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Journal of The Association of Physicians of India ■ Vol.

63 ■ November 2015 77

API RECOMMENDATIONS

API Recommendations for the Management of


Typhoid Fever
Rajesh Upadhyay1, Milind Y Nadkar2, A Muruganathan3, Mangesh Tiwaskar4,
Deepak Amarapurkar5, NH Banka6, Ketan K Mehta7, BS Sathyaprakash8

Introduction a herculean task. Various important The panel of experts who


issues related to this major public participated in the meeting prefers to
nteric fever is a condition that health problem in India were use the term ‘enteric fever’ instead of
E is taking its toll even now in
India, where its prevalence doesn’t
deliberated in this focused group
discussion. The practice patterns
‘typhoid fever,’ as the former covers
both typhoid and paratyphoid. In
seem to be decreasing in spite of from across the country were adults, enteric fever tends to cause
the availability of antibiotics and compared, and the best clinical constipation. Therefore, the presence
vaccines in the market. With the practices were pinpointed. of diarrhea instead in such a case
emergence of antibiotic resistant should raise suspicion of a co-
strains of the pathogenic organisms, Epidemiological Concerns infection. Long-term use of proton
the management of this disease of Enteric Fever in the pump inhibitors (PPIs) increases the
is becoming more challenging. Indian Scenario incidence of EF because less or no
Further, there are no standard acid in the stomach facilitates the
India-specific guidelines to treat T h e t e r m ‘ e n t e r i c f e v er ’ passage of bacteria without
this scourge. In order to bridge (EF) in c lu d e s ty ph oid and destruction by the gastric acid. 2
this need gap and for the benefit of p a r a ty p h o id f e v e r s . T y p h o id Definitions3
primary care doctors, the ‘Enteric f e ve r i s c a us e d by a Gr a m - Confirmed enteric fever: Fever
Conclave,’ the first-of-its-kind, was negative organism, Sa lmon ella ≥38°C for at least three days, with
conducted. This meeting was a very enterica subspecies enterica serovar a laboratory-confirmed positive
innovative initiative that facilitated Typhi (Salmonella typhi), whereas cu lture (b lood, bone ma rro w,
a f rank exchang e of op inio ns paratyphoid fever is caused by any bowel fluid) of S. typhi.
b e tw e e n g a s t r o e n t e r o l o g i s t s , of the three serovars of Salmonella
consulting physicians, and general Probable enteric fever: Fever ≥38°C
enterica subspecies enterica, namely
p r a c t i t i o n e r s , who had b een for at least three days, with a positive
S. paratyphi A, S. schottmuelleri (also
brought together under a common serodiagnosis or antigen detection
c al le d S. p a r a t y p h i B), and S.
roof to discuss the epidemiology, test but without S. typhi isolation.
hirschfeldii (also called S. paratyphi
diagnosis, and management of C). Type A is the most common Chronic carrier state: Excretion of
typhoid. While gastroenterologists pathogen wo rl d wi de, whereas S. typhi in stools or urine (or repeated
usually get to see only complicated Type B predominates in Europe. positive bile or duodenal string
forms of the disease, and consulting Type C is rare, and is seen only in cultures) for longer than one year
physicians mostly deal with cases the Far East. The overall ratio of after the onset of acute enteric fever;
that are severe, majority of the the disease caused by S. typhi to sometimes, S. typhi may be
cases in India are taken care of by that caused by S. paratyphi is about
primary care doctors. Thus, the 10 to 1. 1
specialists barely see 15% of these
cases, whereas it is the primary
Expert Panel
care doctor, who treats typhoid at 1. Director and Head, Dept. of Gastroenterology and Hepatology, Max Super-Specialty Hospital, New Delhi
the grass-root level. Many of these 2. Professor, Dept. of Medicine, Seth G.S. Medical College and K.E.M. Hospital, Mumbai, Maharashtra
doctors are forced to manage their 3. Adjunct Professor, Tamil Nadu Dr. MGR Medical University, Chennai, Tamil Nadu
patients in the absence of diagnostic 4. Consultant Physician and Diabetologist, Asian Heart Institute, Mumbai, Maharashtra
facilities such as blood culture 5. Consultant Gastroenterologist, Bombay Hospital and Medical Research Center and Breach Candy Hospital,
and s e rolog ica l tests. Despite Mumbai, Maharashtra
6. Chief Hepato-Gastroenterologist, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra
the advances in medicine in the
7. Consulting Physician, Asian Heart Institute and Health Harmony, Mumbai, Maharashtra
developing countries, tackling a
8. Professor of Gastroenterology, MS Ramaiah Medical College, Bengaluru, Karanataka
disease like typhoid may seem like
78 Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015

