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Indian Pediatr 2016;53: 329-333 |
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Does Routine Antibiotic Therapy Benefit
Children With Severe Acute Malnutrition?
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Source Citation: Isanaka S, Langendorf C, Berthé F, Gnegne S, Li N,
Ousmane N, et al. Routine amoxicillin for uncomplicated severe acute
malnutrition in children. N Engl J Med. 2016; 374:444-53.
Section Editor: Abhijeet Saha
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Summary
In this double-blind, placebo-controlled trial, the
authors randomly assigned children (age 6-59 mo) with uncomplicated
severe acute malnutrition (SAM) to receive amoxicillin or placebo for 7
days. The primary outcome was nutritional recovery at or before week 8.
A total of 2412 children were randomized, and 2399 children were
included in the analysis. Nutritional recovery occurred in 65.9% of
children in the amoxicillin group (790 of 1199) and in 62.7% of children
in the placebo group (752 of 1200). There was no significant difference
in the likelihood of nutritional recovery (RR 1.05; 95% CI 0.99, 1.12;
P=0.10). In secondary analyses, amoxicillin decreased the risk of
transfer to inpatient care by 14% (26.4% in the amoxicillin group vs.
30.7% in the placebo group; RR 0.86; 95% CI 0.76, 0.98; P=0.02).
The authors found no benefit of routine antibiotic use with respect to
nutritional recovery from uncomplicated SAM, and concluded that in
regions with adequate infrastructure for surveillance and management of
complications, health care facilities could consider eliminating the
routine use of antibiotics in protocols for the treatment of
uncomplicated severe acute malnutrition.
Commentaries
Evidence-based Medicine Viewpoint
Relevance: Traditional teaching and clinical
practice advocate prescribing a course of antibiotic therapy in children
with severe acute malnutrition (SAM) even without confirmation of the
presence of bacterial infection(s). This is because of concerns of
heightened risk of severe bacterial infections on account of diminished
immunity in such children. However, the evidence base for such practice
may be limited by methodological quality, changes in overall child
survival patterns, and better management of SAM and/or its
complications. For these reasons, Isanaka, et al. [1] revisited
the issue of whether routine antibiotic therapy actually benefits
children with severe acute malnutrition.
Table I Outline of the Trial
Hypothesis
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There is
limited evidence supporting the traditional practice of empiric
antibiotic therapy in all children with severe acute
malnutrition (SAM). |
Research question
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Does a course
of oral Amoxicillin (I=Intervention) administered to children
with uncomplicated severe acute malnutrition (SAM)
(P=Population), affect nutritional recovery (O=Outcome),
compared to placebo (C=Comparator)? |
Study design |
Randomized
controlled trial |
Study setting |
Rural setting
in a single district in Niger. The area has previously been
recorded to have high prevalence of SAM in children.
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Participants
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Inclusion
criteria: Children (6 mo to 5y) with SAM defined as (i)
weight-for-height z score <-3, or (ii) mid-arm circumference
(MAC) <11.5 cm, or (iii) both; without complications such as
edema and/or any indication necessitating in-hospital care.
Exclusion criteria: (i) Residence >15 km from the health
facility, (ii) prior nutritional interventions within 3 months,
(iii) antibiotic intake in the preceding week, (iv) congenital
malformations, and (v) stated inability to follow-up for the
duration of the study. |
Sample size |
A priori
calculation assuming that 80% children would achieve the primary
outcome of interest yielded a total sample size of 2010; 20%
additional enrollments were made to account for attrition. Post
hoc analysis revealed a power of 73% as the nutritional recovery
rate was only 63%. |
Intervention |
Amoxicillin
@40mg/kg twice daily x 7 days |
Comparator |
Placebo
(nature, dose, and duration not described) |
Study procedures |
All enrolled
children were administered standard care for SAM as per national
guidelines. This included a commercial ready-to-use formula @170
kcal/kg/day, vitamin supplementation, anti-helminth therapy,
catch-up vaccination, etc.Weight (least count 100 g);
length/height (least count 0.1 cm); MAC (least count 0.1 cm)
were recorded at enrollment and thereafter weekly. Indications
for hospitalization were: occurrence of clinical
condition/complication requiring admission and/or loss of weight
>5% between visits or failure to gain weight after 2 weeks.
