1. Antibiotics as Part of the Management of Severe Acute Malnutrition
Indi Trehan MD MPH DTM&H
Assistant Professor, Washington University in St. Louis Department of Pediatrics
Visiting Lecturer, University of Malawi Department of Paediatrics and Child Health
17 October 2013

2. Community-Based Management of Severe Acute Malnutrition
Adjuncts to RUTF?
WHO, 2003
WHO, 2003; WHO/WFP/UNSCN/UNICEF, 2007

3. Antibiotics for Severe Acute Malnutrition
A need for prospective data
Bulletin of the World Health Organization 2011; 89: 593
PLoS ONE 2013; 8: e53184

4. Antibiotics for Severe Acute Malnutrition RCT design
Population :: Children 6-59 months old with severe acute malnutrition (SAM) who qualify for community-based therapy (i.e., have an appetite and a reliable caretaker)
Kwashiorkor (edematous malnutrition) and/or Marasmus (weight-for-height Z-score < -3)
Within walking distance of one of 18 rural clinic sites in southern Malawi
Exclusions :: obvious chronic debilitating illness (excluding HIV & TB); recently enrolled in a therapeutic feeding program for acute malnutrition (inpatient or outpatient)
Intervention :: Empiric oral antibiotics in addition to RUTF
Amoxicillin mg/kg/d div BID x7d
Cefdinir ~14 mg/kg/d div BID x7d
Comparison :: Placebo in addition to RUTF
Outcomes
Primary :: adverse effects; nutritional recovery; mortality
Secondary :: time to recovery; growth parameters (height, weight, MUAC)

5. Antibiotics for Severe Acute Malnutrition Which antibiotics to use?
Retrospective review of all admission blood cultures obtained from the 4322 children admitted
to the Nutritional Rehabilitation Unit at Queen Elizabeth Central Hospital in Blantyre
August 2005 – March 2008
Malawi Medical Journal 2009; 21: 29

6. Antibiotics for Severe Acute Malnutrition Which antibiotics to use?
Penicillin
or Ampicillin
Erythro-mycin
Chlor-amphenicol
Co-trimoxazole
Gentamicin
Tetra-cycline
Ceftriaxone
Cipro-floxaxin
100 %
Penicillin
Ampicillin
Malawi Medical Journal 2009; 21: 29

7. Baseline Characeristics
New England Journal of Medicine 2013; 368: 425

8. Adverse Events Variable Amoxicillin Cefdinir Placebo
Number of children who took all 7 days of intervention
865/879 (98)
887/897 (99)
865/872 (99)
Fever since enrollment
309/876 (35)
339/889 (38)
337/870 (39)
Cough since enrollment
239/874 (27)A
280/889 (31)
301/871 (35)A
Diarrhea since enrollment
322/878 (37)B
282/889 (32)B,C
352/871 (40)C
Vomiting since enrollment
114/877 (13)
124/890 (14)
137/872 (16)
Rash since enrollment
43/865 (5)
31/872 (4)
37/857 (4)
Reported to have a good appetite since enrollment
883/893 (99)
855/871 (98)
Values are presented as no./total no. (%).
All pairwise comparisons with P > 0.05 except for the following:
AP = for cough since enrollment for amoxicillin vs. placebo
BP = 0.03 for diarrhea since enrollment for amoxicillin vs. cefdinir
CP < for diarrhea since enrollment for cefdinir vs. placebo
New England Journal of Medicine 2013; 368: 425

9. 24.4% (4.1%-40.4%) reduction in failure rate with amoxicillin
38.9% (21.1%-52.7%) reduction in failure rate with cefdinir
35.5% (6.9%-55.4%) reduction in mortality rate with amoxicillin
44.3% (18.0%-62.2%) reduction in mortality rate with cefdinir

