Introduction:
Enteric fever is now a day primarily found in countries where
sanitary conditions are poor. It is an important cause of morbidity and
mortality in many developing countries, with an estimated 33 million
cases worldwide1. In Asia, the mean incidence of enteric fever is
estimated to be 900 per 1,00,000 people per annum2. Around 10% of
total admissions in children ward of St. Stephen’s hospital are cases of
enteric fever.
The resistance of Salmonella enterica subspecies enterica serovar
typhi (S. typhi) to chloramphenicol was first reported in India from
Kerala, where a substantial outbreak took place in 1972 3. Salmonella
typhi resistant to first line treatment (chloramphenicol, cotrimoxazole
and ampicillin) are known as multidrug resistance typhoid fever
(MDTRF)
4-8
. Fluoroquinolones are widely regarded as the most
effective drug for the treatment of typhoid fever. But unfortunately some
strains
of
s.typhi
have
shown
reduced
susceptibility
to
Fluoroquinolones9-17. After the onset of resistance to fluoroquinolones,
treatment choices are limited to expensive alternatives, such as thirdgeneration cephalosporins or azithromycin18-24.
With reporting multiple resistance transfer factors in the New
Delhi Metallo-betalactamase enzyme (NMD1) bacteria, it seems that the
pathogens are again gaining an upper hand25-28. Also it is reported that
newer antibiotics are not being discovered to keep pace and the
antibiotic pipe line is drying up29. This has prompted the efforts to find
innovative cures for infections. The use of probiotic, prebiotics and
foods that help overcome infections are novel fields that are being
investigated30-31.
Recently Adebolu et al, show garlic has antibacterial activity
against S. typhi. They have verified this in vitro and in vivo in albino
rats experiments32. In vitro garlic extract inhibited the growth of S.
typhi on agar plate which was superior to that of most the
conventional antibiotics. In vivo, the consumption of garlic extract
caused a significant (p<0.05) reduction in the number of S.typhi in the
feaces of the infected rats from 2.0 x 108 to 9.0 x 101 cfu/ml and also
reduced the duration of infection from 5 to 3 days 32. These results
indicate that it may be possible to use garlic as an adjunct in the
treatment of S. typhi infection.
Garlic has been used for the prevention and treatment of a variety
of diseases, ranging from infections to heart diseases33-36. It is known for
its antibacterial, antioxidant and anticancer properties33-36. Antibacterial
activity against Gram-negative and Gram-positive bacteria including
such species as Escherichia coli , Salmonella species, Streptococcus,
Staphylococcus, Klebsiella, Proteus and H. pylori have all been studied
earlier37-42. Even acid-fast bacteria such us Mycobacterium tuberculosis
has been found sensitive to garlic in some studies. Garlic has been used
safely in various in vivo studies without any complications or side
effects35,36,38,40-43.
Garlic (Allium sativum) is a commonly used food additive all
over the world for centuries. Garlic is also a common food ingredient in
India. This study is being done to examine if the addition of garlic to the
standard antibiotic regime of children with enteric infection can modify
the duration of illness in these children.
AIM AND OBJECTIVE:
To examine if adding allium sativum as food supplement to the standard antibiotic
regime of children admitted to the hospital with a diagnosis of enteric fever on can
be beneficial to reduce the duration of illness.
 Primary outcome measure:
-Duration of febrile period.
 Secondary outcome measure:
1. Complication rate in the form of major organ system failure.
2. Effect on hematological parameters including total leukocyte count
(TLC), platelets and hemoglobin.
3. Duration of hospital stay.
MATERIALS AND METHOD:
Type of study:
It is an open label randomized control study.
Inclusion criteria:
All the children aged 5 years to 12 years, admitted in children ward with
confirmed diagnosis of enteric fever
Exclusion criteria:
1. Child aged < 5 years or >12 years
2. Patient with complication at admission in the form of major organ
system failure or children who are nil per oral.
Sample size:
Using the method of Fleiss with continuity correction, for 80% chance
of detecting with a two-sided significance level (1-alpha) of 95 keeping
the ratio of exposed to unexposed at 1 and a risk/prevalence ratio of 4
the sample size will have to be 88 children as controls and 88 as
experimental group.
In last 6 month at SSH there were admitted 124 cases of enteric fever
among the total of 1204 admission. Mean of duration of hospital stay
was 4.9 days (SD 2.48). It will therefore be possible to recruit cases and
controls in one calendar year.
All children will be given treatment as per current unit policy for
treatment of enteric fever. The
standardized unit policy for children
admitted with enteric is to use intravenous (IV) Ceftriaxone at a dose of
100 mg/kg/day. If fever is unresponsive, oral Azithromycin (20
mg/kg/day) is added on 4th day. Antibiotics may be changed in culture
positive cases according to sensitivity pattern. Complicated cases may
be admitted into the PICU and if made nil per oral they will move out of
the trial but be included in the analysis according to intention to treat. If
culture is not positive and fever is unresponsive for 8 days then IV
Levofloxacin (10 mg/ kg/ day) is added as third line antibiotic. IV
Aztreonam is used as fourth line antibiotic (50-100mg/kg/day) if fever is
unresponsive to above treatment.