Laboratory assessments included hemoglobin, HIV serology, rapid
test for malaria, bacterial culture of blood, urine and stool
samples (in a sub-group). |
Follow-up protocol |
Enrolled
children were assessed weekly for at least 3 weeks. They were
also followed up 4, 8 and 12 weeks following admission. |
Outcomes |
Primary
outcome: Nutritional recovery (weight-for-height z score >-2 on
two sequential visits, and MAC >11.5 cm) by 8 weeks. Secondary
outcomes: Failure of nutritional recovery at 8 weeks; Mortality
(all-cause); Transfer to in-patient care including
hospitalization |
Statistical methods |
Detailed
statistical methods have been described. Data were analyzed by
intention-to-treat. |
Critical appraisal: Table I
summarizes the trial and Table II presents a critical
appraisal of the study [1]. Overall, this is an excellent trial (as
noted above). However, there are some important issues that need
consideration. The absence of beneficial effect of amoxicillin could be
interpreted as the authors have done; but it is also possible that
amoxicillin may not be the most appropriate antibiotic in such children.
The clinical data suggest that about one-third of children had diarrhea
at presentation and over 10% children had bacteria in stool culture.
Amoxicillin is unlikely to be the appropriate antimicrobial in such
settings. Further, some children had bacteremia and bacteriuria – which
also may not respond to amoxicillin in the clinical setting of SAM.
Therefore it is important to be able to identify such children at
presentation (i.e even before culture results become available).
Although this was not a focus of this study, such data would likely be
available, and can contribute to clinical decision-making.
Table II Critical Appraisal of the Trial
Parameter |
Description and assessment |
Methodology |
Randomization |
The sequence
was generated using a computer program, off-site, by personnel
unconnected with this study. Fixed block sizes of six were used.
The procedure is judged as Adequate. |
Allocation concealment |
Allocation was
concealed using serially numbered, opaque, sealed envelopes
(SNOSE). The procedure is judged as Adequate. |
Blinding (masking) |
The
intervention and comparator were similar in colour and
packaging.The study team members were blinded to the allocation.
However, if a child developed complications requiring
antibiotics, the allocation code could be broken to facilitate
clinical management. The procedure is judged as Adequate. |
Incomplete outcome |
All
participants who were enrolled are accounted for in the data
analysis. The procedure is judged as |
reporting |
Adequate. |
Selective outcome |
Relevant
outcomes have been considered, and a priori listed outcomes have
been presented. |
reporting |
However,
adverse effects associated with amoxicillin/placebo have not
been considered. Barring this, the procedure is judged as
Adequate. |
Other sources of bias |
No obvious
additional sources of bias |
Overall assessment of |
Low risk of
bias |
methodological quality |
Results |
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Similarity of groups at |
The randomized
infants were similar in terms of age, gender distribution,
maternal characteristics, |
baseline |
nutritional
status (weight-for-age, MAC, height/length for age), hemoglobin,
presence of malaria, fever, symptoms/signs of infection, and
prior visits to health facilities. The bacterial culture of
blood, urine and stool showed similar results in both groups.
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Salient Results |
Nutritional
recovery: 790/1199 vs 752/1200 (RR 1.05, 95% CI 0.99, 1.12);
Mortality (all-cause): |
(Amoxicillin vs Placebo) |
7/1199 vs
6/1200 (RR 1.17, 95% CI 0.39, 3.46); Failure of nutritional
recovery at 8 weeks: 72/1199 vs 64/1200 (RR 1.13, 95% CI 0.81,
1.56); Transfer for in-patient care: 316/1199 vs 368/1200 (RR
0.86, 95% CI 0.76, 0.98). Adverse events (AE) have not been
reported. Subgroup analyses showed that the beneficial effect on
“need for in-patient care” existed for acute diarrhea only, and
not for other indications including failure to gain weight,
respiratory tract infection, or severe malaria. There was a
statistically significant benefit on transfer to in-patient care
within 2 weeks of the start of the intervention. There were also
some statistically (but perhaps not clinically) significant
differences in the pattern of gain in weight and MAC. |
Interpretation of results |
The data
suggest that amoxicillin therapy did not have beneficial effect
on nutritional recovery (compared to placebo), but reduced the
need for in-patient care in some children. |
Overall impression |
Validity:
Well-designed and well-conducted RCT with a low risk of bias.
Results: Clinically important results reported. Applicability:
The results can be applied across a broad range of settings.
