% (or ≤88% in the two high
altitude sites of Yemen and Mexico) and continued for
a minimum of three hours. Study doctors assessed the
children every six hours using a standardised form,
which included vital signs; cardiorespiratory examination; use of oxygen, salbutamol, or antipyretics; and
pulse oximetry. If the doctors detected a treatment
failure or if they thought that for any reason a change in
management was indicated, this was reviewed with the
site clinical investigator before a decision was made. An
evaluation form was completed at 48-60 hours after
randomisation and again at 5-6 days after randomisation, recording any treatment failures that had occurred
to these points.
Once children had completed five days of inpatient
care and were improved enough for discharge they
received ampicillin plus gentamicin daily as an outpatient. The parenteral gentamicin was given once
daily at the outpatient clinic or other sites. Sufficient
oral amoxicillin (45 mg/kg/d divided into three doses)
was provided to complete the remainder of the 10 day
course. Likewise, children in the oral chloramphenicol
arm were also given sufficient drugs (75 mg/kg/d in
three doses) to complete a 10 day course of treatment.
The primary caregiver gave the children their oral
antibiotics. Adherence to these regimens was assessed
by pill counts and return of empty drug vials at followup visits.
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Box 2: Inclusion and exclusion criteria
RESEARCH
Study outcomes
Box 3 provides the definitions of primary and
secondary outcomes. Children met the primary outcome of treatment failure after five days of admission if
any of the events in the box occurred at any point after
randomisation. Any change in antibiotic treatment
during this period resulted in classification as treatment
failure and the need to change the regimen was assessed
clinically and throughout the entire five day period, not
just at the end of five days of treatment. The study
protocol did not permit modifications of the antibiotic
regimen. We used the same definitions and approach
for the secondary outcomes of treatment failure as
defined in box 3 by 48 hours (allowing data to be
collected up to 60 hours) and treatment failure plus
relapse (hypoxaemic pneumonia) by day 10 (allowing
data to be collected up to day 12) and by day 30
(allowing data to be collected between study days 2130).
When the study physician suspected treatment
failure (see box 3), the physician contacted the principal
investigator or coinvestigator for confirmation. At that
time the antibiotic was changed and other appropriate
treatment provided. Additional chest radiographs,
blood counts, blood cultures, and other laboratory
tests to aid patient management according to clinical
judgment and the usual practices of the participating
site were obtained. Broad guidelines for the management of children who failed study treatment were:
Box 3: Primary and secondary outcome measures
Primary outcome: treatment failure by five days after admission
New development or persistence of at least two of the following: inability to drink;
tachypnoea (≥50 breaths/min in children aged 2-11 months and ≥40 breaths/min in
children aged 12-59 months), and abnormally sleepy or difficult to wake
Development or diagnosis of any of the following: bacterial meningitis, empyema, septic
shock, renal failure, or newly diagnosed comorbid conditions
Children randomised (n=958)
Allocated to injectable
ampicillin plus gentamicin
All analysed (n=479)
Failed treatment (n=32)
Lost to follow-up (n=0)
Improved (n=447)
Cured (n=407)
Improved (n=402)
Failed treatment (n=8)
Lost to follow-up (n=1)
At 10 to 12
days’
assessment
Failed treatment (n=7)
Lost to follow-up (n=3)
Improved (n=425)
Failed treatment (n=22)
Lost to follow-up (n=1)
At 5 to 6
days’
assessment
Failed treatment (n=9)
Lost to follow-up (n=2)
Cured (n=417)
Failed treatment (n=52)
Lost to follow-up (n=2)
At 48 to 60
hours’
assessment
Failed treatment (n=19)
Lost to follow-up (n=0)
Improved (n=428)
Allocated to
chloramphenicol
All analysed (n=479)
Cured (n=393)
Failed treatment (n=10)
Lost to follow-up (n=1)
At 21 to 30
days’
assessment
Cured (n=382)
Fig 1 Trial profile
Staphylococcal pneumonia —Cloxacillin or oxacillin
(25-50 mg/kg intravenously every six hours) were
added to the regimen. The duration of treatment to be
at least two weeks. Empyema was managed with chest
tube drainage.
Pneumocystis carinii (now Pneumocystis jiroveci)
pneumonia —Cotrimoxazole (with trimethoprim
20 mg/kg/d in two divided doses) and steroids were
added to the treatment regimen. The duration of
treatment was for at least two weeks.
Non-responsive Gram negative infection —If infection
with Gram negative bacilli unresponsive to the study
regimen was suspected on the basis of clinical
deterioration or development of shock, a third generation cephalosporin such as cefotaxime (100-200 mg/
kg/d in four divided doses) or ceftriaxone (100150 mg/kg/d in a single dose) was used. Ceftriaxone
was provided by the study.
Serious adverse drug reaction
Modification of antibiotic treatment
Voluntary withdrawal or absconding
Death
Secondary outcomes
Treatment failure as defined above at 48-60 hours
Treatment failure as defined above plus relapse (hypoxaemic pneumonia at 10-12 days and
21-30 days, with oxygen saturations ≤90%, or ≤88% in the two high altitude sites in Mexico
and Yemen)
Death by 30 days after enrolment
Bacterial pathogens isolated from blood or other sterile sites
Antimicrobial susceptibility of the isolated pathogens
page 4 of 13
Mechanical ventilation —Mechanical ventilation was
provided, when available, to patients with treatment
failure and persistent cyanosis while receiving supplemental oxygen.
Laboratory methods
Standard microbiological techniques31 were used to
isolate and identify S pneumoniae and H influenzae. The
minimum inhibitory concentration of ampicillin,
gentamicin, and chloramphenicol for both H influenzae
and S pneumoniae was determined by E test according to
the manufacturer’s instructions (AB Biodisk, Solna,
Sweden).
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Follow-up evaluation was at 10-12 days and
21-30 days after discharge. The children were discharged from the study at the completion of the
21-30 day visit and no further information was
collected. If children failed to attend for follow-up
study staff attempted to assess them at home.