600 60 57
493.5 52.5 60
Typhoid incidence

500
50

% of resistant isolates
Typhoid prevalence
400 340.1 50
300 40
29.1 40
200 30
119.7
89.2
100 30
18.1
20
0
0-1 2-4 5-15 >= 16 6.9 20
10
Age (years)
0 10 7
1.6
Fig. 1: Incidence of enteric fever in 0-1 2-4
Age (years)
5-15 >= 16
0
India per 10,0000 per year6 Nalidixic acid Ciprofloxacin Multidrug resistant*
Fig. 2: Prevalence of enteric fever
excreted without any history of in India per 1,000 febrile Fig. 3: Incidence of antimicrobial
enteric fever. episodes with blood culture resistance in India6
taken6 chloramphenicol,
*
Contamination and Transmission
ampicillin, cotrimoxazole
Humans are the only natural areas of prevalence include Africa
host and reservoir. The infection and South America. Outbreaks using standardized surveillance
is transmitted by ingestion of have been reported from Zambia, techniques, as well as standardized
food or water contaminated with Zimbabwe, Fiji and the Philippines. c l i n i c a l and m i c r o b i o l o g i c a l
feces. Contaminated water, and There is evidence that enteric fever methods, to provide an updated
raw fruit and vegetables fertilized is often under-reported, so the assessment of the burden of enteric
with sewage water, have been actual figures might be even more in Asia including India. Kolkata
sources of outbreaks. The highest than those mentioned above. 4 was chosen as the study site. Results
incidence occurs where water Prevalence of Enteric Fever in India obtained in India are depicted in
supplies serving large populations In disease-endemic areas, the Figures 1, 2 and 3. 6
are c o n t a m in a te d with f e c es . annual incidence of enteric fever The results showed a high
Cold foods such as Ice-cream is is about 1%. Peak incidence is seen incidence of enteric fever in India,
recognized as a significant risk in children 5–15 years of age; but in with the incidence in pre-school
factor for the tr an smiss ion of regions where the disease is highly children (aged 2–5 years) being of
enteric fever. 3 endemic, as in India, children the same order of magnitude as for
Global Prevalence of Enteric Fever younger than 5 years of age may school-aged children (aged 5–15
The world sees approximately 22 have the highest infection rates. 5 years). The high disease burden in
million new typhoid cases occur each In 2008, Ochiai et al conducted pre-school children underscores the
year. The worst sufferers are young a prospective population-based importance of vaccines and delivery
children in poor, resource- limited survey in five Asian countries systems in this age group, as well as
areas, who make up the majority of considered to be endemic for enteric, older children and adolescents. 6
the new cases and mortality figures
(215,000 deaths annually). Most of
80
these deaths are due to S. typhi 65.54 ± 6.22
infection. The South-east Asian 70 62.08 ± 4.82
countries bear the brunt of the 50.04 ± 9.61
Seropositivity (mean %)

disease, particularly children and 60


young adults. Other
50 32.66 ± 13.79
29.98 ± 11.16 28.42 ± 13.38
70 66%
58% 40
60
Prevalence (%)

50 30
40 34%
20
30
20 10
10 0
0 Total 0 to ≤ 15 years > 15 to ≤ 30 years
1999 2002 2005
Time period 1998-2002 2007-2011
Fig. 4: Rise in the prevalence of
multidrug resistance in the Fig. 5: Prevalence of seropositive titers in Indian patients with different age
period 1999-20058 groups9
Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015 79

