Guidelines for the treatment of severe acute malnutrition: a systematic review of the evidence for antimicrobial therapy

Figures & data

Figure 1. Search strategy.

Table 1. Current WHO inpatient and outpatient management guidelines for severe acute malnutrition.

Condition	Recommendation	Evidence base*	Year updated
Uncomplicated malnutrition [5]	Oral amoxicillin	Conditional recommendation, low quality evidence	2013
	Dosage and time frame not specified — the drug dosage section advises 25 mg/kg twice daily and for pneumonia.
Complicated malnutrition [4,5]	IV benzylpenicillin 50,000 U/kg IM/IV every 6 h for 2 days	Weak recommendation, low quality evidence	2012
	OR
	IV ampicillin 50 mg/kg IM/IV every 6 h for 2 days
	THEN
	Oral amoxicillin 25–40 mg/kg/dose every 8 h for 5 days (total 7-day course)
	AND
	IV/IM gentamicin 7.5 mg/kg IM/IV once daily for 7 days
Complicated malnutrition [4,5]	Oral metronidazole 7.5 mg/kg every 8 h for 7 days may be given in addition to broad-spectrum antibiotics; however, the efficacy of this treatment has not been established in clinical trials	None	2013

* At the time of the recommendation.

Table 2. Search terms used in search strategy.

(1) Amoxicillin OR ampicillin OR penicillin OR procaine penicillin

(2) Amoxicillin + OR amoxicillin–clavulanate combination OR ampicillin + penicillins + OR penicillin G + OR penicillin G, procaine

(3) Gentamicin OR aminoglycoside OR gentamicins+

(4) Cotrimoxazole OR sulfamethoxazole OR sulfamethoxazole OR trimethoprim OR trimethoprim-sulfamethoxazole combination

(5) Ceftriaxone OR cephalosporin OR ceftriaxone+

(6) Ciprofloxacin OR quinolone OR fluoroquinolone OR ciprofloxacin+

(7) Chloramphenicol OR chloramphenicol+

(8) OR 1–7

(9) Malnutrition OR malnourished OR underweight OR kwashiorkor OR marasmus

(10) Malnutrition OR protein-energy malnutrition OR child nutrition disorders OR infant nutrition disorders

(11) OR 9–10

(12) 8 AND 11

(13) Limit 12 to humans (for clinical safety and efficacy trials) AND published between 2010 and 2016

Table 3. Inclusion and exclusion criteria.

Inclusion criteria	Exclusion criteria
• Systematic review, randomised controlled trial or multi-centre study investigating antibiotic therapy in children with complicated or uncomplicated SAM • Where resistance patterns were investigated, information on antimicrobial testing methodologies documented	• Published before 2010 • Not pertaining to treatment in humans (unless informing pharmacokinetics) • Data pertaining to carriage rates only • Irrelevant to clinical question • Duplicates • Correspondence • Case reports or epidemiological studies

Table 4. Bacterial antibiotic susceptibilities (%) for common first- and second-line therapies for treating children with SAM: results of a meta-analysis of 767 children from Uganda, Kenya, Turkey, Nigeria, Kenya and South Africa [30].

Antibiotic	Median	Interquartile range	Population-weighted mean (meta-analysis)*
Amoxicillin	42	27–55	52.9
Co-trimoxazole	22	17–23	35.4
Gentamicin	80	77–85	72.8
Amoxicillin–gentamicin combination	91.4	87–96	90.7
Chloramphenicol	57.5	46–69	73.7
Ciprofloxacin	93	82–93	90.0
Ceftriaxone	84	80–94	89.3
Amoxicillin–clavulanate	51	23–56	30.7

* Mean susceptibility weighed proportionally (coefficient) to number of patients per study.

Table 5. Synopsis of international guidelines on antimicrobial therapy for children with severe acute malnutrition.