Ampicillin plus gentamicin
0.95
Chloramphenicol
0.90
0.85
0.80
0.75
4
67
2
72
0
62
0
52
8
57
6
2
48
43
6
4
33
38
0
8
28
2
24
19
96
14
4
0
0.70
48
Statistical analysis
The sample size of 1182 participants was based on
finding a 30% or greater reduction in treatment failure
with ampicillin plus gentamicin compared with an
expected 25% baseline failure rate with
chloramphenicol,27 32-35 a 1:1 allocation ratio, 80%
power, an α level of 0.05, and two planned interim
analyses for early stopping with O’Brien-Fleming end
points.36 37
We analysed the data using SAS software. PROC
FREQ was used to calculate relative risks and 95%
confidence intervals. To identify risk factors predictive
of treatment failure by day 5 and death by day 30, we
1.00
Time to treatment failure (hours)
Fig 2 Time to treatment failure
selected a group of factors—immunisation status, sex,
hypoxaemia (oxygen saturation ≤90%, or ≤88% in the
two high altitude sites in Mexico and Yemen), blood
glucose, central cyanosis, age, weight for age z score,
and breastfeeding status—and we calculated relative
risks. We then included all variables with statistically
Table 2 | Baseline comparison between children aged 2-59 months with very severe pneumonia allocated to receive
chloramphenicol or ampicillin plus gentamicin. Values are numbers (percentages) of children unless stated otherwise
Characteristic
Boys
Mean (SD) age (months)
Breastfeeding*
Chloramphenicol arm (n=479)
Ampicillin plus gentamicin arm (n=479)
285/479 (59)
303/479 (63)
7.9 (8.03)
8.0 (8.13)
381/455 (84)
367/450 (82)
Immunisation status up to date
321/470 (68)
324/469 (69)
Antibiotic use in previous 24 hours
154/477 (32)
167/473 (35)
Weight for age less than –3 z score
59/478 (12)
67/477 (14)
Median (interquartile range) temperature (°C)
37.5 (37-38)
37.5 (37-38)
Median (interquartile range) heart rate (bpm)
160.0 (146-172)
160.0 (144-177)
90.0 (84-100)
90.0 (82-100)
Fast†
219/479 (46)
218/479 (46)
Very fast‡
251/479 (52)
243/479 (51)
Median (interquartile range) oxygen saturation
88.0 (80-91)
88.0 (80-92)
Abnormally sleepy
93/479 (19)
74/479 (15)
Median (interquartile range) systolic blood
pressure (mm Hg)
Breathing rate:
Convulsions
7/479 (1)
4/479 (1)
Central cyanosis
123/479 (26)
119/479 (25)
Dehydration
58/479 (12)
57/479 (12)
Signs of shock
16/477 (3)
16/478 (3)
447/476 (94)
446/474 (94)
Lower chest indrawing
Haemoglobin level (g/l):
<60
60-90
Median (interquartile range) total leucocyte count
4/479 (1)
5/479 (1)
104/479 (22)
112/479 (23)
12 000 (9000-15 575)
12 000 (8900-16 000)
265/423 (63)
272/429 (63)
Blood glucose level (mmol/l):
<3.3
3.3-4.4
≥4.5
Positive for respiratory syncytial virus§
28/423 (7)
32/429 (7)
130/423 (31)
125/429 (29)
25/365 (7)
22/359 (6)
No patient had malaria.
*Number of children aged less than 24 months.
†Respiratory rate ≥50 breaths per minute for children aged 2-11 months and ≥40 but <70 breaths per minute for children aged 2-59 months.
‡Respiratory rate ≥70 breaths per minute.
§Number of children who had nasopharyngeal aspirates taken.
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Data management procedures
Data were double entered and validated locally with
CENTRY software (US Census Bureau, Washington,
DC). We sent original copies of the data to the Data
Coordinating Center at Boston University, where the
electronic data were cleaned and discrepancies
resolved.
Survival distribution function
RESEARCH
RESEARCH
RESULTS
Enrolment of children occurred between August 2000
and April 2004. The data safety monitoring board
ended accrual at the Zambia site after 23 enrolments
(2.4% of total) in November 2001 because of high
mortality; this was possibly due to HIV/AIDS. The
Ecuador site was added in March 2003 to augment
enrolment. A total of 958 children aged 2-59 months
with very severe pneumonia were randomised:
479 to ampicillin plus gentamicin and 479 to
chloramphenicol (fig 1). Enrolment was discontinued
before full study accrual owing to funding limitations,
which prevented the extension of activities through
another season of acute respiratory tract infections.
Table 1 shows the number of children included from
each study site, and table 2 shows their baseline
characteristics. No statistically significant differences
in the baseline characteristics were seen between the
two treatment groups. All randomised children were
included in the intention to treat analysis for the
primary outcome of treatment failure at five days.
Overall compliance with treatment was 95%: 94.4% of
children in the chloramphenicol group and 96.2% in
the ampicillin plus gentamicin group.
Primary outcome: treatment failure at five days
Of the total 131 (13.6%) children who failed treatment
by day 5, the cumulative rate was higher among those
assigned to the chloramphenicol group (relative risk
1.43, 95% confidence interval 1.03 to 1.97; table 3).
Numerous children had more than one reason for
failure but only one was chosen for the study; either the
first condition to appear or the most severe if two or
Table 3 | Cumulative treatment failures by specific causes at 5, 10, and 21 days and treatment arms for children aged 2-59 months with very severe pneumonia.
