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Routine amoxicillin use in treatment of uncomplicated SAM in children

Summary of research1

Location: Niger

What we know: Routine use of broad-spectrum antibiotics is recommended in uncomplicated SAM case management; there is a lack of evidence on whether this is indicated in different population groups.

What this article adds: A recent randomised, double-blind, placebo-controlled trial was conducted by Médecins Sans Frontières (MSF) in Niger to assess the effect of routine amoxicillin use, as compared with placebo, on nutritional recovery in children with uncomplicated SAM. A total of 1,199 in the amoxicillin group and 1,200 in the placebo group were studied. Baseline characteristics were similar; one confirmed case of HIV was included. The SAM recovery rate was 64%. The prevalence of infection among uncomplicated cases in this study (n=1,000 sub-group) was low. No significant benefit of routine amoxicillin use was found with respect to nutritional recovery. In terms of secondary outcomes, amoxicillin use was associated with significantly shorter time to recovery (28 v 30 days); reduced risk of death among children 24 months of age; decreased risk of inpatient transfer for complications and acute gastroenteritis; and accelerated gains in weight and MUAC. These findings inform the evidence for context-specific recommendations regarding routine antibiotic use in uncomplicated SAM.

Earlier detection of severe acute malnutrition (SAM) cases through community-based management of acute malnutrition (CMAM) has affected the caseload and clinical profile of SAM children. Routine use of broad-spectrum antibiotics is conditionally recommended in uncomplicated SAM case management, based on low-quality evidence. A recent study presents the results of a randomised, double-blind, placebo-controlled trial in Niger that assessed the effect of routine amoxicillin use, as compared with placebo, on nutritional recovery in children with uncomplicated SAM.

Methods and outcomes

The study was conducted at four health centres in the rural health district of Madarounfa, Niger. All children meeting criteria for outpatient treatment were eligible if they lived within 15 km of the centre, were available for the 12-week study period, had not been admitted to a nutritional programme within the previous three months or received any antibiotic within the previous seven days, had no clinical complications requiring antibiotic treatment, and had no congenital abnormalities. Amoxicillin was chosen in accordance with current national guidelines in Niger.

Children were randomly assigned to receive amoxicillin (80 mg per kg of body weight per day, divided into two daily doses) or placebo for seven days. Adherence was evaluated at the first weekly visit through direct questioning of the caregiver and review of a pictorial calendar recording home administration of the study medication.

The primary outcome was nutritional recovery by eight weeks. Nutritional recovery was documented at or after three weeks if a child had a weight-for-height Z score (WHZ) of −2 or higher on two consecutive visits and a mid-upper-arm circumference (MUAC) of 115 mm or greater; if there was no acute complication or oedema for at least seven days; and if the child had completed all antibiotic and antimalarial treatments at the time of discharge from the nutritional programme. Secondary outcomes included non-response at eight weeks, death from any cause, default (defined as three or more consecutive missed weekly visits), and transfer to inpatient care. Non-response was documented if a child did not meet the criteria for nutritional recovery at eight weeks.

Study procedures

All children received standard SAM treatment care with transfer to inpatient care (and subsequent follow-up at weeks two and four) if indicated. Children were seen at the study health centres at four, eight and 12 weeks after study enrolment, regardless of their status in the nutritional programme; physical examination, history-taking and anthropometric assessment were repeated at these follow-up visits.

Stool, urine and blood samples were collected on admission to the nutritional programme from a subset of 1,000 children over a period of 12 months. Bacterial gastroenteritis was defined as a stool culture that was positive for a known pathogen and diarrhoea. Confirmed cases of bacteraemia or bacteriuria were followed up and clinically manged.

Statistical analysis

A sample of 1,005 children in each group was calculated to provide the study with 80% power at a two-sided alpha level of 0.05 to detect a between-group difference in nutritional recovery of at least 5%, assuming an 80% likelihood of nutritional recovery in the amoxicillin group. Allowing for a 20% rate of loss to follow-up, 1,206 children were required for each group. With an observed likelihood of recovery of 63%, the study had 73% power to detect a 5% difference between groups. All analyses were based on the intention-to-treat principle. Risk ratios and 95% confidence intervals for each secondary outcome were calculated by means of unadjusted log-binomial regression. Between-group comparisons of time to recovery, transfer to inpatient care and death among children without a response were performed with the use of t-tests.

Results

Between October 2012 and November 2013, a total of 16,421 children presented at the four health centres. A total of 2,412 children were randomly assigned to a study group; 13 were subsequently excluded for protocol violations and 2,399 children (1,199 in the amoxicillin group and 1,200 in the placebo group) were included in the final analysis. Baseline characteristics were similar in the two groups, with no clinically relevant differences. One child was confirmed to be HIV-positive and was included in the study. Programme outcome was attributed to all children at eight weeks after admission to the nutritional programme. The rate of reported adherence, defined as completion of all seven days of the study regimen, was 99% and did not differ significantly between the two groups (P>0.05).

