Antibiotics as Part of the Management of Severe Acute Malnutrition

Indi Trehan MD MPH DTM&HAssistant Professor, Washington University in St. Louis Department of PediatricsVisiting Lecturer, University of Malawi Department of Paediatrics and Child Health17 October 2013

Community-Based Management of Severe Acute MalnutritionAdjuncts to RUTF?

WHO, 2003; WHO/WFP/UNSCN/UNICEF, 2007WHO, 2003

Antibiotics for Severe Acute MalnutritionA need for prospective data

PLoS ONE 2013; 8: e53184Bulletin of the World Health Organization 2011; 89: 593

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 MalnutritionRCT design

Antibiotics for Severe Acute MalnutritionWhich antibiotics to use?

Retrospective review of all admission blood cultures obtained from the 4322 children admittedto the Nutritional Rehabilitation Unit at Queen Elizabeth Central Hospital in BlantyreAugust 2005 – March 2008

971bloo

d cul-ture

s

3351no blood culture

33 (3.4%)Gram-

pos-itives

73 (7.5%)non

-Ty-phoidal Salmonella

57 (5.9%) other

Gram-negatives

808 (83%)

no growth or con-

taminants

Malawi Medical Journal 2009; 21: 29

Antibiotics for Severe Acute MalnutritionWhich antibiotics to use?

Malawi Medical Journal 2009; 21: 29

Penicillinor

Ampicillin

Erythro-mycin

Chlor-ampheni

col

Co-trimoxaz

oleGentami

cinTetra-

cyclineCeftriaxo

neCipro-

floxaxin

73 (7.5%)non-Ty-

phoidal Sal-

monella

33 (3.4%)Gram-posi-tives

57 (5.9%

) other Gram-neg-atives

100%

100%

100%

100%

100%

Penicillin

Ampicillin

Ampicillin

Baseline Characeristics

New England Journal of Medicine 2013; 368: 425

Adverse Events

New England Journal of Medicine 2013; 368: 425

VariableAmoxicilli

n Cefdinir Placebo

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 enrollment 43/865 (5) 31/872 (4) 37/857 (4)Reported to have a good

appetite since enrollment865/879

(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:AP = 0.001 for cough since enrollment for amoxicillin vs. placeboBP = 0.03 for diarrhea since enrollment for amoxicillin vs. cefdinirCP < 0.001 for diarrhea since enrollment for cefdinir vs. placebo

24.4% (4.1%-40.4%) reduction in failure rate with amoxicillin38.9% (21.1%-52.7%) reduction in failure rate with cefdinir35.5% (6.9%-55.4%) reduction in mortality rate with amoxicillin44.3% (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

Amox-icillin

Cefdinir Placebo

88.7% 90.9%85.1%

Recovered2 p=0.0005

p=0.0001RR 0.94

(0.91 - 0.97)5.8%

difference(2.8% - 8.8%)

p=0.021RR 0.96

(0.93 - 0.99)3.6% difference(0.6% - 6.7%)

Amox-icillin

Cefdinir Placebo

4.8%4.1%

7.4%

Died2 p=0.0045

p=0.018RR 1.55 (1.07-2.24)

2.6% diff (0.5% - 4.8%)

p=0.0025RR 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 MalnutritionBacteremia and gut translocation

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

Antibiotics for Severe Acute MalnutritionBacteremia and gut translocation

Archives of Disease in Childhood 1997; 76: 236American Journal of Clinical Nutrition 1987; 45: 1433American Journal of Clinical Nutrition 1987; 45: 1433Trends in Microbiology 2010; 18: 487PLoS 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 KwashiorkorDisruption in normal development

Science 2013; 339: 548

Understanding the Gut Microbiome…in KwashiorkorDisruption 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

• 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 KwashiorkorGnotobiotic mouse model

Nature Reviews Gastroenterology & Hepatology 2013; 10: 261

Understanding the Gut Microbiome…in KwashiorkorGnotobiotic mouse model

Understanding the Gut Microbiome…in KwashiorkorGnotobiotic 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 KwashiorkorGnotobiotic 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