Author	Year	Guideline title	Uncomplicated SAM	Complicated SAM
BMJ	2011	Clinical evidence: kwashiorkor	7-day course	Gentamicin 7.5 mg/kg IM/IV once daily for 7 days
			Amoxicillin 80–90 mg/kg/day orally in two divided doses	AND
				Ampicillin 200 mg/kg/day IM/IV in four divided doses
			OR	OR
			Cefdinir 14 mg/kg/day orally as a single dose, or as two divided doses (recommendation based on ref. 40)	Chloramphenicol 50 mg/kg/day IM/IV in divided doses every 6–8 hours^a
				Second line:
				Ceftriaxone 50–75 mg/kg/day IM/IV in divided doses every 1–4 hrs (based on ref. 63)
					ACF (Action Contre la Faim)^b	2011	Guidelines for the treatment of SAM	Amoxicillin for 7 days; 50–100 mg/kg/day in two divided doses	Add ‘low-dose’ gentamicin 5 mg/kg daily
									If no improvement or signs of sepsis, change to co-amoxiclav plus antifungal (fluconazole)
Médecins Sans Frontières	2016	Clinical guidelines	Amoxicillin for 5 days (70–100 mg/kg/day) in two divided doses	“Since the infectious focus may be difficult to determine, a broad-spectrum antibiotic therapy (cloxacillin + ceftriaxone) is recommended” (dosage and time-frame not specified)
Valid International	2006	CTC Field Manual	Amoxicillin for 7 days (<10 kg 3 × 125 mg; 10–30 kg 3 × 250 mg; >30 kg 3 × 500 mg)	Chloramphenicol PO (2–5.9 kg: 3 × 62.5 mg; 6–9.9 kg: 3 × 125 mg; 10–30 kg: 3 × 250 mg) (7 days) as outpatient with moderate complications (e.g. fever not responding)
Indian Academy of Pediatrics	2006	IAP Guidelines 2006 on Hospital Based Management of Severely Malnourished Children	Not documented	Ampicillin 50 mg/kg/dose 6-hourly IM or IV for at least 2 days; followed by oral Amoxycillin 15 mg/kg 8-hourly for 5 days (once the child starts improving) plus
	2013
				Gentamicin 7.5 mg/kg or Amikacin 15–20 mg/kg IM or IV once daily for 7 days.
			Updated 2013 guidelines did not address antibiotic use
				If the child fails to improve within 48 hours, change to IV Cefotaxime (100–150 mg/kg/day 6–8-hourly)/Ceftriaxone (50–75 mg/kg/day 12-hourly).
				“However, depending on local resistance patterns, these regimens should be accordingly modified”.
				“Some experienced doctors routinely give metronidazole (7.5 mg/kg 8-hourly for 7 days) in addition to broadspectrum antibiotics. However, the efficacy of this treatment has not been established by clinical trials”.
Government of Bangladesh	2008	“National Guidelines for the Management of Severely Malnourished Children in Bangladesh”	Amoxicillin oral 15 mg/kg 8-hourly for 5 days OR	Ampicillin IM/IV 50 mg/kg 6-hourly for 2 days, then amoxycillin oral 15 mg/kg 8-hourly for 5 days AND gentamicin IM/IV 7.5 mg/kg once daily for 7 days. If the child is not passing urine, gentamicin may accumulate in the body and cause deafness. Do not give second dose until the child is passing urine.
			cotrimoxazole oral; trimethoprim 5 mg/kg and sulphamethoxazole 25 mg/kg 12-hourly for 5 days
				If the child fails to improve clinically by 48 hrs or deteriorates after 24 hrs, or presents with septic shock or meningitis, antibiotics with a broader spectrum may be needed (e.g. ceftriaxone 50–100 mg/kg/d IV/IM once daily with or without gentamicin).
UNICEF, MoH Kenya	2009	National Guideline for Integrated Management of Acute Malnutrition	Oral amoxicillin, by weight range, equivalent to 25–50 mg/kg twice daily	Add chloramphenicol (do not stop amoxicillin)
				OR
				add gentamicin (do not stop amoxicillin)
				OR
				Switch to amoxicillin/clavulinic acid.
			Age <6 months, 30 mg/kg twice daily
Kenya MoH and Kenya Paediatric Association	2016	Basic Paediatric Protocols	Not covered	Penicillin (or ampicillin)
				AND gentamicin. Give 5 days gentamicin, if improved change Pen to amoxicillin at 48 hrs.
Malawi Government	2006	Guidelines for the Management of Severe Acute Malnutrition.	Oral amoxicillin 15 mg/kg three times daily.	Gentamicin IM/IV 7.5 mg/kg once daily for 7 days AND chloramphenicol IM/IV 25 mg/kg three times daily for 5 days

^a Choice depends on local microbiological sensitivity patterns.

^b This regimen is used in many national protocols e.g. Ethiopia, Niger.

Table 6. Common adverse reactions to antibiotics used in severe acute malnutrition in children [55].