Values are numbers (percentages) of children unless stated otherwise
Cumulative treatment failure at 5 days
Chloramphenicol arm
(n=479)
Ampicillin
plus
gentamicin
arm (n=479)
Total
77 (16)
Persistence or worsening of
very severe pneumonia
Cumulative treatment failure at 10 days
Relative
risk (95%
CI)
Chloramphenicol arm
(n=479)
Ampicillin
plus
gentamicin
arm (n=479)
54 (11)
1.43 (1.03
to 1.97)
92 (19)
14 (3)
17 (4)
0.82 (0.41
to 1.65)
Death
15 (3)
9 (2)
Voluntary withdrawal
3 (1)
Antibiotic changed
Cumulative treatment failure at 21 days
Relative
risk (95%
CI)
Chloramphenicol arm
(n=479)
Ampicillin
plus
gentamicin
arm (n=479)
67 (14)
1.37 (1.03
to 1.83)
103 (22)
77 (16)
1.34 (1.02
to 1.75)
15 (3)
19 (4)
0.79 (0.41
to 1.54)
17 (4)
20 (4)
0.85 (0.45
to 1.60)
1.67 (0.74
to 3.77)
15 (3)
9 (2)
1.67 (0.74
to 3.77)
15 (3)
9 (2)
1.67 (0.74
to 3.77)
2 (0)
1.50 (0.25
to 8.94)
5 (1)
4 (1)
1.25 (0.34
to 4.63)
7 (1)
7 (1)
1.00 (0.35
to 2.83)
45 (9)
26 (5)
1.73 (1.09
to 2.76)
57 (12)
35 (7)
1.63 (1.09
to 2.43)
64 (13)
41 (9)
1.56 (1.08
to 2.26)
Persistence of one
danger sign
18 (4)
9 (2)
2.00 (0.91
to 4.41)
18 (4)
9 (2)
2.00 (0.91
to 4.41)
18 (4)
9 (2)
2.00 (0.91
to 4.41)
Bacterial
meningitis
3 (1)
2 (0)
1.50 (0.25
to 8.94)
3 (1)
2 (0)
1.50 (0.25
to 8.94)
3 (1)
3 (1)
1.00 (0.20
to 4.93)
Empyema
3 (1)
2 (0)
1.50 (0.25
to 8.94)
4 (1)
3 (1)
1.33 (0.30
to 5.93)
4 (1)
3 (1)
1.33 (0.30
to 5.93)
Septic shock
14 (3)
9 (2)
1.56 (0.68
to 3.56)
14 (3)
9 (2)
1.56 (0.68
to 3.56)
15 (3)
10 (2)
1.50 (0.68
to 3.31)
Outcome
Relative
risk (95%
CI)
Reason for changing antibiotic:
*
Renal failure
3 (1)
0 (0)
—
3 (1)
0 (0)
—
3 (1)
0 (0)
—
Serious adverse
drug reaction
1 (0)
0 (0)
—
1 (0)
0 (0)
—
1 (0)
0 (0)
—
New comorbid
condition
8 (2)
5 (1)
1.60 (0.53
to 4.86)
8 (2)
7 (1)
1.14 (0.42
to 3.13)
11 (2)
7 (1)
1.57 (0.61
to 4.02)
Oxygen saturation
<90% on room air
NA
NA
NA
7 (1)
5 (1)
1.40 (0.45
to 4.38)
13 (3)
9 (2)
1.44 (0.62
to 3.35)
Doctor’s decision
6 (1)
5 (1)
1.20 (0.37
to 3.91)
14 (3)
10 (2)
1.40 (0.63
to 3.12)
14 (3)
10 (2)
1.40 (0.63
to 3.12)
*Participants could have only one reason for failure (persistence or worsening of severe pneumonia, voluntary withdrawal, death, or change of antibiotic). Participants could have more than
one reason for change of antibiotic.
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significant relative risks in a multivariate logistic
regression model built using a backward elimination
procedure with PROC LOGISTIC. Treatment group
and study site were forced into the model and we
retained all variables with a Wald P value of 0.20 or less.
We used the GLIMMIX macro to calculate the final
multivariate models, in which study site was included
as a random effect. Because diagnostics are not
available for the random effects model we report
model diagnostics (area under the receiver operating
curve characteristic and Hosmer and Lemeshow
goodness of fit test) for a fixed effects model.
RESEARCH
Univariate analysis
Failed treatment by day 5
Relative risk (95% CI)
Deaths by day 30
Relative risk (95% CI)
Immunisation status:
Up to date
54/294 (18)
Not up to date
75/645 (12)
28/294 (10)
1.58 (1.15 to 2.18)
36/645 (6)
1.71 (1.06 to 2.74)
Sex:
Girls
61/370 (16)
Boys
70/588 (12)
37/370 (10)
1.38 (1.01 to 1.90)
28/588 (5)
2.10 (1.31 to 3.37)
Hypoxaemia at baseline:
Yes
102/619 (16)
No
29/339 (9)
53/619 (9)
1.93 (1.30 to 2.85)
12/339 (4)
2.42 (1.31 to 4.46)
Blood glucose level <3.3 mmol/l:
Yes
69/537 (13)
No
46/315 (15)
32/537 (6)
0.88 (0.61 to 1.24)
23/315 (7)
0.82 (0.49 to 1.37)
Central cyanosis:
Yes
39/242 (16)
No
92/716 (13)
22/242 (9)
1.25 (0.89 to 1.77)
43/716 (6)
1.51 (0.92 to 2.48)
Age (months):
2-5
73/506 (14)
6-59
58/452 (13)
37/506 (7)
1.12 (0.82 to 1.55)
28/452 (6)
1.18 (0.73 to 1.90)
Weight for age z score less than −3:
Yes
19/126 (15)
No
112/829 (14)
11/126 (9)
1.12 (0.71 to 1.75)
54/829 (7)
1.34 (0.72 to 2.49)
Breastfed:
Yes
105/748 (14)
No
21/157 (13)
48/748 (6)
1.05 (0.68 to 1.62)
13/157 (8)
0.77 (0.43 to 1.40)
Exclusively breastfed:
Yes
38/261 (15)
No
34/238 (14)
17/261 (7)
1.02 (0.66 to 1.56)
19/238 (8)
0.82 (0.43 to 1.53)
Received chloramphenicol:
Yes
77/479 (16)
No
54/479 (11)
40/479 (8)
1.43 (1.03 to 1.97)
more were reported simultaneously. Treatment failure
at day 5 most commonly occurred as a result of a
change in antibiotic treatment (n=71) for several
reasons, including a diagnosis of septic shock (n=23),
bacterial meningitis (n=5), empyema (n=5), or other
comorbid conditions. Persistence or worsening of very
severe pneumonia (n=31) accounted for the second
most common cause of failure followed by death
(n=24) and the persistence of danger signs (n=27). With
the exception of persistence of very severe pneumonia,
25/479 (5)
1.60 (0.99 to 2.59)
all of these individual outcomes occurred more
commonly in the chloramphenicol group but only
change in antibiotic treatment approached statistical
significance.
Several factors were associated with treatment failure
on univariate analysis: poor immunisation status, being
female, baseline hypoxaemia, and receiving chloramphenicol (table 4). By multivariate analysis predictors
of treatment failure were hypoxaemia, poor immunisation status, and being female (table 5).