Table 1: Antibiotic sensitivity pattern in vivo for Salmonella14 York who infected approximately 50
Antibiotic Patients Responded Resistant Effervescences people (three fatally), highlights the
(No.) (N%) (N%) period* role of asymptomatic carriers in
Ampicillin 32 7 (21.8%) 25 (78.12%) 7.5 maintaining the cycle of person-to-
Amoxycillin 40 9 (22.5%) 31 (77.5%) 8.0 person spread.11
Cotrimoxazole 19 3 (15.78%) 16 (84.2%) 7.2 Besides, the chronic carrier state is
Ciprofloxacin 42 34 (80.5%) 8 (19.5%) 5.5 the single most important risk factor
Ofloxacin 14 12 (85.71%) 2 (14.28%) 5.0
for development of hepatobiliary
Amikacin 9 8 (88.8%) 1 (11.9%) 5.0
carcinomas, as salmonella carriers
Cefixime 6 6 (100%) - 6.5
with gallstones have been shown to
Cefotaxime 5 4 (80%) 1 (20.0%) 6.5
carry an 8.47-fold higher risk of
Ceftriaxone 38 38 (100%) - 5.0
developing cancer of the
Chloramphenicol 2 - 2 (100%) -
gallbladder.10
*
Mean in days
It is for these reasons that the
Fifty-seven percent of isolates hospitalized. This results in loss eradication of carriage is of prime
were found resistant to nalidixic of work days and, consequently, importance.
acid, 1.6% to ciprofloxacin, and income.3 In the study by Ochiai et al,6 Factors Affecting Epidemiology12,13
7 % were mul t id r u g - r e s i s ta n t 2% of Indian patients with enteric Age
(resistant to chloramphenicol, fever required hospitalization.
The incidence of enteric fever in
ampicillin and cotrimoxazole). A study analyzed the trend of
endemic areas is typically low in the
Nalidixic acid resistance being an antibody titers to O and H antigens
first few years of life, peaking in
indirect marker of fluoroquinolone of S. typhi over a period of ten
school-aged children and young
resistance; indicates high resistance years (1998-2002 and 2007-2011)
adults and then falling in middle age.
to f l u o r o q u i n o l o n e . 6 S i n c e in Indian patients of different age
Older adults are relatively resistant,
fluoroquinolones are empirical groups, who had been diagnosed
probably due to frequent boosting of
therapy of choice in enteric fever, 7 with enteric fever. This study found
immunity.
in c r ea s ing rates of a ntib io tic that the overall seropositivity rates
Season
resistance may necessitate the over the 10-year study period had
r e p l a c em e n t of i n e x p e n s ive increased significantly, as shown in In endem ic area s, peaks of
antibiotics with newer, expensive Figure 5.9 transmission occur in dry weather
agents, which may be unavailable Carrier State or at the onset of rains. This is
and unaffordable to many poor because warm and moist conditions
On entering the human body,
pa tients. This also h igh ligh ts favor the growth of the organism.
S a l m o n e l l a ty p h i c r o s s e s the
the need to monitor patterns of Also, in summer, people are more
intestinal epithelial layer and is
resistance and to consider vaccines likely to drink water outside their
carried by macrophages to the
as disease control tools. 6 homes which may be of quality.
liver, pancreas, and spleen. From
A prospective study that was In rainy season, the water may be
the liver, the organisms can be shed
conducted in an Indian tertiary care contaminated.
into the gallbladder, where, being
hospital found that the prevalence Food habits
resistant to bile, they can stay for
of m u l t i d r u g r e s i s t a n c e ( to long periods and give rise to either Eating food prepared outside
chloramphenicol, ampicillin, and an active infection (cholecystitis) or the home, such as ice creams or
co-trimoxazole) in the organisms a chronic infection (carrier state). 10 flavored iced drinks from street
causing enteric fever had nearly About 3 to 5% of infected people vendors; drinking contaminated
doubled between 1999 and 2005 become carriers, particularly those water; and eating vegetables and
(Figure 4). While 80% of the patients salads grown with human waste as
with gallbladder abnormalities,
were infected by S. typhi, paratyphi fertilizer are major risks.
such as gallstones. These people
A was the pathogen in 9% of the
are often asymptomatic and can Other
cases. The remaining 11% of the
remain in this state for many years A close contact or relative with
patients were found to be infected with little or no deleterious effect. recent enteric fever
by other S. enterica and E. salmonella However, they continue to excrete
groups, typhimurium, and paratyphi Poor socioeconomic status
bacteria for prolonged periods of
C and senftenberg. 8 High population density
time, thus constituting a potential
The social and economic impact source of infection, 10 particularly Poor personal hygiene
of enteric fever is also high because in the setting of food preparation. Lack of sanitation
patients with acute disease and The story of “Typhoid Mary,” a Lack of safe water supply
complications may need to be cook in early 20th century New
Low latrine use
80 Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015