Antibiotic	Life threatening	Mild adverse effects, which may result in dis-continuation of treatment	Other	Relevant interactions
Benzylpenicillin	Hypersensitivity reactions; anaphylaxis (<0.05% of patients)	Joint pain; diarrhoea; rashes; urticaria	Cerebral irritation; coagulation disorders; haemolytic anaemia; leucopenia; thrombocytopenia	Antagonised by tetracyclines
		Allergic reactions occur in up to 10% of exposed individuals
Ampicillin; Amoxicillin	As for benzylpenicillin	Erythematous rashes may occur with CMV or EBV infections	As for benzylpenicillin	As for benzylpenicillin
Gentamicin	Hypersensitivity reactions	Nausea; stomatitis; vomiting	Nephrotoxicity, especially in children with impaired renal function, of note when administering to children presenting with severe dehydration in complicated SAM	Plasma concentration of gentamicin in neonates possibly increased by indomethacin
				-All aminoglycosides have increased risk of nephrotoxicity when administered with amphoterocin, capreomycin, cephalosporins, polymyxins, tacrolimus, vancomycin, cyclosporin, and loop diuretics
			Antibiotic associated colitis; electrolyte disturbances; auditory damage; irreversible ototoxicity; vestibular damage
				Plasma monitoring is recommended after 3-4 doses
Amoxicillin-Clavulanate	Hypersensitivity reactions	Cholestatic jaundice; hepatitis; nausea; vomiting; dizziness; headache	Vasculitis	As for benzylpenicillin
Metronidazole	Hypersensitivity reactions	Anorexia; gastrointestinal disturbance; nausea; taste disturbance; vomiting	Aseptic meningitis; ataxia; pancytopenia
Co-trimoxazole	Agranulocytosis; bone marrow suppression	Diarrhoea; headache; hyperkalaemia; nausea; rash; vomiting	Antibiotic-associated colitis; myocarditis; pericarditis; pancreatitis; vasculitis	Increase toxicity of anti-neoplastic drugs
Chloramphenicol	Grey syndrome may occur with intravenous use in neonates (abdominal distension, pallid cyanosis, circulatory collapse)	Diarrhoea; depression; erythema multiforme; headache; nausea; urticaria; vomiting	Nocturnal haemoglobinuria; optic or peripheral neuritis	Increases plasma concentration of cyclosporin, anti-epileptic therapies
				Metabolism of chloramphenicol is accelerated by rifampicin
				Chloramphenicol enhances effects of sulfonylureas
	Bone marrow toxicity: reversible and irreversible aplastic anaemia
Fluoroquinolones: ciprofloxacin	Hypersensitivity reactions; Prolonged QT syndrome	Dyspepsia, headache, diarrhoea, vomiting, hypotension	Tendinitis and tendon rupture; peripheral neuropathy	All fluoroquinolones should be used with caution in patients receiving drugs known to prolong the QT interval (see below)
				The toxicity of fluoroquinolones is increased by the concurrent use of systemic steroidal medications
				Fluoroquinolones’ effects are reduced by the co-administration of iron- and zinc- containing products, of importance when zinc-containing products are used to treat diarrhoea in children
				Fluoroquinolones cause additive toxicity with non-steroidal anti-inflammatory drugs (ibuprofen, meloxicam, naproxen)
Azithromycin	Hypersensitivity reactions; Prolonged QT syndrome	Dyspepsia, flatulence, headache, disturbance in taste, anorexia	Malaise, paraesthesia	All macrolides are advised to be avoided concomitantly with other drugs which prolong the QT interval, (including anti-malarial medications such as artemether-lumefantrine) owing to the risk of ventricular arrhythmias (see below)
				Plasma concentrations of azithromycin are increased by ritonavir
				Azithromycin in combination with rifabutin results in increased
				side effects of ritabutin, including neutropenia
Ceftriaxone	Hypersensitivity reactions	Diarrhoea, headache, abdominal discomfort	Transient cholestatic jaundice owing to biliary sludge formation	Relevant interactions for all cephalosporins: increased risk of nephrotoxicity when co-administered with aminoglycosides.
				Enhance anticoagulant effect of coumarins
Cefixime (specific cefdinir side effects and interactions not published)	Hypersensitivity reactions; immune-mediated haemolytic anaemia	Flatulence, headache, abdominal pain, defaecation urgency, nausea, constipation, vomiting	Transient cholestatic jaundice owing to biliary sludge formation	As per ceftriaxone