Table 5 | Multivariate of risk factors predictive of treatment failure by day 5 and deaths by day 30 in children aged 2-59 months with very severe pneumonia
Multivariate analysis
Adjusted odds ratio (95% CI)*
Adjusted odds ratio (95% CI)†
Immunisations not up to date
1.71 (1.15 to 2.55)
1.77 (1.00 to 3.15)
Girls
1.34 (0.91 to 1.97)
1.95 (1.11 to 3.43)
Hypoxaemia
2.99 (1.86 to 4.80)
4.7 (2.29 to 9.67)
—
1.48 (0.69 to 3.19)
1.44 (0.98 to 2.11)
1.62 (0.91 to 2.86)
Weight for age z score less than −3
Received chloramphenicol
*Fixed effects model diagnostics: area under receiver operating curve 0.72, Hosmer and Lemesho goodness of fit test P=0.34, deviance P=0.15.
†Fixed effects model diagnostics: area under receiver operating curve 0.69, Hosmer and Lemesho goodness of fit test P=0.74, deviance P=0.65.
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Table 4 | Univariate analysis of risk factors predictive of treatment failure at day 5 and deaths by day 30 in children aged 2-59 months with very severe pneumonia.
Values are numbers (percentages) of children unless stated otherwise
RESEARCH
Deaths
Of the 65 deaths, 24 occurred in children after
treatment failure had already been declared for other
reasons. In 46 cases (74%) the child died within 48
hours of enrolment, indicating the rapidly progressive
or advanced nature of the illness. By univariate analysis
poor immunisation status, being female, and hypoxaemia at presentation were associated with mortality,
and by multivariate analysis these factors independently predicted mortality (table 4).
Microbiology
Baseline bacteriological investigations were done on
471 children in the chloramphenicol group and 474 in
the ampicillin plus gentamicin group. Of the cultures
undertaken at enrolment (958 blood aspirates, 24
cerebrospinal fluid aspirates, and five lung aspirates),
112 (two children had two organisms isolated) gave
positive results for pathogenic organisms in all but one
aspirate, from the blood (table 6). The two most
common organisms isolated were Staphylococcus aureus
(n=47) and Streptococcus pneumoniae (n=22), followed
less commonly by Haemophilus influenzae (n=8), Escherichia coli (n=6), and Pseudomonas aeruginosa (n=6; table 6).
On antibiotic sensitivity testing most of the
S pneumoniae organisms were susceptible to chloramphenicol (13/14) or ampicillin (15/16), and all were
susceptible to third generation cephalosporins. By
contrast, only half (19/37) of the S aureus isolates
exhibited in vitro susceptibility to chloramphenicol
and 42% (16/38) to ampicillin.
Treatment failure in the presence of bacteraemia
Treatment failure at 21 days was significantly more
likely if bacteraemia with any pathogenic organism was
present at enrolment (table 7). The size of the effect and
the degree of statistical significance for treatment
failure at 21 days and death increased in the presence
of S pneumoniae bacteraemia, however, but was not
associated with bacteraemia due to S aureus, irrespective of treatment group.
In a subgroup analysis of children with bacteraemia
stratified by treatment group (tables 8 and 9),
chloramphenicol was associated with a higher risk of
treatment failure at 5, 10, and 21 days. No increased
risk of treatment failure was, however, found among
those children with bacteraemia in the ampicillin plus
gentamicin group. The excess risk in the chloramphenicol group occurred in children with S pneumoniae
bacteraemia. In this group, treatment failure was three
Table 6 | Bacterial and antibiotic sensitivities from blood culture and lung aspirate isolates of children aged 2-59 months with very severe pneumonia
Not susceptible to antibiotic*/No tested
No of positive isolates
No of positive cultures
from blood or
cerebrospinal fluid
Chloramphenicol
Gentamicin
Ampicillin
Third generation
cephalosporin
Streptococcus pneumoniae
22
21†
13/14
12/17
15/16
12/12
Haemophilus influenzae
8
8
6/7
5/5
6/7
6/6
Staphylococcus aureus
47
45‡
19/37
29/45
16/38
10/40
Klebsiella pneumoniae
3
3
1/1
2/2
1/2
1/1
Escherichia coli
6
6
1/2
3/4
1/4
4/4
Salmonella spp
5
5
5/5
5/5
5/5
4/4
Enterobacter aerogenes
1
1
1/1
0/1
0/0
1/1
Pseudomonas aeruginosa
6
5‡
1/2
3/3
0/2
0/3
Acinetobacter spp
5
5
2/4
2/4
1/4
0/2
Morganella spp
1
1
1/1
1/1
0/1
0/1
Moraxella spp
1
1
1/1
1/1
1/1
0/0
Flavobacterium
meningosepticum
1
1
0/1
0/0
0/1
0/0
Bacteria
Pseudomonas spp
2
2
2/2
2/2
0/2
0/2
Streptococcus spp
3
3
0/2
2/2
2/2
0/0
Gram negative bacillus
(undetermined)
1
1
0/0
0/0
0/0
0/0
*Sensitivity according to manufacturer’s guidelines (AB Biodisk, Solna, Sweden).
†One case of S pneumoniae isolated from cerebrospinal fluid.
‡One pleural fluid sample also positive.
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Secondary outcomes: treatment failure at 48 hours and
10 and 21 days
By 48 hours after randomisation 87 (9.1%) children had
failed treatment, consisting of 48% of the total
cumulative number of treatment failures. At this early
time point an excess of children failed treatment in the
chloramphenicol group (n=54) compared with the
ampicillin plus gentamicin group (n=33; relative risk
1.6, 95% confidence interval 1.1 to 2.5). Similarly, with
the exception of persistence of very severe pneumonia,
the cumulative total number of children who failed
treatment through days 10 and 21 remained higher in
the chloramphenicol group, and the distribution of
reasons for this remained similar to those observed at
day 5 (table 3). Figure 2 also shows the time to treatment
failure (log rank test P=0.024).