ENTERIC FEVER - The fever goes up completely in agreement about this


TYPICAL STEP-LADDER PATTERN and felt that enteric fever can be
a little each day.
diagnosed clinically by symptoms
such as fever with rigors, headache,
toxemia, abdominal pain (early in
41° children), nausea, dry and coated
tongue, relative bradycardia (most
40°
important clinical sign), and rose
39° spots, which are rarely seen in
clinical practice. First, the liver
38° becomes palpable. The spleen
usually becomes palpable only
37°
after a week. 2
36° Typical Presentation16
1 2 3 4 5 6 7 8 7-14 days after ingestion of S.
Days of illness typhi
First Week
Fever
Fig. 6: Step-ladder pattern of fever
Exhibits a step-ladder pattern —
Living near an open water body episode of blood culture-confirmed i.e., the temperature rises over the
R e c e nt c o ns u m p ti o n o f enteric fever was INR 3,597 in an course of each day and drops by
antimicrobials outdoor setting. This cost increased the subsequent morning. The peaks
several fold (INR 18,131) in case of and troughs rise progressively over
Transmission of enteric fever has
hospitalization. Almost similar time (Figure 6).
also been attributed to flies,
observations have been made in Gastrointestinal manifestations
laboratory mishaps, unsterile
other studies from other parts of the
instruments, and anal intercourse. Diffuse abdominal pain and
country. The costs increased several
MDR Enteric Fever t e n de r ne s s ; so metim es, fierce
times due to increased
In 1972, chloramphenicol- c o lic ky p a in i n r i g h t u p p e r
hospitalizations and growing
resistant S. typhi was first reported, quadrant.
resistance to available antibiotics.
and since then, chloramphenicol or These costs also add to the annual Monocytic infiltration in Peyer’s
multidrug-resistant enteric fever loss of income to the affected patches, causing inflammation and
(MDREF) has been reported during individuals and their families.15 narrowing of bowel lumen, resulting
outbreaks from many parts of the in constipation.
world. MDREF is most commonly The Diagnostic Approach Other symptoms
seen in school-going children, but in Enteric Fever Dry cough
may affect younger children as well.
Dull frontal headache
MDREF is associated more Isolation of S. typhi from blood,
commonly with hepatomegaly and bone marrow, or a specific Delirium
splenomegaly. Resistance to anatomical lesion is the only Stupor
ceftriaxone and cefixime has been definitive way of diagnosing enteric Malaise
seen in many studies, as is resistance fever.3 The presence of characteristic
Second week
to quinolones, indicating that clinical symptoms or the
Salmonella develops resistance demonstration of a specific antibody Progression of above signs and
rapidly against quinolones and hence, response is suggestive of the disease, symptoms
existing quinolones, like but not definitive. Fever plateaus at 39-40°C
sparfloxacin, levofloxacin, Clinical Features Rose spots
gatifloxacin and moxifloxacin, The panelists were of the opinion Salmon-colored, blanching,
should be used very rationally (Table that a good clinical history and maculopapules on the chest,
1).14 physical examination are very abdomen, and back, may not be
Economic Implications of Enteric Fever important for the diagnosis of enteric visible in dark-skinned individuals
Management of enteric fever in fever. In fact, the presence of fever 1-4 cm in width, less than 5 in
India is a costly affair. According to with hepatosplenomegaly should number, present in up to 25% of
a prospective surveillance carried make one think of this condition as patients
out in an urban slum in Delhi, one of the differential diagnoses. The
They resolve within 2-5 days.
the direct and indirect costs per participants were
Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015 81

