A narrative review of efficacy of antibiotics in treatment of children with severe acute malnutrition in community based out-patient treatment

Background

Children with severe acute malnutrition have a high prevalence rate of pneumonia, bacteraemia, urinary tract infections and small bowel bacterial overgrowth that may affect intestinal functions. These children however may not show symptoms as they have a suppressed immune response. The WHO manual for management of severe malnutrition (1999) ¹ recommended parenteral antibiotic treatment for children presenting with clinical complications and a course of oral antibiotic treatment for all children with uncomplicated SAM during in-patient care. In 2013, the WHO commissioned a systematic review ² which found one retrospective cohort study ³ that showed lower rate of recovery among uncomplicated SAM children at eight weeks (40 v. 71%) and similar rate of recovery (84 v. 86%), death (2.6 v 1.7%) or default (7.8 v 9.3%) rates compared to children who did not receive antibiotics, at twelve weeks of age. However, the baseline characteristics of children in the two groups were different, and other unidentified factors may have confounded the findings. ⁴ In another randomised superiority-controlled trial in Sudan ⁵ with children aged 6–59 months with uncomplicated SAM, a recovery rate of 70% was seen in children treated with amoxicillin and 74.6% among children treated with ceftriaxone; case fatality rates (CFR) were 3.9% and 3.1%, respectively. One randomised control trial (RCT) that compared the efficacy of amoxicillin versus cefdinir versus no treatment in children with uncomplicated SAM was still underway during the systematic review. ⁴

There was therefore a lack of evidence to determine whether or not antibiotics should be routinely administered to children with uncomplicated SAM in community based out-patient programmes. Based on the very limited evidence available, the WHO Committee considered that the prevalence of infections and the risk of mortality even in uncomplicated cases were both high. There was significant reduction in mortality among children with uncomplicated SAM through use of antibiotics, which far outweighed the risk of developing antimicrobial resistance potentially arising from using broad spectrum antibiotics for out-patient treatment. Though the mechanism by which oral antibiotics benefitted children with SAM was not clear, it possibly reduced excessive proliferation of small bowel flora, helped in translocation of gut bacteria into the bloodstream or modified the microbiome. Based on this evidence, WHO recommended treatment of uncomplicated SAM children with oral antibiotics such as amoxicillin even in community based care along with nutritional rehabilitation, while children showing complications including hypoglycaemia, septic shock, hypothermia, skin infections, children with lethargy, children with respiratory or urinary tract infections to be provided in-patient care with nutritional therapy and a course of parenteral antibiotics. ⁶ The systematic review however could not identify any studies on ceftriaxone, ciprofloxacin or co-trimoxazole as first line treatment of children with SAM.

Community based management of children with uncomplicated SAM is gaining momentum and more than 70 countries have started such intervention. ⁷ However, need and efficacy of treating uncomplicated SAM with broad based antibiotics has remained inconclusive owing to limited available evidence.

Methodology

A search for observational and experimental studies was undertaken using search terms: antibiotics, amoxicillin, ceftriaxone, ciprofloxacin, co-trimoxazole, mortality, recovery, severe acute malnutrition, kwashiorkor, marasmus, child. The database of Pubmed, Google Scholar, Cochrane Database of Systematic Review were searched. Articles were also identified from references of other published literature. The search pertained to articles published in English language in open access and full-text format, for the period 2011 to 2020, to update the evidence that informed WHO 2013 Guidelines.

We included studies that specifically referred to treatment of severe acute malnutrition among children 6–59 months of age, studied the efficacy of antibiotics for first line treatment for reducing mortality or improving recovery rates among children with uncomplicated SAM, in out-patient care, experimental or observational studies were included.

We excluded studies providing only qualitative information, published before 2011, correspondence, studies not directly answering the research question, systematic reviews and meta-analysis.

Results

Our search yielded 261 articles, of which 86 were shortlisted based on title review, and six excluded as duplicates (Figure 1). Full text was not available for six articles. 44 articles did not answer the research question. Four articles were systematic reviews or meta-analysis and were also excluded from the review; a further. 21 studies were related to complicated SAM and were excluded. Finally, only seven experimental or observational studies based on out-patient settings were included for review of evidence: one randomised double-blind, placebo control trial, ⁴ one study double-blind, placebo control trial, ⁸ two retrospective cohort studies,^9,10 two prospective cohort studies,^11,12 and one retrospective cross-sectional study. ¹³

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Figure 1.

Search result on PRISMA flowchart.