Table

Author	Title	Year	Methods (study type, setting, participants)	Results	Conclusions	GRADE level of evidence
Alcoba et al. [43]	Do children with uncomplicated severe acute malnutrition need antibiotics? A systematic review and meta-analysis	2013	• Systematic review and meta-analysis • Not restricted by region • Children aged 6–59 months; plus 0–15 years for indirect evidence • Children with HIV and TB were included in the analysis • 2767 strictly SAM children; • Case definitions: Complicated SAM = WfH < –3 Z-score and/or bilateral pitting oedema and/or WfH < 70% of median and/or MUAC < 110 mm. Uncomplicated SAM = SAM children passing appetite test, afebrile, no clinical infections or complications, treated by health centre • Outcomes: Antibiotic efficacy was defined as a measure of effect such as OR, RR, or risk reduction % in endpoints including: case-fatality rates (CFR), recovery rate, nutritional cure (weight-for-height within normal range >80% of median or >2 Z scores), infection incidence, AB susceptibility/resistance • Owing to heterogeneity of inclusion criteria, a meta-analysis of intervention studies was not possible though meta-analysis of observational data were conducted	• 3 RCTs, 5 Cochrane reviews, 37 observational studies identified as meeting inclusion criteria • Prevalence of serious infections in SAM, pooled from 24 studies, ranged from 17% to 35.2% • One cohort-study showed no increase in nutritional-cure and mortality in uncomplicated SAM where no AB were used (p > 0.05) • However, an unpublished RCT in this setting did show mortality benefits (Trehan 2013) • Another RCT did not show superiority of ceftriaxone over amoxicillin for these same outcomes, but addressed SAM children with and without complications (p  =  0.27) • One RCT showed no difference between amoxicillin and cotrimoxazole efficacies for pneumonia in underweight, but not SAM • Review of international guidelines revealed inconsistencies in the recommended first-line antibiotic (AMX and CTX) with 5 different dosages: CTX 4–5 mg/kg/d, AMX 50–100 or 70–100 mg/kg/day or 3 weight classes and 2 different durations (5 or 7 days)	• Meta-analysis of 12 pooled susceptibility studies for all types of bacterial isolates, including 2767 strictly SAM children, favoured amoxicillin over cotrimoxazole for susceptibility medians: 42% (IQR 27–55%) vs. 22% (IQR 17–23%) and population-weighted-means 52.9% (range 23–57%) vs. 35.4% (range 6.7–42%) • Susceptibilities to 2nd-line AB were better, above 80% • No study inferred any association of infection prevalence with AB regimens in SAM • The authors concluded that: “the evidence underlying current antibiotic recommendations for uncomplicated SAM is weak” and called for placebo-controlled RCTs to demonstrate efficacy • Given that antibiotics have side effects, costs and risks as well as benefits, the authors conclude that their routine use needs urgent testing • The 3 studies that directly evaluate antibiotics in SAM revealed three contrasting results: ◦ AB not superior to no AB ◦ CEF superior to AMX and AMX superior to placebo ◦ CEF not superior to AMX. None of these studies provided stratified analyses for HIV+ SAM children	B (meta-analysis based on observational data)
					• The authors concluded that there is very limited evidence regarding many aspects of SAM in children <5 years, including management of subgroups (children <6/12 or children with SAM who are HIV+) and the use of antibiotics
Picot et al. [31]	The effectiveness of interventions to treat severe acute malnutrition in young children: a systematic review	2012	• Systematic review • Children <5 years • Search period 2010–2012 • Not restricted by region	• 8 databases were searched: Medline, Embase, Medline in-process and other non-indexed citations, CAB abstracts Ovid, Bioline, centre for reviews and dissemination, EconLit EBSCO and Cochrane • 74 articles describing 68 studies (RCTs, CCTs, cohort studies and case-control studies) met the inclusion criteria • No evidence focused on HIV+ children; and no trials were conducted on children <6/12 • Two studies (one RCT and one retrospective cohort study - Dubray 2008; Trehan 2010) of moderate methodological quality investigated the use of antibiotic therapy in children with SAM • Dubray 2008: An unblinded RCT conducted in Sudan (n = 458) which indicated oral amoxicillin (80 mg/kg/day in two divided doses) for 5 days was as effective as IM ceftriaxone for 2 days [36]. ITT analysis revealed that 53.5% (123/230) in the amoxicillin group and 55.7% (127/228, difference 2.2%, 95% CI –6.9–11.3) in the ceftriaxone group had a weight gain of ≥10 g/kg/day during a 14-day period. Recovery rate was 70% (161/230) in the amoxicillin group and 74.6% (170/228) in the ceftriaxone group (p = 0.27). Case fatality rates were 3.9% (9/230) and 3.1% (7/228), respectively (p = 0.67). Most deaths occurred within the 1st 2 weeks of admission • A second large retrospective study in Malawi (Trehan 2010) compared oral amoxicillin (60 mg/kg/day, n = 498) for 7 days with no antibiotics (n = 1955), revealing a poorer recovery rate in children receiving amoxicillin at 4 weeks (39.8% vs. 70.8%; p < 0.001), but a similar rate of recovery at 12 weeks, with similar rates of death and default [37]. However, this research is at risk of bias not just owing to its retrospective data collection, but also because of the different district locations of the two cohorts of patients, who were also not stratified by risk of HIV-infectivity status (with a high burden in the study population)		B (systematic review with only 2 studies retrieved with epidemiological limitations)
Lazzerini and Tickell [38]	Antibiotics in severely malnourished children: systematic review of efficacy, safety and pharmacokinetics	2011	• Systematic review of CENTRAL, MEDLINE, EMBASE, LILACS, POPLINE, and CAB • Abstracts and ongoing trials registers were searched, plus thorough grey literature search • For PK review, all study types, except single case reports, were included	• Overall, 23 studies were identified for inclusion: • 2 RCTs, 1 before-and-after study and 2 retrospective reports on clinical efficacy and safety were retrieved, together with 18 pharmacokinetic studies • Trial quality was generally poor and results could not be pooled owing to heterogeneity	• The authors concluded that ‘the existing evidence is not strong enough to further clarify recommendations for antibiotic treatment in children with SAM’. • Pharmacokinetic data suggest that normal doses of penicillins, cotrimoxazole and gentamicin are safe in malnourished children, while the dose or frequency of chloramphenicol requires adjustment • First-line antibiotics for uncomplicated SAM: Benefit vs. harm remains undetermined. There is a lack of epidemiological data on the risk of infection in children with uncomplicated SAM and what data there are have not been stratified by HIV prevalence. Cotrimoxazole is losing efficacy owing to resistance; amoxicillin remains a valuable alternative owing to findings of similar efficacy of ceftriaxone and cheaper price • Complicated SAM: Current data continue to support broadspectrum antibiotics for children with complicated SAM; however, only one retrospective study has reported on the use of Amp+Gent, which resulted in lower case fatality rates when combined with treatment for hypoglycaemia. The comparative efficacy of other parenteral antibiotics has not been studied • High rates of in vitro resistance have been reported in several African countries • Many institutions vary in their extent of following recommendations and instead give more potent broadspectrum antibiotics as 1st-line therapy, largely guided by local in vitro susceptibility data	B (systematic review with poor quality trials retrieved)