RESEARCH
Variable
Treatment failures in children with
bacteraemia
Treatment failures in children
without bacteraemia
n=110
n=848
Relative risk (95% CI)
Any bacteraemia
Follow-up:
48 hours
8 (7)
78 (9)
5 days
21 (19)
107 (13)
1.51 (0.99 to 2.31)
10 days
23 (21)
125 (15)
1.42 (0.95 to 2.11)
21 days
30 (27)
139 (16)
1.66 (1.18 to 2.34)
11 (10)
54 (6)
1.57 (0.85 to 2.91)
n=47
n=911
Death
0.79 (0.39 to 1.59)
Staphylococcusaureus bacteraemia (n=
=47)
Follow-up:
48 hours
0
86 (9)
5 days
6 (13)
122 (13)
0.95 (0.44 to 2.05)
10 days
6 (13)
142 (16)
0.82 (0.38 to 1.76)
21 days
9 (19)
160 (18)
1.10 (0.60 to 1.99)
0
65 (7)
—
n=21
n=937
Death
Streptococcus pneumoniae bacteraemia
Follow-up:
48 hours
3 (14)
83 (9)
1.61 (0.55 to 4.69)
5 days
5 (24)
123 (13)
1.81 (0.83 to 3.97)
10 days
5 (24)
143 (15)
1.56 (0.72 to 3.40)
21 days
8 (38)
161 (17)
2.22 (1.26 to 3.89)
5 (24)
60 (6)
3.72 (1.67 to 8.30)
Death
to four times more likely at any of the study end points,
and death was nearly six times more likely. By
comparison, bacteraemia due to S aureus or S
pneumoniae was not associated with higher treatment
failure or death in the ampicillin plus gentamicin
group.
DISCUSSION
In our randomised controlled trial of injectable
chloramphenicol compared with injectable ampicillin
plus gentamicin for the treatment of very severe
pneumonia in children aged 2-59 months, children
who received chloramphenicol were more likely to
experience treatment failure than those who received
ampicillin plus gentamicin. A trend to higher treatment
failure in the chloramphenicol group was evident after
24 hours of treatment (fig 2). Of particular concern are
the adverse outcomes of treatment failure and death
when children develop bacteraemia due to Streptococcus
pneumoniae. Although the most common isolate from
sterile sites was Staphylococcus aureus, optimally treated
with a penicillinase resistant antibiotic such as cloxacillin, our findings indicate that very severe pneumonia due to this organism may be adequately treated with
chloramphenicol or ampicillin plus gentamicin (gentamicin does have activity against S aureus). The high rate
of S aureus found in blood was unexpected. It might
have been a contaminant in some cases although we did
provide training in an aseptic technique for obtaining
blood cultures and this procedure was evaluated by the
study monitors during site visits.
The clear benefit we observed among children
receiving ampicillin plus gentamicin in the presence
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of confirmed S pneumoniae bacteraemia occurred
despite a high degree of in vitro antimicrobial
susceptibility to both chloramphenicol and ampicillin.
Only half of the S pneumoniae isolates were tested for
antimicrobial sensitivity to the study drug, however,
and it is possible, although unlikely, that a high degree
of resistance to chloramphenicol among the untested
isolates accounts for our findings. Alternatively, this
might constitute further evidence that in vitro antimicrobial susceptibility testing may not correlate
closely with clinical outcome of bacterial
pneumonia.18-21
In addition to being one of the commonest causes of
childhood pneumonia, S pneumoniae is also one of the
more common causes of meningitis—often occurring
concurrently with pneumonia.38-40 It is possible that
some children in this study who presented with very
severe pneumonia due to S pneumoniae also had
meningitis. Although no child with suspected meningitis was admitted to this study, in a previous trial of
very severe pneumonia, 13% of a similar group of
children in Papua New Guinea had meningitis during
the course of illness.28 In our study the bacteriostatic
properties of chloramphenicol might have been
insufficient to kill S pneumoniae organisms in the central
nervous system, thus accounting for the higher failure
and death rate in this group.40 Likewise, the bacteriostatic properties of chloramphenicol might have been
insufficient to eradicate advanced infection of the lungs
with S pneumoniae in children with very severe
pneumonia.
Our rate of adverse treatment outcome is consistent
with the findings reported in a trial of benzylpenicillin
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Table 7 | Association between bacteraemia and clinical failure in children aged 2-59 months treated for very severe pneumonia.
Values are numbers (percentages) unless stated otherwise
RESEARCH
health status behaviours, as evidenced by many deaths
occurring within 48 hours of the children’s presentation to hospital. Being female was independently
associated with higher treatment failure and death,
which is similar to other studies of overall mortality41
and severity of acute lower respiratory tract infections
and mortality.42 43 Hypoxaemia at presentation was
strongly associated with failure, as has been observed in
other settings.28 44-47 The multivariate models adequately fit the study data and had reasonable discriminatory power.
Strengths and limitations of the study
The strengths of this study are its randomised
controlled design using a standardised protocol that
was applied across different paediatric populations in
seven low income countries. In addition, the microbiological data increase our understanding of the
bacteria associated with WHO defined very severe
pneumonia in these settings and permit us to determine
the treatment failure and death rates by specific
organism isolated. Also, the low losses to follow-up in
both groups (<1%) strengthen confidence in the
outcomes and minimise classification error associated
with an intention to treat analysis.
Limitations of the study are its non-blinded study
design, which may have introduced bias by study
doctors’ determination of treatment failure, particularly for the specific outcome of change in antibiotic. It
was considered unethical to give placebo injections to
tackle differences in inpatient antibiotic schedules,
however, and it was not possible to adequately blind
Table 8 | Association between bacteraemia and clinical failure in children aged 2-59 months receiving chloramphenicol for very
severe pneumonia
Variable
Treatment failures in children with
bacteraemia
Treatment failures in children
without bacteraemia
Relative risk (95% CI)
Any bacteraemia
Follow-up:
n=56
n=423
48 hours
6 (11)
48 (11)
0.94 (0.42 to 2.10)
5 days
14 (25)
63 (15)
1.68 (1.01 to 2.79)
10 days
16 (29)
70 (17)
1.73 (1.08 to 2.75)
21 days
21 (38)
76 (18)
2.09 (1.41 to 3.10)
7 (13)
33 (8)
1.60 (0.74 to 3.45)
Death
Staphylococcus aureus bacteraemia
Follow-up:
n=26
n=453
0
54 (12)
5 days
4 (15)
73 (16)
0.95 (0.38 to 2.41)
10 days
4 (15)
82 (18)
0.85 (0.34 to 2.14)
21 days
6 (23)
91 (20)
1.15 (0.56 to 2.37)
0
40 (9)
—
48 hours
Death
Streptococcus pneumoniae bacteraemia
Follow-up:
n=9
n=470
48 hours
3 (33)
51 (11)
3.07 (1.18 to 8.02)
5 days
5 (57)
72 (15)
3.63 (1.95 to 6.75)
10 days
5 (57)
81 (17)
3.22 (1.74 to 5.97)
21 days
7 (78)
90 (19)
4.06 (2.73 to 6.03)
4 (44)
36 (8)
5.80 (2.62 to 12.85)
Death
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plus gentamicin.28 The relative risk for an adverse
outcome in that study was 1.14 (95% confidence
interval 0.97 to1.47), which falls within the 95%
confidence limits of our study’s results; however, we
show a larger and statistically significant effect size,
with a 43% relative improvement in treatment failure at
five days and a greater than twofold better outcome
among children with confirmed bacteraemia due to S
pneumoniae at enrolment. Moreover, the bacteriological data reported in the benzylpenicillin plus gentamicin trial were obtained only once children failed initial
treatment (to guide change in treatment), whereas our
microbiological samples were obtained at baseline,
before study treatment had begun. The investigators
and members of the data safety monitoring board
reviewed the benzylpenicillin plus gentamicin paper
after its publication and concluded that it was ethical to
continue with our study to tackle some of the
limitations of that study. Superiority of ampicillin
plus gentamicin was shown until analysis of the final
dataset.
