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Antibiotics as Part of the Management of Severe Acute Malnutrition Indi Trehan MD MPH DTM&H Assistant Professor, Washington University in St. Louis Department.

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Presentation on theme: "Antibiotics as Part of the Management of Severe Acute Malnutrition Indi Trehan MD MPH DTM&H Assistant Professor, Washington University in St. Louis Department."— Presentation transcript:

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/WFP/UNSCN/UNICEF, 2007WHO, 2003

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

4 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) Antibiotics for Severe Acute Malnutrition RCT design

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? Malawi Medical Journal 2009; 21: 29 Penicillin or Ampicillin Erythro- mycin Chlor- amphenicol Co- trimoxazoleGentamicin Tetra- cyclineCeftriaxone Cipro- floxaxin 100 % 100 % 100 % 100 % 100 % Penicillin Ampicillin

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

8 Adverse Events New England Journal of Medicine 2013; 368: 425 VariableAmoxicillinCefdinirPlacebo Number of children who took all 7 days of intervention 865/879 (98)887/897 (99)865/872 (99) Fever since enrollment309/876 (35)339/889 (38)337/870 (39) Cough since enrollment239/874 (27) A 280/889 (31)301/871 (35) A Diarrhea since enrollment322/878 (37) B 282/889 (32) B,C 352/871 (40) C Vomiting since enrollment114/877 (13)124/890 (14)137/872 (16) Rash since enrollment43/865 (5)31/872 (4)37/857 (4) Reported to have a good appetite since enrollment 865/879 (98)883/893 (99)855/871 (98) Values are presented as no./total no. (%). All pairwise comparisons with P > 0.05 except for the following: A P = for cough since enrollment for amoxicillin vs. placebo B P = 0.03 for diarrhea since enrollment for amoxicillin vs. cefdinir C P < for diarrhea since enrollment for cefdinir vs. placebo

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 p= 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= 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 Annals of Tropical Paediatrics 1992; 12: 433 Annals of Tropical Paediatrics 2006; 26: 319 International Journal of Infectious Diseases 2002; 6: 187 Pediatric Infectious Disease Journal 2000; 19: 312American Journal of Diseases in Childhood 1984; 138: 551

14 Antibiotics for Severe Acute Malnutrition Bacteremia and gut translocation Archives of Disease in Childhood 1997; 76: 236 American Journal of Clinical Nutrition 1987; 45: 1433 Trends in Microbiology 2010; 18: 487 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-HD L40-HD Hickey Family Foundation USAID Agency for Educational Development Office of Health, Infectious Diseases, and Nutrition Office of Food for Peace

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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 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 Understanding the Gut Microbiome…in Kwashiorkor Gnotobiotic mouse model

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

23 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


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