Of the seven studies, six showed significant difference in recovery rates (Table 1, Figure 2). Trehan (2016) reported 1.38 times (OR 1.38; p = 0.03) greater likelihood of recovery of uncomplicated SAM children when treated with amoxicillin and 1.69 times (OR 1.69; p = 0.001) greater likelihood of recovery when treated with Cefdinir. Similarly, Yebyo (2013) reported 1.95 times (RR  =  1.95; 95% CI, 1.17–3.23) greater likelihood of recovery when treated with amoxicillin as compared to the untreated group. Kabalo (2017) and Abate (2020) respectively reported 1.52 (AOR  =  1.52; 95% CI: 1.09- 2.11) and 3.38 times (AOR = 3.38; 95% CI: 1.61–7.08) greater likelihood of recovery of uncomplicated SAM children when treated with amoxicillin while Liben (2019) and Mamo (2019) respectively reported 1.38 (AHR, 1.38; 95% CI: 1.01, 1.89) and 2.3 times (AHR = 2.30; 95%CI: 1.68–3.16) increased likelihood of recovery of uncomplicated SAM children when treated with amoxicillin. Trehan, I., et al., 2016 also reported lower risk of mortality among uncomplicated SAM children when treated with amoxicillin (OR 0.67; p = 0.05) and cefdinir (OR 0.57; p = 0.01). The same study also reported significant weight gain and gain in MUAC when uncomplicated SAM children were treated with Cefdinir, however the same was not true when uncomplicated SAM children were treated with amoxicillin. Isanka, S., et al., 2016 did not find any significant increase in recovery (RR 1.05; 95% CI: 0.99–1.1) and decrease in mortality (RR 1.17; 95% CI: 0.39–3.46; p = 0.78) among uncomplicated SAM children when treated with amoxicillin however, there was significantly lower risk of in-patient care transfer (RR 0.62; 95% CI: 0.42–0.91; p = 0.01) and slightly improved gain in MUAC (RR 0.06; 95% CI: 0.04–0.08; p < 0.001) among them. Five studies did not report the effect of antibiotics on mortality rate, weight gain, change in MUAC and risk of in-patient transfer.^9–13

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Figure 2.

Visual representation showing distribution of outcome for treatment of SAM children with antibiotics.

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Table 1.

Summary of efficacy outcome of treating uncomplicated SAM with antibiotics from 7 studies.

Study	Antibiotic used	Sample size	Recovery	Mortality rate	Weight gain	Other outcomes
Trehan, I., et al., 2016	Amoxicillin	1844	OR 1.38 (95% CI:1.02–1.86), p = 0.03	OR 0.67 (95% CI: 0.44–1.00), p = 0.05	weight gain (g/Kg/day) 3.4 + /-4 compared to 3.1 ± 4.1 in placebo group	Gain in MUAC (mm/day) 0.27 ± 0.42 (p = 0.01) compared to 0.22 ± 0.41 in placebo group
Trehan, I., et al, 2016	Cefdinir	1843	OR 1.69 (95% CI:1.24–2.31), p = 0.001	OR0.57 (95% CI: 0.37–0.88), p = 0.01	weight gain (g/Kg/day) 3.9 + /-6.3 (p = 0.002) compared to 3.1 ± 4.1 in placebo group	Gain in MUAC (mm/day) 0.28 ± 0.42 (p = 0.002) compared to 0.22 ± 0.41 in placebo group
Isank, S., et al, 2016	Amoxicillin	2412	RR 1.05, (95% CI: 0.99–1.1)	RR 1.17 (95% CI: 0.39–3.46) p = 0.78	RR 0.89 (95% CI: 0.78–1.02) p = 0.10	Risk of transfer to in-patient care RR 0.62; (95% CI: 0.42–0.91; p = 0.01). Mean difference in gain in MUAC RR 0.06 (95% CI: 0.04–0.08) p < 0.001
Yebyo, H. G., et al, 2013	Amoxicillin	628	RR  =  1.95, (95% CI: 1.17–3.23)	Not reported	Not reported	Not reported
Kabalo, M. Y., et al, 2017	Amoxicillin	794	AOR  =  1.52 (95% CI: 1.09- 2.11)	Not reported	Not reported	Not reported
Liben, M. L., et al, 2019	Amoxicillin	286	AHR = 1.38 (95% CI: 1.01- 1.89)	Not reported	Not reported	Not reported
Mamo, W. N., et al, 2019	Amoxicillin	408	AHR = 2.30 (95% CI:1.68–3.16)	Not reported	Not reported	Not reported
Abate, B.B., et al, 2020	Amoxicillin	600	AOR = 3.38 (95% CI: 1.61–7.08)	Not reported	Not reported	Not reported

MUAC, mid upper arm circumference.

Conclusion

The current analysis from 7 studies shows a positive impact on recovery of children with SAM treated with antibiotics (amoxicillin) in out-patient programmes. Children with uncomplicated SAM remain at risk for severe bacterial infection, even when they qualify for outpatient therapy and therefore the inclusion of antibiotics as part of their nutritional therapy is warranted.