Several baseline factors predicted treatment failure
on multivariate analysis: poor immunisation status,
being female, hypoxaemia, and receiving chloramphenicol. Neither the newer conjugate pneumococcal
vaccine nor the older polysaccharide vaccine was
routinely used at any of the study sites and could not
account for this factor being associated with increased
treatment failure. It is more likely that not being up to
day with immunisations was a proxy for poor health
seeking behaviour, which might have contributed to
delay in the onset of seeking care or other non-specific
RESEARCH
Variable
Treatment failures in children with
bacteraemia
Treatment failures in children
without bacteraemia
n=54
n=425
Relative risk (95% CI)
Any bacteraemia
Follow-up:
48 hours
2 (4)
30 (7)
0.52 (0.13 to 2.13)
5 days
7 (13)
44 (10)
1.25 (0.59 to 2.64)
10 days
7 (13)
55 (13)
1.00 (0.48 to 2.09)
21 days
9 (17)
63 (15)
1.12 (0.59 to 2.13)
4 (7)
21 (5)
1.50 (0.53 to 4.20)
n=21
n=458
Death
Staphylococcus aureus bacteraemia
Follow-up:
48 hours
5 days
0
32 (7)
—
2 (6)
49 (11)
0.89 (0.23 to 3.42)
10 days
2 (6)
60 (13)
0.73 (0.19 to 2.77)
21 days
3 (14)
69 (15)
0.95 (0.33 to 2.76)
0
25 (6)
n=12
n=467
Death
Streptococcus pneumoniae bacteraemia
Follow-up:
48 hours
0
32 (7)
—
5 days
0
51 (11)
—
10 days
0
62 (13)
—
21 days
1 (8)
71 (15)
0.55 (0.08 to 3.62)
1 (8)
24 (5)
1.62 (0.24 to 11.02)
Death
extra study doctors at each site to treatment assignment
because of differences in outpatient antibiotic schedules (daily oral amoxicillin plus gentamicin injections
v oral chloramphenicol). We therefore developed
rigorous criteria for treatment failure, and study
monitors who visited each site monitored all treatment
failures to ensure that the study was being done
according to protocol. Misclassification of pneumonia
due to a bacterial cause may have also been present
owing to the non-specific nature of the definition of
very severe pneumonia. Although this would tend to
minimise our power to detect a difference in treatment
groups, we none the less detected a statistically
significant difference between chloramphenicol and
ampicillin plus gentamicin. It should be noted that
these findings have limited applicability in areas of high
HIV prevalence, where the spectrum of causes
for pneumonia is different and includes Pneumocystis
jiroveci,48 49 an organism not covered by either study
WHAT IS ALREADY KNOWN ON THIS TOPIC
Community acquired very severe pneumonia has high
mortality and is caused by a variety of bacterial organisms
Parenteral chloramphenicol is the standard treatment but
has not been rigorously tested
WHAT THIS STUDY ADDS
Streptococcus pneumoniae and Staphylococcus aureus are
the most common causes of very severe pneumonia
Ampicillin plus gentamicin is superior to chloramphenicol,
especially against S pneumoniae
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drug. Finally, we determined whether one of our sites
(Zambia) that was removed from the trial prematurely
because of inadequacy of the treatment regimen in
HIV infected children unduly influenced the study
results. We concluded that it did not as the proportions
of children failing treatment at day 5 were similar after
exclusion of the Zambian site: 70 (15%) failed
treatment with chloramphenicol and 50 (11%) failed
treatment with ampicillin plus gentamicin (relative risk
1.40, 95% confidence interval 1.00 to 1.97) compared
with 16% v 11% (1.43, 1.03 to 1.97) in the entire cohort.
We believe that our study shows clinical superiority
of injectable ampicillin plus gentamicin in the treatment of very severe pneumonia in children aged
2-59 months in an urban referral hospital setting, where
all patients with very severe pneumonia are expected to
be treated. These findings have important implications
for updating WHO’s global guidelines for the case
management of pneumonia, which until now have
recommended chloramphenicol as the first line antibiotic treatment for very severe pneumonia.
Contributors:RA, SB, GJB, OF, PH, II, CL, MK-B, WM, MS, S Singhi, DMT, and
SQ conceived and designed the study and developed the protocol. DMT,
SQ, and MS monitored the study. S Saha, Muhammad Ruhul Amin,
Muhammad Hanif, PL, FS, JE, GM, S Singhi, Pallab Ray, Akashdeep, IM-R,
Sandra Villagómez Martínez, II, Jameel ur Rehman Naeem, Ismaeel
Shafeeu, ZK, RA, SB, Abdul Hakeem Bawazeer, Abdul Hakeem Al-Silwi,
and MK-B implemented the study and collected data. SB, JE, PH, PL, WM,
GM, S Saha, S Singhi, DMT, and SQ analysed the data and prepared the
manuscript. PH and WM managed and coordinated the data and carried
out the statistical analysis.