				Conclusion of included studies: • Oral amoxicillin for 5 days was as effective as intramuscular ceftriaxone for 2 days (1 RCT) • For uncomplicated SAM, amoxicillin showed no benefit over placebo (1 retrospective study) • The introduction of a standardised regimen that included the administration of ampicillin and gentamicin significantly reduced mortality in hospitalised children (OR 4.0; 95% CI 1.7–9.8; 1 before-and-after study); however, this was pooled with intervention to address hypoglycaemia • Oral chloramphenicol was as effective as cotrimoxazole in children with pneumonia (1 RCT); this study was poorly generalisable • PK studies support the use of oral penicillin in children with SAM at the same doses as eutrophic children unless severe diarrhoea or malabsorption are present • PK studies: Suggest parenteral Pen+Gent can be safely given to malnourished children at the same doses as eutrophic children, unless renal failure or shock are present • PK studies on oral chloramphenicol suggest it is erratically absorbed (with a risk of accumulation and toxicity) in malnourished children and parenteral administration is preferable • No studies have been published on the efficacy, safety or PK of ciprofloxacin or ceftriaxone in children with SAM
Milion et al. [32]	Meta-analysis on efficacy of amoxicillin in uncomplicated severe acute malnutrition	2016	• Meta-analysis combining Isanaka’s (2016) and Trehan’s (2013) RCTs	• A significant beneficial effect was found for amoxicillin in children with marasmus (summary risk ratio 1.05, 95% CI 1.00–1.11, p = 0.05) • This significant effect was also found when taking into account all three clinical forms of severe acute malnutrition; kwashiorkor, marasmic kwashiorkor and marasmus (summary risk ratio 1.03, 95% CI 1.00–1.06, p = 0 .03) • Size-effects seem to be greater in children with marasmic kwashiorkor but the sample size was very low in this high-risk subgroup	• The authors concluded that further studies should clarify whether amoxicillin has a different effect according to clinical presentation of SAM. Cephalosporins may also have greater efficacy (RR of treatment failure: 1.64 for placebo vs. cefdinir; 1.32 for placebo vs. amoxicillin) • The findings were in accordance with 2 recent research projects (conducted by the authors) that suggest a proliferation of gut aerotolerant potential pathogens, particularly streptococcus, which is systematically susceptible to amoxicillin, and proteobacteria, which are better inhibited by cephalosporins in SAM	A (meta-analysis with large sample size)
Trehan et al. [33]	Antibiotics as part of the management of severe acute malnutrition	2013	• 3-arm placebo-controlled, double blinded RCT in Malawi comparing oral amoxicillin (80–90 mg/kg/day in 2 divided doses) vs. placebo (twice daily) and an oral 3rd-generation cephalosporin (cefdinir; 14 mg/kg/day in 2 divided doses) in uncomplicated SAM • n = 2767 • 6–59 months • 2009–2011 study period • Computer-generated block randomisation lists were created in permuted blocks of 54 • Participating children were allocated to their study arm when their caregivers drew an opaque envelope containing one of 9 coded letters corresponding to one of the 3 medication groups • Caregivers, study nurses, and all study personnel involved in clinical assessments and data analysis were blinded to the intervention each child received • The medications and placebo were distributed in opaque plastic bottles with plastic syringes marked to indicate the dose of medication each child was to receive • After randomisation and distribution of the medications and placebo, study nurses educated each child’s caregiver on how to use the syringe to give the medications, supervised administration of the first dose in the clinic; and provided them with a pictorial calendar for recording each dose given, with instructions to give the medication twice daily for 7 days • Children were brought back for up to 6 follow-up visits at 2-week intervals at which time repeat anthropometric measurements were taken and caregivers were asked about the child’s interim clinical and appetite history • At the first follow-up visit, study nurses assessed how much medication was given to the child by examining how much medication remained in the study bottle, examining how many doses were marked off on the dosing calendar, and considering the caregiver’s verbal report • Primary endpoints: Rates of nutritional recovery and mortality rates in the 3 study arms • Secondary outcomes of interest included weight gain, length gain, tolerance of the medications and time to recovery	• Less than a third of the children had been tested for HIV; of those, more than a fifth were HIV-positive, and less than a third of those were receiving antiretroviral therapy (ART). About three-quarters of the children’s mothers had been tested for HIV, with 19% being HIV-positive; less than half of those were receiving ART • Adherence to the intervention was very high in each of the 3 study groups • No reports of severe allergy or anaphylaxis were reported in any children in the study • Primary outcomes: The proportion of children who recovered was significantly lower in those who received placebo (85.1%) than in those who received either amoxicillin (88.7%, p = 0.02) or cefdinir (90.9%, p = 0.0001) • Subgroup analysis showed that, when stratified by type of SAM, children with kwashiorkor who received placebo recovered less frequently than those who received cefdinir (92.2% vs. 95.2%, p = 0.04) • Similarly, children with marasmus who received placebo also recovered less frequently than those who received cefdinir (74.4% vs. 79.2%, p = 0.02) • The overall mortality rate was 5.4%, but significantly higher in children who received placebo (7.4%) than in those who received either amoxicillin (4.8%, p = 0.02) or cefdinir (4.1%, p = 0.003) • This corresponds to a 36% (95% CI, 7%–55%) reduction in mortality when given amoxicillin and a 44% (95% CI 18%–62%) reduction in mortality with cefdinir	• In children who recovered, the rate of weight gain was increased in those who received antibiotics • No interaction between type of SAM and intervention group was observed for the rate of nutritional recovery or mortality • Cefdinir was superior to amoxicillin, and amoxicillin was superior to placebo, resulting in significantly improved recovery at 12 weeks (90.9%, 87.7%, 85.1%, respectively) and mortality (4.1%, 4.8%, 7.4%) • Trial included a high rate of HIV+ children (n = 188); however, distribution was equitable across intervention groups • The authors concluded that these results provide clear evidence to support the recommendation for routine oral antibiotics as part of the outpatient management of SAM	B (RCT with strong methodological quality)
