ww.sciencedirect.com

p e d i a t r i c i n f e c t i o u s d i s e a s e 5 ( 2 0 1 3 ) 4 8e5 0

Available online at w

journal homepage: www.elsevier .com/locate/p id

What’s in

Anita Shet*

Associate Professor, Department of Pediatrics, St. John’s Medical College and Hospital, Bangalore 560034, Karnataka, India

a r t i c l e i n f o

Article history:

Received 25 March 2013

Accepted 2 April 2013

Available online 6 April 2013

* Tel.: þ91 (0) 9980524512 (mobile).E-mail address: anitashet@gmail.com.

2212-8328/$ e see front matter Copyright ªhttp://dx.doi.org/10.1016/j.pid.2013.04.002

1. Antibiotics in malnutrition: food for received antibiotics. Children in the antibiotic group also

thought

The world continues to reel under the substantial burden of

malnutrition, despite the availability of several different

strategies for improving nutritional intake. Any additional

therapy that may reduce this toll of malnutrition will be

welcome. A group of researchers thus set out to determine

whether the routine administration of oral antibiotics as part

of the outpatient management of severe acutemalnutrition in

children can improve clinical outcomes. (Trehan I et al N Engl J

Med 2013 Jan 31; 368:425). The research group from theUS and

Malawi conducted a randomized, double-blind, placebo-

controlled trial to assess the role of antibiotics as an adjunct to

nutritional rehabilitation in 2767 severely malnourished

Malawian children (age range, 6e59 months). All children

received appropriate ready-to-use therapeutic food, and were

randomized to receive either a seven-day course of two daily

doses of ampicillin (80e90 mg/kg), cefdinir (14 mg/kg), or

placebo. Nutritional recovery was experienced at a higher

proportion among children who received either antibiotic

(90%) compared to placebo (85%). Mortality was significantly

higher among children in the placebo group (7.4%) compared

to those who received ampicillin (4.8%) or cefdinir (4.1%).

There was also significant improvement in weight and mid-

upper arm circumference among those children who

received either antibiotic. Among children who recovered, the

rate of weight gain was also increased among those who

2013, Indian Academy of

experienced fewer diarrhea episodes compared to children in

the placebo group. No significant difference in the nutritional

recovery or survival was observed between the two antibiotic

groups, and reported adverse events attributable to the anti-

biotics were minimal. These results suggest that adding a

short one-week course of oral antibiotics may improve

nutritional outcomes and survival in children with severe

malnutrition. Widespread employment of antibiotics for non-

infectious causes can only proceed with the greatest caution

as the spectre of antibiotic resistance looms ominously.

Nevertheless, this study offers hope that thousands of lives

may be saved with this inexpensive and feasible strategy.

2. On the flip side: antibiotics as fatteningagents?

We just read above that use of antibiotics may help improved

outcomes in those children who are malnourished. On the

other end of the spectrum, is the question of how antibiotics

may regulate weight gain in normal children. Recent research

throws some interesting and perhaps disturbing light on the

potential association between antibiotic use in early infancy

and subsequent risk of obesity in early childhood. (Trasande

et al, International Journal of Obesity 2013, 37, 16e23). The in-

vestigators examined 11,532 children in the United Kingdom,

during 1991 and 1992 whowere part of a longitudinal study on

Pediatrics, Infectious Disease Chapter. All rights reserved.

p e d i a t r i c i n f e c t i o u s d i s e a s e 5 ( 2 0 1 3 ) 4 8e5 0 49

childhood health and development. They asked parents to

record their children’s exposures to antibiotics within the first

2 years of their lives. They then analyzed the infants during 3

different time periods (birth to 5months; 6e14 months; 15e23

months). Bodymass or weight was also observed at 5 different

times (6 weeks, 10months, 20months, 38months, and 7 years

of age). The researchers used a model that incorporated the

possible effects of parental obesity, duration of breastfeeding,

childhood physical activity and dietary patterns, on the effect

of body mass gain in children. The results of this longitudinal

study showed that at 3 years of age, children who were

exposed to antibiotics at ages less 0e6 months, had signifi-

cantly higher standardized BMI scores, and were 22% more

likely to be overweight than children who had not been

exposed. Those who were exposed from 6 months to 14

months did not have an increase in body mass that was

significantly higher than those who did not use antibiotics in

that same time period, indicating that the timing of exposure

was important. These results gave way to a strong line of

reasoning that the use of antibiotics at an early age may

change the pattern of gut bacteria that corresponds to a

change in the way nutrients were absorbed such that there is

increased growth and weight gain in these children. The an-

imal husbandry industry has utilized the “antibiotic fattening

effect” by adding antibiotics to animal feed at an early age in

order to increase their weight gain. Can it be the same case in

human beings? Although the results do not definitively show

that young infants who were given antibiotics will turn out to

be obese, it does make one think of the effects of changing gut

microbiomes at such an early age.