We thank the following from the participating sites: Ruth Flor, Patricia
Parrales, Sebastian Prado, Norma Villamar, Nelson Nieto, and Brenda
Mosquera (Ecuador); Lata Kumar and Shailesh Mehta (India); Patricia
Arzate (Instituto Nacional De Pediatria, Mexico); Maximilliano Gonzalez
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Table 9 | Associationbetweenbacteraemiaandclinicalfailure inchildrenaged2-59monthsreceiving ampicillin plus gentamicinfor
very severe pneumonia
RESEARCH
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
page 12 of 13
Williams BG, Gouws E, Boschi-Pinto C, Bryce J, Dye C. Estimates of
world-wide distribution of child deaths from acute respiratory
infections. Lancet Infect Dis 2002;2:25-32.
Black RE, Morris SS, Bryce J. Where and why are 10 million children
dying every year? Lancet 2003;361:2226-34.
WHO. World health report 2005: make every child count . Geneva:
WHO, 2005.
WHO programme for the control of acute respiratory infections.
Technical basis for the WHO recommendations on the management of
pneumonia in children at first level health facilities . WHO/ARI/91.20.
Geneva: WHO, 1991.
WHO. Management of the child with a serious infection or severe
malnutrition: guidelines for care at the first-referral level in developing
countries . FCH/CAH/00.1. Geneva: WHO, 2000:1-175.
Shann F, Barker J, Poore P. Clinical signs that predict death in children
with severe pneumonia. Pediatr Infect Dis J 1989;8:852-5.
Shann F. Etiology of severe pneumonia in children in developing
countries. Pediatr Infect Dis 1986;5:247-52.
WHO. Technical bases for the WHO recommendations on the
management of pneumonia in children at first level health facilities.
WHO Technical Report 2004;WHO/ARI/91.20.
Duke T, Michael A. Increase in sepsis due to multi-resistant enteric
gram-negative bacilli in Papua New Guinea. Lancet
1999;353:2210-1.
Mastro TD, Ghafoor A, Nomani NK, Ishaq Z, Anwar F, Granoff DM, et al.
Antimicrobial resistance of pneumococci in children with acute lower
respiratory tract infection in Pakistan [see comments]. Lancet
1991;337:156-9.
Ostroff SM, Harrison LH, Khallaf N, Assaad MT, Guirguis NI,
Harrington S, et al. Resistance patterns of Streptococcus pneumoniae
and Haemophilus influenzae isolates recovered in Egypt from
children with pneumonia. The Antimicrobial Resistance Surveillance
Study Group. Clin Infect Dis 1996;23:1069-74.
Steinhoff MC. Invasive Haemophilus influenzae disease in India: a
preliminary report of prospective multihospital surveillance. IBIS
(Invasive Bacterial Infections Surveillance) Group. Pediatr Infect Dis J
1998;17:S172-5.
Likitnukul S. Systemic Haemophilus influenzae disease in Thai
children. Southeast Asian J Trop Med Public Health 1994;25:672-7.
Muhe L, Klugman KP. Pneumococcal and Haemophilus influenzae
meningitis in a children’s hospital in Ethiopia: serotypes and
susceptibility patterns. Trop Med Int Health 1999;4:421-7.
Mastro TD, Nomani NK, Ishaq Z, Ghafoor A, Shaukat NF, Esko E, et al.
Use of nasopharyngeal isolates of Streptococcus pneumoniae and
Haemophilus influenzae from children in Pakistan for surveillance for
antimicrobial resistance. Pediatr Infect Dis J 1993;12:824-30.
Gratten M, Naraqi S, Hansman D. High prevalence of penicillininsensitive pneumococci in Port Moresby, Papua New Guinea. Lancet
1980;2:192-5.
Klugman KP. Bacteriological evidence of antibiotic failure in
pneumococcal lower respiratory tract infections. Eur Respir J Suppl
2002;36:3s-8s.
Straus WL, Qazi SA, Kundi Z, Nomani NK, Schwartz B. Antimicrobial
resistance and clinical effectiveness of co-trimoxazole versus
amoxycillin for pneumonia among children in Pakistan: randomised
controlled trial. Pakistan Co-trimoxazole Study Group. Lancet
1998;352:270-4.
Deeks SL, Palacio R, Ruvinsky R, Kertesz DA, Hortal M, Rossi A, et al.
Risk factors and course of illness among children with invasive
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
penicillin-resistant Streptococcus pneumoniae. The Streptococcus
pneumoniae Working Group. Pediatrics 1999;103:409-13.
Rios AM, de la Hoz F, Leal AL, Castillo O, Castaneda E. [The impact of
antimicrobial resistance and Streptococcus pneumoniae serotype
distribution on the mortality of children under 5 years of age with
invasive disease]. Rev Panam Salud Publica 1999;5:69-76.
Pallares R, Linares J, Vadillo M, Cabellos C, Manresa F, Viladrich PF,
et al. Resistance to penicillin and cephalosporin and mortality from
severe pneumococcal pneumonia in Barcelona, Spain [see
comments] [published erratum appears in N Engl J Med 1995 14
Dec;333:1655]. N Engl J Med 1995;333:474-80.
Qazi SA, Rehman GN, Khan MA. Reduction in acute respiratory
infection hospital mortality with standard ari case management.
Islamabad, Pakistan, Federal ARI Cell, National ARI Control
Programme: The Children Hospital, Institute of Medical Sciences,
1995:1-19.
Sazawal S, Black RE. Effect of pneumonia case management on
mortality in neonates, infants, and preschool children: a metaanalysis of community-based trials. Lancet Infect Dis 2003;3:547-56.
Bahl R, Mishra S, Sharma D, Singhal A, Kumari S. A bacteriological
study in hospitalized children with pneumonia. Ann Trop Paediatr
1995;15:173-7.
Mulholland EK, Falade AG, Corrah PT, Omosigho C, N’Jai P, Giadom B,
et al. A randomized trial of chloramphenicol vs. trimethoprimsulfamethoxazole for the treatment of malnourished children with
community-acquired pneumonia. Pediatr Infect Dis J
1995;14:959-65.
Pepin J, Demers AM, Mberyo-Yaah F, Jaffar S, Blais C, Somse P, et al.
Acute lower respiratory infections among children hospitalized in
Bangui, Central African Republic: toward a new case-management
algorithm. Trans R Soc Trop Med Hyg 2001;95:410-7.