However, there are some caveats to generalizability, as
described in the text. |
Inexplicably, adverse effects of the interventions
have not been documented. This is especially pertinent as amoxicillin
itself can cause diarrhea and its frequency in children in the study
would have been helpful to balance the benefits reported for some
outcomes. It would also have been useful to assess whether
amoxicillin-induced diarrhea led to in-patient care subsequently. It is
also odd that the group receiving Amoxicillin developed diarrhea less
frequently than those who received placebo. Since the content and nature
of the placebo was not described, this could be related to the placebo
itself. Another unusual finding is that although 55% children in this
study had malaria, fever (>38.5°C) was present in only about 5%. This
reflects either low grade fever in children with malaria (which is
unusual/unlikely) or faulty test kits. The concern is that if 55%
children had malaria, a proportion of these could progress to
severe/complicated malaria, requiring hospitalization. Such data are not
presented in this study.
Extendibility: As mentioned above, it is
relatively easy to extend the study findings to diverse health-care
settings, including our own. However, we need to carefully consider
whether the findings are a ‘flash in the pan’ or can be consistently
demonstrated and thereby applied. In this light, some trials have
demonstrated that severe pneumonia in children (traditionally
hospitalized and treated with parenteral antibiotics) could be managed
with oral antibiotic therapy [2-4] even without hospitalization [5].
Likewise, recent data suggest that oral antibiotics may be as effective
as parenteral antibiotics in children with febrile neutropenia [6].
However, in both situations, a sub-group would exist (in real-world
settings) that would require the conventional treatment (although these
may not be detected in clinical trials). Failure to identify these could
result in adverse clinical outcomes at the individual level despite
apparent success at the group level. Similarly, there may be a
sub-cohort of children with uncomplicated SAM who would require
antibiotic therapy. Future studies should concentrate on early
identification of these children.
Conclusion: Routine amoxicillin therapy does not
appear to benefit nutritional recovery in children with uncomplicated
severe acute malnutrition. However, it may reduce the need for
in-hospital care in some children.
References
1. Isanaka S, Langendorf C, Berthé F, Gnegne S,
Li N, Ousmane N, et al . Routine amoxicillin for
uncomplicated severe acute malnutrition in children. N Engl J Med.
2016;374:444-53.
2. Agweyu A, Gathara D, Oliwa J, Muinga N,
Edwards T, Allen E, et al. Severe Pneumonia Study Group. Oral
amoxicillin versus benzyl penicillin for severe pneumonia among
kenyan children: A pragmatic randomized controlled non-inferiority
trial. Clin Infect Dis. 2015;60:1216-24.
3. Soofi S, Ahmed S, Fox MP, MacLeod WB, Thea DM,
Qazi SA, et al. Effectiveness of community case management of
severe pneumonia with oral amoxicillin in children aged 2-59 months
in Matiari district, rural Pakistan: A cluster-randomized controlled
trial. Lancet. 2012; 379:729-37.
4. Addo-Yobo E, Anh DD, El-Sayed HF, Fox LM, Fox
MP, MacLeod W, et al. Multicenter Amoxicillin Severe
pneumonia Study (MASS) Group. Outpatient treatment of children with
severe pneumonia with oral amoxicillin in four countries: the MASS
study. Trop Med Int Health. 2011;16:995-1006.
5. Bari A, Sadruddin S, Khan A, Khan IU, Khan A,
Lehri IA, et al. Community case management of severe
pneumonia with oral amoxicillin in children aged 2-59 months in
Haripur district, Pakistan: a cluster randomized trial. Lancet.
2011; 378:1796-1803.
6. Vidal L, Ben Dor I, Paul M, Eliakim-Raz N,
Pokroy E, Soares-Weiser K, et al. Oral versus intravenous
antibiotic treatment for febrile neutropenia in cancer patients.
Cochrane Database Syst Rev. 2013;10:CD003992.
Joseph L Mathew
Department of Pediatrics,
PGIMER, Chandigarh, India.
Email:
[email protected]
Pediatrician’s Viewpoint
Facility-based management spearheaded the fight
against acute malnutrition in children until a few years ago. But it was
increasingly being felt that a significant number of children even with
severe acute malnutrition (SAM) did not require hospital admission and
could be managed in the community. In 2007, WHO and UNICEF endorsed the
community-based management of acute malnutrition. This is based on a
community outreach model and aims at management of children aged more
than 6 months with SAM who have no medical complications and a good
appetite with ready to use therapeutic foods (RUTF). The Government of
India (GOI) and the National Health Mission (NHM) have not yet adopted
the program, and we are largely restricted to the facility-based
approach except in some pockets [1]. But there is a growing consensus on
the community based model and the Indian Academy of Pediatrics in 2013
issued a Consensus Statement on Integrated Management of SAM stressing
on the need for a home-based management [2].