Overall, 64% of the children enrolled in the study (1,542 of 2,399) recovered from SAM. There was no significant between-group difference in the likelihood of nutritional recovery (risk ratio with amoxicillin vs. placebo, 1.05; 95% confidence interval [CI], 0.99 to 1.12)

Among children who recovered, the time to recovery was significantly shorter with amoxicillin than with placebo; 28 days versus 30 days (P<0.001). Amoxi+llin had no significant effect among children with a confirmed bacterial infection at admission to the nutritional programme and the effect did not vary significantly according to age or sex (P>0.05 for interaction).

The risks of non-response at eight weeks, default and death were similar in both groups. There was a significant interaction of age in the risk of death (P=0.04 for interaction); amoxicillin tended to reduce the risk of death among children aged 24 months or older (risk ratio, 0.24; 95% CI, 0.03 to 2.12) but not among children younger than 24 months (risk ratio, 3.04; 95% CI, 0.61 to 15.01). A total of 13 children died during treatment (seven in the amoxicillin group and six in the placebo group); the time to death did not differ significantly between the groups.

Amoxicillin significantly decreased the overall risk of a transfer to inpatient care and the risk of a transfer within the first two weeks. Amoxicillin significantly reduced the risk of a transfer for clinical complications in general (by 31%) and for acute gastroenteritis in particular (by 33%). The study intervention had no effect on the risk of a transfer to inpatient care among children with any bacterial infection.

Amoxicillin significantly accelerated early gains in weight and MUAC that appeared to contribute to a slightly faster time to recovery (mean, two days). There was no significant effect on height gain.

The frequency of diarrhoea was lower in the amoxicillin group than in the placebo group at week one, with no significant effect of amoxicillin on the incidence of other clinical symptoms. The overall prevalence of bacterial infection in blood, urine and stool from children with diarrhoea was low. The likelihood of resistance to amoxicillin was 35% for enterobacteria isolated from stool in children with diarrhoea and 66% for enterobacteria isolated from blood.

Discussion

Routine provision of amoxicillin was not superior to placebo for nutritional recovery in children with uncomplicated SAM. Amoxicillin reduced the risk of a transfer to inpatient care by 14%, as compared with placebo. Of note:

  • Half (53%) of children transferred to inpatient care according to the study protocol (49% in the amoxicillin group and 56% in the placebo group) were admitted to a hospital. For a multitude of reasons, only 50% of children who were eligible for inpatient care because of weight loss or lack of weight gain were actually admitted. Amoxicillin reduced the risk of hospitalisation, potentially a more specific and generalisable secondary end-point than transfer to inpatient care, by 24%, as compared with placebo (risk ratio, 0.76; 95% CI, 0.62 to 0.92).
  • Among hospitalised children, there were no significant between-group differences in the mean length of stay (4.9 days in the amoxicillin group and 4.4 days in the placebo group, P=0.32) or the rate of recovery (94% and 96%, respectively). All children recovered quickly, suggesting that adequate inpatient care may mitigate any risk of absent routine antibiotics.
  • The reduced risk of transfers for gastroenteritis was an unexpected finding, since the responsible viruses and parasites are not sensitive to amoxicillin. Reasons may include translocation of bacteria across compromised intestinal surfaces resulting in bacteremia or modification of the composition and function of the gut microbiome by oral antibiotics.

There are a number of considerations when interpreting the findings. The prevalence of infection among uncomplicated cases in this study was low. Assumed nutritional recovery (80%) was not achieved; amoxicillin may have had a protective or harmful effect on nutritional recovery. Mortality was lower than expected and previously reported. Alternative antibiotic regimens could have maximised recovery. Finally, the study interventions were performed by well-trained and supervised medical personnel; not typical field conditions.

Conclusions

In conclusion, no significant benefit of routine amoxicillin use was found with respect to nutritional recovery among children with uncomplicated SAM in Niger. These findings provide useful information for public health authorities and their implementing partners regarding the routine use of antibiotics in the treatment of uncomplicated SAM.

Read more...

1 Isanaka S, Langendorf C, Berthé F, Gnegne S, Li N, Ousmane N, Harouna S, Hassane H, Schaefer M, Adehossi E & Grais R. Routine Amoxicillin for Uncomplicated Severe Acute Malnutrition in Children. N Engl J Med 2016; 374:444-453 February 4, 2016 DOI: 10.1056/NEJMoa1507024.

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Routine amoxicillin use in treatment of uncomplicated SAM in children. Field Exchange 52, June 2016. p15. www.ennonline.net/fex/52/amoxicillinsamchildren