10. Secondary Outcomes
New England Journal of Medicine 2013; 368: 425

11. Survival Analyses
New England Journal of Medicine 2013; 368: 425

12. Amoxicillin decreased failure rate by 24% and death rate by 36%.
p=0.0001
RR 0.94
( )
5.8% difference
(2.8% - 8.8%)
p=0.021
RR 0.96
( )
3.6% difference
(0.6% - 6.7%)
p=0.018
RR 1.55 ( )
2.6% diff (0.5% - 4.8%)
p=0.0025
RR 1.80 ( )
3.3% diff (1.2% - 5.4%)
Amoxicillin decreased failure rate by 24% and death rate by 36%.
Cefdinir decreased failure rate by 39% and death rate by 44%.
Need to treat only 31 children with this $5 intervention to save 1 life.
Antibiotic therapy needs to be vigorously incorporated into CMAM programs and its role emphasized to funding agencies and to those involved in frontline implementation.
New England Journal of Medicine 2013; 368: 425

13. Antibiotics for Severe Acute Malnutrition Bacteremia and gut translocation
American Journal of Diseases in Childhood 1984; 138: 551
Pediatric Infectious Disease Journal 2000; 19: 312
Annals of Tropical Paediatrics 2006; 26: 319
Annals of Tropical Paediatrics 1992; 12: 433
International Journal of Infectious Diseases 2002; 6: 187

14. Antibiotics for Severe Acute Malnutrition Bacteremia and gut translocation
American Journal of Clinical Nutrition 1987; 45: 1433
Archives of Disease in Childhood 1997; 76: 236
Trends in Microbiology 2010; 18: 487
American Journal of Clinical Nutrition 1987; 45: 1433
PLoS ONE 2011; 6: e18580

15. Support Mark Manary St. Louis Nutrition Project Project Peanut Butter
Eunice Kennedy Shriver National Institute for Child Health and Development
T32-HD049338
L40-HD066655
Hickey Family Foundation
USAID
Agency for Educational Development
Office of Health, Infectious Diseases, and Nutrition
Office of Food for Peace

19. Understanding the Gut Microbiome…in Kwashiorkor Disruption in normal development
Science 2013; 339: 548

20. Understanding the Gut Microbiome…in Kwashiorkor Disruption in normal development
“Identical” twin pairs discordant for kwashiorkor
Overall gene contents of the fecal microbiota in children with kwashiorkor fails to develop with increasing age
Microbiome of children kwashiorkor less “mature” than their healthy co-twin

21. Understanding the Gut Microbiome…in Kwashiorkor Gnotobiotic mouse model
Fecal microbial communities from discordant twins at the time of diagnosis were transferred into germ-free gnotobiotic mice
Mice then fed diet based on typical Malawian foods
Mice who received kwashiorkor microbiome lost weight
Mice who received healthy microbiome sustained their weight
Kwashiorkor mice fed RUTF gained weight
Unfortunately, weight gain not that well sustained after RUTF ended

22. Understanding the Gut Microbiome…in Kwashiorkor Gnotobiotic mouse model
Nature Reviews Gastroenterology & Hepatology 2013; 10: 261

23. Understanding the Gut Microbiome…in Kwashiorkor Gnotobiotic mouse model
Meaningful changes in the fecal taxonomic, genetic, and metabolic content accompanied these transplantations and dietary shifts in the recipient mice
PCR for 22 common bacterial, protozoal, and viral enteric pathogens revealed no evidence that this was due to any of these microbes
Significant differences in 37 species-level taxa
Bilophila wadsworthia, a sulphite-reducing organism previously linked to IBD flares
Clostridia innocuum, a symbiont that is an opportunistic pathogen in immunocompromised hosts
3 species of Bifidobacteria, 2 species of Lactobacilli, 2 Ruminococcus species recovered after receiving RUTF, as did amounts of essential and nonessential amino acids

24. Understanding the Gut Microbiome…in Kwashiorkor Gnotobiotic mouse model
Analysis of urinary metabolites revealed an inhibition of the Krebs (TCA) cycle in kwashiorkor mice fed a Malawian diet -- indicative of impaired cellular metabolism and energy production
Taurine, cysteine, methionine concentrations also disrupted, suggestive of disordered sulfur metabolism -- consistent with prior data linking sulfur amino acid metabolism to kwashiorkor