Isanaka et al. [7]	Routine amoxicillin for uncomplicatedsevere acute malnutrition in children	2016	• Double-blind, placebo-controlled RCT at 4 health centres in rural Niger to assess the effect of routine amoxicillin on nutritional recovery in children with severe malnutrition • n = 2399 (1199 in treatment, 1200 in placebo) • Children randomly assigned (computer-generated) 1:1 ratio in blocks of 6 to receive 80 mg/kg amoxicillin in 2 daily doses or placebo for 7 days; adherence monitored by home visits • Inclusion criteria: Children must not have received any antibiotic treatment within the prior 7 days; 6–59 months, WfH Z-score <-3 and/or MUAC 115 mm; passed appetite testing; absence of clinical complications (including oedema) • Primary aim: examining the effect of routine antibiotic use • Primary outcome: nutritional recovery by 8 weeks (WfH Z-score >-2 on 2 consecutive visits or MUAC >115 mm)	• Overall, 64% of children enrolled in the study recovered • No significant difference in likelihood of recovery between amoxicillin vs. placebo (RR with amoxicillin 1.05, 95% CI 0.99–1.12) • Among children who recovered, time to recovery was significantly shorter with amoxicillin than placebo (mean treatment of 28 vs. 30 days, p < 0.001) • Amoxicillin had no significant affect in children with confirmed bacterial infection on admission • Secondary outcomes: Amoxicillin tended to reduce the risk of death in children who were >24 months (RR 0.24, 95% CI 0.02–2.12) but not in those <24 months (RR3.04, 95% CI 0.61–15.01) • 13 children died during treatment, 7 in the amoxicillin group and 6 in the placebo group; time to death did not differ significantly between the two groups (p = 0.4) • Amoxicillin significantly decreased the overall risk of transfer to inpatient care (26.4% vs. 30.7%, RR 0.86, 95% CI 0.78–0.98, p = 0.02) and for acute gastroenteritis in particular (RR 0.67, 95% CI 0.48–0.94, p = 0.02) • Amoxicillin significantly accelerated early gains in weight and MUAC (week 1: RR 3.8, 95% CI 3.1–4.6, p<0.001), with no significant effect on overall weight gain by week 4 or height gain during treatment • No cases of severe allergy or anaphylaxis were identified; diarrhoea was less frequent in the amoxicillin group than in the placebo group at week 1. None of the clinical complications or deaths were reported to be related to the study drug • RESISTANCE: the likelihood of resistance to amoxicillin was 35% for enterobacteria isolated from stool in children with diarrhoea, and 66% for enterobacteria isolated in blood	• Routine provision of amoxicillin was not superior to placebo for nutritional recovery in children with uncomplicated SAM. • “This finding challenges the view that routine antibiotic therapy is always necessary or beneficial”. • Amoxicillin reduced the risk of a transfer to inpatient care by 14% compared with placebo • Amoxicillin specifically reduced the risk of transfer to inpatient care for clinical complications owing to gastroenteritis. This was unexpected as the viruses and parasites primarily responsible for gastroenteritis in young children are not sensitive to amoxicillin [30]. A possible explanation provided by the authors is that poor mucosal integrity in malnourished children allows the translocation of bacteria across compromised intestinal surfaces, resulting in bacteraemia, or that oral antibiotics may reduce excessive proliferation of small-bowel flora, modifying the composition and function of the gut microbiome • Limitations: Assumed a likelihood of nutritional recovery of 80%, which was not achieved so cannot rule out the possibility that amoxicillin had a protective effect of 12% or a harmful effect of 1% on nutritional recovery • Risk of bias: excluded children with mild-moderate oedema – ?patient population too well	B (RCT with strong methodological quality)
Berkley et al. [34]	Daily co-trimoxazole prophylaxis to prevent mortality in children with complicated severe acute malnutrition: a multicentre, double-blind, randomised placebo-controlled trial	2016	• A multi-centre, double-blind, randomised, placebo-controlled study in 4 hospitals in Kenya (two rural hospitals in Kilifi and Malindi, and 2 urban hospitals in Mombasa and Nairobi) • n = 1778 • 2009–2013 • Children aged 3 months-59 months without HIV admitted to hospital and diagnosed with (complicated) SAM • After nutritional stabilisation, participants were randomly assigned (1:1) to 6 months of either daily oral co-trimoxazole prophylaxis (water-dispersible tablets; 120 mg per day for age <6 months, 240 mg per day for age 6 months to 5 years) or matching placebo • Assignment was done with computer-generated randomisation in permuted blocks of 20, stratified by centre and age (younger or older than 6 months) • Treatment allocation was concealed in opaque, sealed envelopes and patients, their families, and all trial staff were masked to treatment assignment • Children were given recommended medical care and feeding, and followed up for 12 months • The efficacy of co-trimoxazole was chosen for investigation due to its well documented effect on mortality in children with HIV who present with infectious syndromes that are broadly similar to those noted in children with SAM • Primary endpoint was mortality, assessed each month for the first 6 months, then every 2 months for the second 6 months • Secondary endpoints were nutritional recovery, readmission to hospital, and illness episodes treated as an outpatient • Analysis was by intention to treat	• Median age was 11 months (IQR 7–16 months); 306 (17%) were younger than 6 months • 300 (17%) had oedematous malnutrition (kwashiorkor) • 1221 (69%) were stunted (length-for-age Z score < –2) • During 1527 child-years of observation, 122 (14%) of 887 children in the co-trimoxazole group died, compared with 135 (15%) of 891 in the placebo group (unadjusted hazard ratio [HR] 0·90, 95% CI 0·71–1·16, p = 0·429; 16·0 vs. 17·7 events per 100 child-years observed (CYO); difference –1·7 events per 100 CYO, 95% CI –5·8 to 2·4]) • In the first 6 months of the study (while participants received study medication), 63 suspected grade 3 or 4 associated adverse events were recorded in 57 (3%) children; 31 (2%) in the co-trimoxazole group and 32 (2%) in the placebo group (incidence rate ratio 0·98, 95% CI 0·58–1·65) • The most common adverse events of these grades were urticarial rash (grade 3, equally common in both groups), neutropenia (grade 4, more common in the cotrimoxazole group) and anaemia (both grades equally common in both groups) • One child in the placebo group had fatal toxic epidermal necrolysis with concurrent Pseudomonas aeruginosa bacteraemia	• The authors conclude that in HIV-negative Kenyan children with complicated SAM, daily co-trimoxazole for 6 months was well tolerated but did not reduce mortality or improve growth. • The authors questioned if low bacterial susceptibility to co-trimoxazole may be the reason for an absence of a protective effect on mortality • In children with SAM, two main reasons were noted for initial admission, diarrhoea and pneumonia, which raised the hypothesis that SAM with diarrhoea might represent a phenotype amenable to antimicrobial prophylaxis targeting pathogens and commensal microbes, intestinal barrier function, and immune homeostasis that could be tested in further trials.	B (RCT with strong methodological quality)