3. New TB vaccine trial shows cloudy results:any a silver lining in sight?

The hunt for an improved and more efficacious vaccine

against tuberculosis has been going on with great fervor,

despite the global use of BCG in TB endemic countries. Re-

searchers reported a phase 2 trial in rural South Africa using

one such candidate vaccine, MVA85A, developed as a boost

for Bacille CalmetteeGuerin (BCG) (Tameris MD et al Lancet

2013 Feb 4). This candidate vaccine contains a recombinant

strain of modified vaccinia Ankara virus expressing a TB

protein, antigen 85A. Normal, healthy HIV-negative,

BCG-vaccinated infants aged 4e6 months were enrolled, and

randomized to receive one intradermal dose of MVA85A or

Candida skin-test antigen as placebo. Children were moni-

tored every 3 months for a period of 37 months. Although the

primary aim of the trial was to assess safety of the candidate

vaccine, the trial also made a preliminary assessment of ef-

ficacy. The results indicated that 2% of 1399 vaccine recipients

and 3% of 1395 controls developed TB disease during the

follow-up period based on clinical, radiological and microbi-

ological criteria. There was no evidence for protection against

Mycobacterium tuberculosis infection, as determined by an in-

vitro interferon g release assay, which was positive in 13%

of vaccine recipients and 12% of controls. Vaccine efficacy

was 17.3% against tuberculosis disease, and 3.8% against M.

tuberculosis infection. In terms of safety, there appeared to be

moreminor events reported in the vaccine group (89% vs. 45%

of placebo), although serious or systemic adverse events were

similar in both groups. A modest degree of vaccine antigen-

specific T-cell response was seen in the vaccine recipients,

but this degree of immune response did not turn out to be

protective against TB disease or infection. On the face of it,

although the results of this trail appear disappointing, there is

still hope that this vaccine may protect against severe forms

of TB or TB disease in adolescents or adults. Other candidate

vaccines are waiting in the wings for trials, and the quest for a

superior TB vaccine continues.

4. Stretching the injectable inactivated poliovaccine for a post-polio era

There is much rejoicing that India has remained polio-free for

the last 2 years, and the authorities are gearing up toward a

near future when the last case of wild poliovirus will remain a

historical event only to be recounted in medical tomes, and

generations of doctors will grow up not having seeing seen the

devastating effects of paralytic polio. Althoughmuch progress

has been made toward eradicating poliomyelitis, pockets of

poliovirus infection still exist in a few parts of the world,

necessitating the continued use of injectable inactivated

poliovirus vaccine (IPV) or oral polio vaccine (OPV) in all parts

of the world. As countries achieve the title of being “polio-

free”, the live oral vaccine is replaced by IPV. However the cost

of adding another injection to the national vaccine schedule is

not unsubstantial and the Indian government is still grappling

with this reality as we march on toward polio eradication. In

this light, it is interesting to note that scientific teams from

different parts of theworld are looking into ways to reduce the

costs and increase efficiency of the injectable polio vaccine.

One way is to reduce the quantity of injectable vaccine used

per injection in order to stretch the vaccine for use in several

more children, and still achieve the same efficiency.We report

one such study conducted in Cuba (Resik S et al N Engl J Med

2013 Jan 31; 368:416). Researchers randomized 310 Cuban

infants to receive either a standard full intramuscular dose of

IPV or a fractional intradermal dose of IPV (given at one fifth

the standard dose) at ages 4 and 8 months. They found that

more than 90% of infants who received the reduced dose had

protective titers to all three poliovirus types after the second

dose. This response was comparable to the immune response

of infants who had received the full intramuscular dose.

Although responses to fractional doses of inactivated polio-

virus vaccine were lower than responses to full doses, these

differences became marginal after the second dose, and a

good immune response to all serotypeswere found. The use of

fractional IPV doses can result in considerable financial sav-

ings in resource-limited settings. However this strategy has to

be evaluated in greater numbers to truly assess the impact on

children and societies.

5. Improving outcomes in early onset sepsisin neonates: PIP-TAZ and all that JAZZ

In an era of evolving drug resistance in bacterial pathogens,

selecting appropriate empiric antibiotic therapy is a moving

p e d i a t r i c i n f e c t i o u s d i s e a s e 5 ( 2 0 1 3 ) 4 8e5 050

target. For early onset sepsis in neonates, the commonly used

combination antibiotics include ampicillin and gentamicin.

Mounting evidence pointing to emergence of ampicillin-

resistant Escherichia coli infections in neonates, and the asso-

ciation of ampicillin with necrotizing enterocolitis (NEC) has

led investigators to look for strong alternatives in this setting.

Perinatologists from the United States decided to evaluate

piperacillinetazobactam as a suitable option for empiric

therapy for neonatal sepsis, and designed a “before and after”

study using matched and unmatched comparison of the two

combination antibiotic options (Chong et al, J of Perinatol

(2013), 1e4). They assessed 714 low birth weight infants (birth

weights ranging from 500 to 1500 g) who were available for

comparison of outcomes when ampicillin plus gentamicin or

piperacillinetazobactam (PT) was used for suspected sepsis.

Themost significant finding was that there was a reduction in

the incidence of NEC among those neonates given piper-

acillinetazobactam compared to those given ampi-

cillinegentamicin (1% versus 11% in thematched group). They

also found a lower incidence of diaper rash in the PT group.

There was no serious microbiological impact of PT use for

suspected neonatal sepsis. The only adverse finding with PT

was a statistically significant but clinically non-significant

elevation in alkaline phosphatase. Although the study used

PT as monotherapy in early onset sepsis, there is wider

acceptance for its use in combination with gentamicin or

other narrow spectrum Gram negative antibiotic in order to

minimize emergence of resistance. This study may have the

inherent limitations of a retrospective study that uses his-

torical controls, but it does make one ponder on the advan-

tages of newer algorithms for empiric therapy, and

underscores the importance of ongoing surveillance of caus-

ative pathogens and drug resistance testing. Meanwhile the

challenges in saving the lives of our littlest ones, protecting

them from adverse sequelae of drugs used during this sensi-

tive period, all the while preserving treatment options for the

future continues to keep us on our toes.

Conflicts of interest

The author has none to declare.