In this study 1 gm (one small clove of average size) garlic per day will
be given in crushed or chopped form according to palatability of the
child.
Consent:
Written informed consent will be obtained from all patients before
randomization. Parents will be asked if they have any religious or other
objection to using garlic. Only those who do not have objections will be
explained the RCT nature of the trial and told that if they participate they
may be randomized to either treatment groups (Standard drug or
standard drug plus Garlic). Informed written consent will be obtained.
Block randomization by drawing of lots will be done for treatment
allocation.
Consent form
Experiments have suggested that garlic has benefits in typhoid fever but
this is not proven in humans. This is a common food item and as such
carries no known risks. We are looking to see if it decreases fever
duration. We are giving standard antibiotics plus garlic to one group and
only standard antibiotics to other group.
If you as parents are willing to participate your child may be
selected to receive garlic or not.
If you elect not to enter the study please be assured that your
child will receive the same standard of care as otherwise.
Statistical analysis:
Clinical and demographic profile of two groups will be compared by
using parameters like mean duration of febrile period, hospital stay. Two
groups will be compared by using chi square test. P < 0.05 will be
considered significant.
Following definitions will be adopted for this study purpose as per
current unit policy.
 Confirmed case of enteric fever:
A patient with fever that has lasted for at least 5 days and any of
following laboratory test parameter
1. Confirmed positive blood culture for salmonella species.
2. Positive typhi dot.
3. Positive Widal test (TO antigen titer >1:160 in an active infection,
or if TH antigen titer is > 1:160 in past infection or in immunized
persons)
REVIEW OF LITREATURE
Enteric fever is a infectious disease of global distribution with
significant morbidity and mortality. The emergence of multi drug
resistance to S. typhi (MDRST) has been of major concern in recent
years4-8. MDRST is defined as strains of S. typhi resistant to all three
first line antibiotics for typhoid fever. The number of reported multi
resistant typhoid fever increased rapidly through out the world from
1989 onwards with most of the cases from the Middle East and Asia
especially in the Indian subcontinent, Pakistan and China. Resistance to
these agents is associated with the plasmid present in the bacteria44.
The most important factor in preventing death due to enteric
fever is the timely introduction of treatment with effective antibacterial.
The emergence of antibacterial resistance has been rapid throughout the
treatment history of typhoid and was first reported in 1950 after the
introduction of chloramphenicol 2 years previously. In the 1980s and
1990s, S.typhi developed simultaneous resistance to all first line drugs,
notably
chloramphenicol,
amoxicillin,
and
trimethoprim-
sulfamethoxazole(TMP-SMZ), encoded on a single plasmid44. These
multidrug-resistant strains are now widespread, and fluoroquinolones
have largely replaced other agents as the drugs of choice. Emerging
resistance to fluoroquinolones has been a major setback45. Over recent
years, we have noticed an increased rate of poor response to first line
treatment
(ofloxacin)
in
patients
with
enteric
fever.
After
fluoroquinolones, treatment choices are limited to expensive alternatives,
such as third-generation cephalosporins or azithromycin18-24. Salmonella
bacteria however, have become resistant to antibiotics; therefore there is
the need to search for alternative therapeutic measures.
In our hospital, diagnosis of enteric fever is commonly done by
using blood culture, widal test and typhi dot. Blood culture is a gold
standard test. The sensitivity of blood culture is highest in the first week
of the illness46. Overall sensitivity is around 50% but drops considerably
with prior antibiotic therapy44. Blood culture is 100% specific. It also
provides information on the antimicrobial sensitivity of the isolate.
Widal test detects agglutinating antibodies against the O and H antigen
of Salmonella typhi and H antigen of paratyphi A and B. The widal test
has suboptimal sensitivity and specificity47-48. It can be negative in up to
30% of culture proven cases of enteric fever. Typhi dot is a enzyme
immunoassay that detects IgG and IgM antibodies against a 50 KD outer
membrane protein. The sensitivity and specificity of this test has been
reported to vary from 70% - 100% and 43% - 90% respectively49-51.
Garlic (Allium sativum) is a perennial plant in the family Alliaceae, a
member of the same group of plants as the onions.
Active Compounds:
Garlic contains more than 200 chemical compounds. Some of its more
important ones include: volatile oil with sulphur containing compounds:
(allicin, alliin, and ajoene), and enzymes: (allinase, peroxidase and
myrosinase).
Mechanism of action of garlic as antibacterial:
The active ingredient in garlic is called allicin, volatile oil
containing sulphur that is responsible for its pungent odour52-54.