Table

Authors	Title	Year	Methods (study type, setting, participants)	Results	Conclusions	GRADE level of evidence
Chisti et al. [41]	Treatment failure and mortality amongst children with severe acute malnutrition presenting with cough or respiratory difficulty and radiological pneumonia	2015	• Cohort study: Prospective enrolment of SAM children aged 0–59 months admitted to the Intensive Care Unit or Acute Respiratory Infection ward of the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh in April 2011 to June 2012 with cough or respiratory difficulty and radiological pneumonia • All the enrolled children were treated with ampicillin and gentamicin and micronutrients as recommended by the WHO • Comparison was made between pneumonic children with (n = 111) and without (n = 296) WHO-defined danger signs of severe pneumonia • Primary outcomes: Treatment failure (if a child required change of antibiotics) and deaths during hospitalisation • Further comparison was made of those who developed treatment failure and those who did not	• SAM children with danger signs of severe pneumonia more often experienced treatment failure (58% vs. 20%, p < 0.001) and fatal outcome (21% vs. 4%, p < 0.001) than those without danger signs • Only 6/111 (5.4%) SAM children with danger signs of severe pneumonia and 12/296 (4.0%) without danger signs had bacterial isolates in blood • In log-linear binomial regression analysis, after adjusting for potential confounders, danger signs of severe pneumonia, dehydration, hypocalcaemia and bacteraemia were independently associated with treatment failure and deaths in SAM children presenting with cough or respiratory difficulty and radiological pneumonia (p < 0.01) • Only 2 children with danger signs and 4 without danger signs of severe pneumonia had a blood culture isolate that was not susceptible to ampicillin and gentamicin • 3 study children had a blood culture isolate which was not susceptible to ceftriaxone and only one child to ciprofloxacin • Overall, 18 (4.4%) children had bacteraemia, and the difference in bacteraemia between the groups was not significant • 67 (16.5%) children had a history of prior use of antibiotics and only 2 (3%) of them had bacteraemia	• Ampicillin and gentamicin are insufficient for children with complicated SAM presenting with pneumonia • The result underscores the importance of further research, especially a randomised, controlled clinical trial to validate standard WHO therapy in SAM children with pneumonia, especially with danger signs of severe pneumonia, to reduce treatment failure and deaths • Biased by previous administration of antibiotics	C
Yebyo et al. [40]	Outpatient therapeutic feeding program outcomes and determinants in treatment of severe acute malnutrition in Tigray northern Ethiopia: a retrospective cohort study	2013	• Retrospective cohort study • 628 children 6–59 months who had been managed for SAM as outpatients from April 2008 to Jan 2012 • The children were selected using systematic random sampling from 12 health posts and 4 health centres  • Tigray, Northern Ethiopia • Details of amoxicillin mg/kg not clarified • Children admitted to the outpatient treatment programme receive weekly rations of Plumpy Nut and supplements including vitamin A, folic acid tabs, antibiotics, deworming tabs and measles vaccine • Children did not have medication administration supervised	• Children who took amoxicillin had significantly faster recovery compared to children who did not take amoxicillin (χ^2 = 136.59, p < 0.0001) • Children who took amoxicillin had 95% (HR 1.95, 95% CI 1.17–3.23) a higher probability of recovery compared to those who didn't take amoxicillin	• The authors conclude that amoxicillin is a positive predictor of faster recovery in children with uncomplicated SAM, and postulate this is secondary to treating small bowel bacterial overgrowth which may be the source of systemic infection by translocation across the bowel wall, resulting in malabsorption of nutrients, failure to eliminate substances excreted in the bile, fatty liver and intestinal damage causing chronic diarrhoea • Biased by retrospective design and poor monitoring of medication administration	D
Page et al. [14]	Infections in Children Admitted with Complicated Severe Acute Malnutrition in Niger	2013	• A clinical and biological characterisation of infections in hospitalised children with complicated SAM in Maradi, Niger • 311 children 6–59 months • Study period October 2007 to July 2008 • SAM WfH<−3 Z-score of the median WHO growth standards and/or MUAC <110 mm and/or bipedal oedema • Complicated SAM defined as SAM accompanied by anorexia and/or kwashiorkor with bilateral pitting oedema and/or another severe condition (severe anaemia, severe respiratory tract infection, malaria with signs of severity, other severe infections such as meningitis or sepsis, diarrhoea with dehydration, lethargy or acute neurological disorders, sickle cell crisis) • Clinical examination, blood, urine and stool cultures and chest radiography were performed systematically on admission • Amoxicillin was given systematically or parenteral ceftriaxone in cases of suspected severe or complicated infectious syndrome. No mention of gentamicin in methodology • Treatment was modified based on indications such as non-improvement of clinical condition and/or results of bacterial culture and antibiotic sensitivity testing. Depending on the type of infection suspected, cloxacillin (skin infection, severe pneumonia, S. aureus bacteraemia) or ciprofloxacin (urinary tract infection, severe, explosive or persistent diarrhoea >72 hours, bloody diarrhoea, bacteraemia with suspected Gram-negative bacteria) was added in case of treatment failure, based on lack of improvement or worsening of symptoms within 72 hours of treatment • Children with uncomplicated malaria diagnosed either by rapid test and/or smear microscopy were given oral artesunate and amodiaquine for 3 days. Children with severe or complicated malaria received arthemether IM and then artesunate-amodiaquine if their condition improved, for 7 days in all	• Prevalence data: In the 311 children in the study, gastroenteritis was the most frequent clinical diagnosis on admission, followed by respiratory tract infections and malaria. • Blood or urine culture was positive in 17% and 16% of cases, respectively, and 36% had abnormal chest radiography. • Enterobacteria were sensitive to most antibiotics except amoxicillin and cotrimoxazole. • The median length of stay in the inpatient treatment facility was 8 days (IQR 6–13 days). • 29 (9%) of children died; almost half of all deaths (48%, n  =  14/29) occurred within 48 h of admission. • The main causes of death recorded were sepsis (15), respiratory tract infection (4) and clinical suspicion of tuberculosis (2). • Overall, 20 (69%) children who died had one or several laboratory or X-ray-proven infections, including 8 bacteraemia (4 S. aureus, 2. H. influenzae, 1 Salmonella spp., 1 E. coli); 7 UTI (6 E. coli, 1 K. pneumoniae); 3 infectious diarrhoea (1 S. flexneri, 1 S. sonnei, 1 Salmonella spp.); 2 malaria and 2 RTI. • The CFR was 16% (n  =  8/51, p  =  0.1) in patients with a positive blood culture, 15% (n  =  7/41, p  =  0.2) in children with a UTI, 8.3% (n  =  4/62, p  =  0.5) in children with infectious diarrhoea and 4.5% (n  =  2/44, p  =  0.5) in those with malaria. • Clinical signs were poor indicators of infection and initial diagnoses correlated poorly with biologically or radiography-confirmed diagnoses	• The authors concluded that the data confirm the high level of infections and poor correlation with clinical signs in children with complicated SAM, and provide antibiotic resistance profiles from an area with limited microbiological data. These results contribute unique data to the ongoing debate on the use and choice of broad-spectrum antibiotics as first-line treatment in children with complicated SAM and reinforce the call for an update of international guidelines on management of complicated SAM based on more recent data’. • Limitations: Did not reach target sample size (n = 1000) owing to the premature closure of the MSF programme; resulted in missing data in particular the months of August to October, which correspond to the malnutrition and malaria peaks; secondly, diagnostic capacity is limited compared with developed country settings and it was difficult to ascertain diagnoses in some cases (e.g. TB diagnosed clinically). Third, glycaemia was not analysed here because it was measured after children were administered the appetite test, limiting its interpretation. Fourth, high prevalence of blood culture contamination may have resulted in underestimation of children who died from sepsis owing to inaccurate characterisation of culture results	D

