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

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

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

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 80-90 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 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

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

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

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 = 0.001 for cough since enrollment for amoxicillin vs. placebo BP = 0.03 for diarrhea since enrollment for amoxicillin vs. cefdinir CP < 0.001 for diarrhea since enrollment for cefdinir vs. placebo New England Journal of Medicine 2013; 368: 425

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

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

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

Amoxicillin decreased failure rate by 24% and death rate by 36%. p=0.0001 RR 0.94 (0.91 - 0.97) 5.8% difference (2.8% - 8.8%) p=0.021 RR 0.96 (0.93 - 0.99) 3.6% difference (0.6% - 6.7%) p=0.018 RR 1.55 (1.07-2.24) 2.6% diff (0.5% - 4.8%) p=0.0025 RR 1.80 (1.22 - 2.64) 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

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

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

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

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

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

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

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

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

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