Allicin is generated by action of the enzyme alliinase on alliin. Allicin
normally protects the plant from soil parasites and fungi when
garlic cloves are crushed52,54. Antimicrobial activity of garlic is
known to be due to allicin37. Antimicrobial activity of garlic could
be explained by blocking mechanism by which allicin blocks
certain
groups
of
enzymes as cysteine proteinases and alcohol
dehydrogenases55-57. These groups of enzymes are found in a wide
variety of infectious organisms such as bacteria, fungi and viruses and
this provides a scientific basis for broad-spectrum antimicrobial activity
of garlic56-57. It is unlikely that bacteria would develop resistance to
allicin because this would require modifying the very enzymes that
make their survival and activity possible56.
Garlic is well known for its medicinal, antibacterial and pesticidal
properties. It has also been shown to possess anti-parasitic and antitumour properties. Garlic has been in use since ancient times in India
and China for a valuable effect on the
heart
and
circulation,
cardiovascular disease33,34,53,54,56,57. In addition, garlic extract has
been reported to show an in vitro growth inhibition effect against a
large number of yeasts including Candida species55.
Various garlic preparations have been shown to exhibit a wide
spectrum of antibacterial activity against Gram-negative and Gram-
positive bacteria including such species as Escherichia coli, Salmonella
species, Streptococcus, Staphylococcus, Klebsiella, Proteus and H.
pylori37-42. In the USA, trials in AIDS patients have demonstrated
enhancement of natural killer cell activity using garlic extracts and
Chinese studies with viral infections in bone marrow transplant patients
have demonstrated a potent antiviral activity42. Human population
studies have shown that regular intake reduces the risk of oesophageal,
stomach and colon cancer. This was thought to be due to the antioxidant
effect of allicin in reducing the formation of carcinogenic compounds in
the gastro-intestinal tract.
One study showed that active agent of garlic, allicin, effective
agent to eradicate H.pylori41. In this study allicin was given at the dose
of 4200microgram/day safely to patient without any complication. In
study garlic extract was safely used at the dose of 180mg/day of allicin
content for common cold40. Many studies showed that allium sativum
can be safely used anticancer and cholesterol lowering medicine 58-61.
Adebolu et al have recently found in study, done on
albino rats to see the effect of consumption of Allium sativum in
treating Salmonella typhi infection and on the gastrointestinal flora
and hematological parameters of rats was investigated. Crude garlic
extract inhibited the growth of S. typhi on agar plate with a zone of
inhibition averaging 23.8 mm in diameter using the agar diffusion
assay. This inhibition was superior to that of all the conventional
antibiotics used except streptomycin which gave a growth inhibitory
value of 24.0 mm. In the in vivo assay, although, pretreatment with
the extract did not protect rats orogastrically dosed with the infective
dose of S. typhi from the infection, the consumption of crude
garlic extract however, caused a significant (p<0.05) reduction in the
number of S. typhi in the feaces of the infected rats from 2.0 x 10 8 to 9.0
x 101 cfu/ml and also reduced the duration of infection from 5 to
3 days. On the effect of consumption of garlic extract on the type
and load of gastrointestinal flora and hematological parameters of rats,
garlic extract caused a significant (p<0.05) reduction in the type of
bacteria present in the gastrointestinal tract of rats fed 1 ml daily for
7 weeks from six microbial types to one microbial species, reduction
in microbial load of the flora from 1.64 x 1012 to 1.3 x 107
cfu/ml, reduction in packed cell volume (PCV), total white blood
cells (WBC) and lymphocytes counts but caused an increase in
neutrophils and monocytes counts of the rats. The observed increases in
the neutrophils and monocytes counts of the blood suggested that
garlic may possess immune stimulatory effect in addition to its
antibacterial effect32.
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Effect of allium sativum in Enteric fever: An open label RCT
1. Hospital no: _____________
2. Age: ________years
3. Sex: ________
4. Date of admission: _____________
5. Date of discharge:_____________
6. No. days of fever prior to entry point in the study:_________
7. Clinical parameters at the time of admission:
 Maximum temperature over last 24 hours:
 Frequency of fever spike:
 Vitals:
1.HR-_____
/min
2. RR-______
/min
3. BP-
____________mmhg
8. No. of days of fever: ______days
9. No. of days of hospital stay: ________days
10.
No. of antibiotics to be given: ____________________
11.
Antibiotics to be given:
Name
of Date of start Date
antibiotic
Ceftriaxone
Azithromycin
Amikacin
Aztreonam
12.
Complications:
stop
of Total days
 Pneumonia / Bronchitis
 Intestinal perforation
 Toxic myocarditis
 Neurological complication
 Osteomylitis
 Other known complication:
13.
CBC
Day 1
HB
TLC
DLC
Platelets
count
Consent form
Day 5
Experiments suggest that garlic benefits for typhoid fever but this is not proven in
humans. As this common food item there are literally no risks in entering the trial.
We are looking to see if it decreases fever duration. We are giving standard
antibiotics plus garlic to one group and only standard antibiotics to other group.
If you are willing to participate in study, your child may be selected in
any of groups on the basis of randomization.
If you elect not to enter the study, please be assured that he/she will
receive the same standard of care as otherwise.
SIGN OF FATHER/MOTHER