World Health Organization. Pocket book of hospital care for children. 2nd ed. Geneva: WHO; 2013.

 Google Scholar

Alcoba G, Kerac M, Breysse S, et al. Do children with uncomplicated severe acute malnutrition need antibiotics? A systematic review and meta-analysis. PLoS ONE. 2013;8:e53184.

 PubMed Web of Science ®Google Scholar

Jones KD, Hunten-Kirsch B, Laving AM, et al. Mesalazine in the initial management of severely acutely malnourished children with environmental enteric dysfunction: a pilot randomized controlled trial. BMC Med. 2014;12:357.

 Web of Science ®Google Scholar

Kotloff K, Nataro JP, Blackwelder WC, et al. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study. Lancet. 2013;382:209–222.

 PubMed Web of Science ®Google Scholar

Picot J, Hartwell D, Harris P, et al. The effectiveness of interventions to treat severe acute malnutrition in young children: a systematic review. Health Technol Assess. 2012;16:1–316.

 PubMed Web of Science ®Google Scholar

Dubray C, Ibrahim SA, Abdelmutalib M, et al. Treatment of severe malnutrition with 2-day intramuscular ceftriaxone vs 5-day amoxicillin. Ann Trop Paediatr. 2008;28:13–22.

 PubMed Web of Science ®Google Scholar

Trehan I, Amthor R, Maleta K, et al. Evaluation of the routine use of amoxicillin as part of the home-based treatment of severe acute malnutrition. Trop Med Int Health. 2010;15:1022–1028.

 PubMed Web of Science ®Google Scholar

Lazzerini M, Tickell D. Antibiotics in severely malnourished children: systematic review of efficacy, safety and pharmacokinetics. Bull WHO. 2011;89:594–607.

 PubMed Web of Science ®Google Scholar

Milion M, Lagier J, Raoult D. Meta-analysis on efficacy of amoxicillin in uncomplicated severe acute malnutrition. Microb Pathog. 2016;106:76–77.

 PubMed Web of Science ®Google Scholar

Trehan I, Goldbach HS, LaGrone LN, et al. Antibiotics as part of the management of severe acute malnutrition. N Engl J Med. 2013;368:425–435.

 PubMed Web of Science ®Google Scholar

Isanaka S, Villamor E, Shepherd S, et al. Assessing the impact of the introduction of the world health organization growth standards and weight-for-height z-score criterion on the response to treatment of severe acute malnutrition in children: secondary data analysis. Pediatrics. 2009;123:e54–e59.

 PubMed Web of Science ®Google Scholar

Berkley JA, Ngari M, Thitiri J, et al. Daily co-trimoxazole prophylaxis to prevent mortality in children with complicated severe acute malnutrition: a multicentre, double-blind, randomised placebo-controlled trial. Lancet Glob Health. 2016;4:e464–e473.

 PubMed Web of Science ®Google Scholar

M Chisti, M Salam, P Bardhan, et al. Treatment failure and mortality amongst children with severe acute malnutrition presenting with dough or respiratory difficulty and radiological pneumonia. PLoS One. 2015;10:e0140327. DOI:10.1371/journal.pone.0140327

 PubMed Web of Science ®Google Scholar

Yebyo H, Kendall C, Nigusse D, et al. Outpatient therapeutic feeding program outcomes and determinants in treatment of severe acute malnutrition in Tigray, Northern Ethiopia: a retrospective cohort study. PLoS ONE. 2013;8:e65840.

 PubMed Web of Science ®Google Scholar

Page AL, de Rekeneire N, Sayadi S, et al. Infections in children admitted with complicated severe acute malnutrition in Niger. PLoS ONE. 2013;8:e68699.

 PubMed Web of Science ®Google Scholar