Apart from the nutritional rehabilitation, a routine
use of amoxicillin for 7 days to all the children with uncomplicated SAM
is recommended by the WHO. High prevalence of bacteremia, urinary tract
infections and other bacterial infections have been shown in children
with malnutrition but there are no such data available for the children
with uncomplicated SAM, and therefore there is no clear rationale for
routine use of amoxicillin in these children [3]. In a retrospective
study on the effect of amoxicillin on the recovery rate of children with
SAM, Trehan, et al. [4] documented no significant difference in
the rate of nutritional recovery of children at 12 weeks (84% in
amoxicillin group vs 86% in the group with no amoxicillin). The
death and default rates were also comparable. In a double blind placebo
controlled trial by the same group of authors, significantly higher risk
of treatment failure with placebo in comparison to amoxicillin (RR 1.32,
95% CI 1.04, 1.68) was documented [5]. The risk of death was also higher
with placebo (RR 1.55, 95% CI 1.07, 2.24). A meta-analysis done by
Alcoba, et al. [6] concluded that there is little evidence to
continue with the routine amoxicillin therapy in children with
uncomplicated SAM, especially in low HIV prevalence populations.
This study is a well-designed randomized controlled
trial (RCT) with low risk of bias. They have used amoxicillin in a dose
of 80 mg/kg/d, which is the upper range of the recommended dosage. A
lower dose of 50 mg/kg/d could have been used. The secondary outcome of
non-response at 8 weeks does not hold too much relevance as the primary
outcome as nutritional recovery was already taken. Only one child was
found to be HIV positive whereas in the study done by Trehan, et al.
[5], the prevalence of HIV was 22%. This could explain the contradiction
in the results of the two studies. HIV-positive children with SAM are
likely to be more immune-deficient, and therefore may benefit with the
routine use of antibiotics. The authors have reported a significantly
shorter time to recovery in the amoxicillin group (28 d vs 30 d).
This reduction of 2 days may be statistically significant but may not
translate into clinical significance. Rapid diagnostic test for malaria
was positive in 55.3% of the total study population although only 4.7%
had fever. This points needs to be highlighted in the discussion.
There is a need to review the policy of routine
amoxicillin in children in uncomplicated SAM, but before that we need to
have well designed RCTs from different parts of the world including
India which should include stratification of the participants according
to the HIV status. Routine use of amoxicillin is associated with the
possibility of emergence of bacterial resistance, toxicity and
allergies, and also adds to the cost and complexity of treatment. But
routine use of amoxicillin may benefit those children who may be falsely
labelled as uncomplicated, and may actually be harbouring a
complication. Therefore, if we do away with the use of amoxicillin, we
must also be able to ensure that even the grass root level health worker
is well trained in identification of danger signs and early referral.
References
1. Burza S, Mahajan R, Marino E, Sunyoto T,
Shandilya C, Tabrez M, et al. Community-based management of
severe acute malnutrition in India: New evidence from Bihar. Am J
Clin Nutr. 2015;101:847-59.
2. Dalwai S, Choudhury P, Bavdekar SB, Dalal R,
Kapil U, Dubey AP, et al. Consensus statement of the
Indian Academy of Pediatrics on integrated management of severe
acute malnutrition. Indian Pediatr. 2013; 50:399-404.
3. Lazzerini M, Tickell D. Antibiotics in
severely malnourished children: Systematic review of efficacy,
safety and pharmacokinetics. Bull World Health Organ.
2011;89:594-607.
4. Trehan I, Amthor RE, Maleta K, Manary MJ.
Evaluation of the routine use of amoxicillin as part of the
home-based treatment of severe acute malnutrition. Trop Med Int
Health. 2010;15:1022-8.
5. Trehan I, Goldbach HS, LaGrone LN, Meuli GJ,
Wang RJ, Maleta KM, et al. Antibiotics as part of the
management of severe acute malnutrition. N Engl J Med.
2013;368:425-35.
6. Alcoba G, Kerac M, Breysse S, Salpeteur C,
Galetto-Lacour A, Briend A, et al. Do children with
uncomplicated severe acute malnutrition need antibiotics? A
systematic review and Meta-Analysis. PLoS One. 2013;8:e53184.
Ruchi Rai
Department of Neonatology,
Superspecialty Pediatric Hospital &
Post Graduate Teaching Institute, Noida, India.
Email: [email protected]
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