Qazi SA, Rehman GN, Khan MA. Standard management of acute
respiratory infections in a children’s hospital in Pakistan: impact on
antibiotic use and case fatality. Bull World Health Organ
1996;74:501-7.
Duke T, Poka H, Dale F, Michael A, Mgone J, Wal T. Chloramphenicol
versus benzylpenicillin and gentamicin for the treatment of severe
pneumonia in children in Papua New Guinea: a randomised trial.
Lancet 2002;359:474-80.
Bahwere P, Levy J, Hennart P, Donnen P, Lomoyo W,
Dramaix-Wilmet M, et al. Community-acquired bacteremia among
hospitalized children in rural central Africa. Int J Infect Dis
2001;5:180-8.
WHO. Acute respiratory infections in children: case management in
small hospitals in developing countries . WHO/ARI/90.5. Geneva:
WHO, 1990.
Forrest KV, Jorgensen JH, Murray PR. Manual of clinical microbiology .
Washington, DC: American Society for Microbiology 2003.
Shann F, Barker J, Poore P. Chloramphenicol alone versus
chloramphenicol plus penicillin for severe pneumonia in children.
Lancet 1985;2:684-6.
Mishra S, Kumar H, Anand VK, Patwari AK, Sharma D. ARI control
programme: results in hospitalized children. J Trop Pediatr
1993;39:288-92.
Deivanayagam N, Nedunchelian K, Ashok TP, Mala N, Sheela D,
Rathnam SR. Effectiveness of ampicillin and combination of penicillin
and chloramphenicol in the treatment of pneumonias: randomized
controlled trial. Indian Pediatrics 1996;33:813-6.
Sehgal V, Sethi GR, Sachdev HP, Satyanarayana L. Predictors of
mortality in subjects hospitalized with acute lower respiratory tract
infections. Indian Pediatr 1997;34:213-9.
O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials.
Biometrics 1979;35:549-56.
O’Brien PC. Procedures for comparing samples with multiple
endpoints. Biometrics 1984;40:1079-87.
Shann F, Gratten M, Germer S, Linnemann V, Hazlett D, Payne R.
Aetiology of pneumonia in children in Goroka Hospital, Papua New
Guinea. Lancet 1984;2:537-41.
Shann F. Bacterial pneumonia: commoner than perceived. Lancet
2001;357:2070-2.
Friedland IR, Klugman KP. Failure of chloramphenicol therapy in
penicillin-resistant pneumococcal meningitis. Lancet
1992;339:405-8.
Khalique N, Sinha SN, Yunus M, Malik A. Early childhood mortality—a
rural study. J R Soc Health 1993;113:247-9.
Spooner V, Barker J, Tulloch S, Lehmann D, Marshall TF, Kajoi M, et al.
Clinical signs and risk factors associated with pneumonia in children
admitted to Goroka Hospital, Papua New Guinea. J Trop Pediatr
1989;35:295-300.
Tupasi TE, Lucero MG, Magdangal DM, Mangubat NV, Sunico ME,
Torres CU, et al. Etiology of acute lower respiratory tract infection in
children from Alabang, Metro Manila. Rev Infect Dis
1990;12(Suppl 8):S929-39.
Addo-Yobo E, Chisaka N, Hassan M, Hibberd P, Lozano JM, Jeena P,
et al. Oral amoxicillin versus injectable penicillin for severe
BMJ | ONLINE FIRST | bmj.com
BMJ: first published as 10.1136/bmj.39421.435949.BE on 8 January 2008. Downloaded from http://www.bmj.com/ on 15 December 2022 by guest. Protected by copyright.
and Lilliana Martinez (Juarez Hospital, Mexico); Fatum Maktari, Amin MohiEl-din, and Basil Maktari (Yemen). Steering committee: S Saha
(Bangladesh); FS (Ecuador); S Singhi (India); IM-R (Mexico); II (Pakistan);
ZK (Pakistan); SB (Yemen); MK-B (Zambia); SQ (Switzerland); DMT, BM,
and JS (Boston, United States); MS (Baltimore, United States); PH (Boston,
United States). Data safety monitoring board: Ted Colton (Boston
University School of Public Health); Elizabeth Barnett (Boston University
Medical Center); Christopher Duggan (Boston Children’s Hospital and
Harvard School of Public Health).
Funding: Department of Child and Adolescent Health and Development,
WHO; Center of International Health and Development, Boston University;
and Johns Hopkins Bloomberg School of Public Health, Baltimore (USAID
grant No HRN-A-00-96-90010-00).
Competing interests: None declared.
Ethical approval: This study was approved by the institutional ethical
review committees at all study institutions, plus Boston University School
of Public Health, Johns Hopkins University Bloomberg School of Public
Health, and WHO. A data safety monitoring board reviewed cumulative
data once a year. O’Brien Fleming stopping rules were used twice to
determine the safety and utility of continuing the study.
Provenance and peer review: Not commissioned; externally peer
reviewed.
RESEARCH
BMJ | ONLINE FIRST | bmj.com
48 Chintu C, Bhat GJ, Walker AS, Mulenga V, Sinyinza F, Lishimpi K, et al.
Co-trimoxazole as prophylaxis against opportunistic infections in HIVinfected Zambian children (CHAP): a double-blind randomised
placebo-controlled trial. Lancet 2004;364:1865-71.
49 Ruffini DD, Madhi SA. The high burden of Pneumocystis carinii
pneumonia in African HIV-1-infected children hospitalized for severe
pneumonia. AIDS 2002;16:105-12.
Accepted: 5 November 2007
page 13 of 13
BMJ: first published as 10.1136/bmj.39421.435949.BE on 8 January 2008. Downloaded from http://www.bmj.com/ on 15 December 2022 by guest. Protected by copyright.
pneumonia in children aged 3 to 59 months: a randomised
multicentre equivalency study. Lancet 2004;364:1141-8.
45 Dyke T, Brown N. Hypoxia in childhood pneumonia: better detection
and more oxygen needed in developing countries. BMJ
1994;308:119-20.
46 Onyango FE, Steinhoff MC, Wafula EM, Wariua S, Musia J, Kitonyi J.
Hypoxaemia in young Kenyan children with acute lower respiratory
infection. [see comments.] BMJ 1993;306:612-5.
47 Lozano JM. Epidemiology of hypoxaemia in children with acute lower
respiratory infection. Int J Tuberc Lung Dis 2001;5:496-504.