Represent bacterial emboli to the stepladder fever pattern is seen in Significant hepatic dysfunction
dermis just about 12% of cases, and the is rare
Abdominal distension fever has a steady insidious onset. Cultures
Soft splenomegaly GI symptoms: Diarrhea, and not Blood culture:
constipation, is common in young
Relativ e bradycardia — tem The specificity of a blood culture
children in AIDS and one-third
perature elev ations not accompanied is 100%. At least 25-30 ml of blood
of immunocompetent adults with
by a physiological increase in the should be collected for a good
enteric fever
pulse rate yield. The larger is the volume of
Other atypical manifestations: blood, the better the yield. The
Dicrotic pulse — double beat, the
second beat weaker than the first Only fever ideal time of doing a blood culture
is when the patient is having
Third week S e v e r e h e a d a c h e s
mimicking meningitis chills (and not when the fever
Fever persists spikes, as is commonly thought).
Acute lobar pneumonia
Increase in toxemia Blood for culture should be taken
Arthralgias before giving the first dose of
Anorexia
Urinary symptoms antibiotics. However, in clinical
Weight loss
Severe jaundice practice, an tibio tic therapy is
Conjunctivitis initiated based on the diagnosis,
N e u r o l o g i c a l s y m p to m s in
Thready pulse and a blood culture is advised. It
some patients, especially in India
Tachypnea is always better to do an antibiotic
and Af ric a, such as de lir ium,
sensitivity test along with the
Crackles over lung bases P a r k i n s o n i a n s y m p t o m s or
culture, as this will help to select
Severe abdominal distension Guillain-Barré syndrome
the most appropriate antibiotic.
Sometimes, foul, green-yellow, Pancreatitis Culture should be repeated after
liquid diarrhea (pea-soup diarrhea) Meningitis an hour and then after 24 hours.
Typhoid state — characterized by Orchitis A single culture should not be
apathy, confusion, psychosis encouraged. (The participants,
Osteomyelitis
on the other hand, revealed that
Bowel perforation and peritonitis Abscesses they seldom did a blood culture
due to necrosis in Peyer’s patches
Laboratory Evaluation \ in a primary healthcare setup, as
Death may occur due to severe it was expensive for the patients.
The expert panelists opined that a
toxemia, myocarditis or intestinal They usually depended on the
very toxic-looking patient with low
hemorrhage findings of the Widal test and the
counts should raise suspicion of
Fourth week enteric fever or a viral infection. complete blood cell count, which
Gradual improvement in fever, Increased counts usually signify shows eosinopenia and relative
mental state, and abdominal sepsis or perforation, with lymphocytosis). The positivity of
distension over a few days eosinopenia being an important the blood culture is as follows:
Untreated patients may suffer finding. Monocytosis is also a usual 1st week – 90%
from intestinal and neurological finding. The presence of both 2nd week – 75%
complications eosinopenia and thrombocytopenia is
3rd week – 60%
Weight loss and debilitating strongly suggestive of enteric fever. 2
4th week – 25%
weakness (may last for months) Hematological tests 17,18
Complete blood count The positivity of blood culture
Asymptomatic carrier state in decreases due to the administration
some patients, who can transmit the Hemoglobin: Mild anemia
of antibiotics; however, the blood
bacteria indefinitely Total leucocytic count (TLC): c u ltu r e w ill c o n tin u e to te s t
Atypical presentation16 Low to normal positive in resistant cases. Many a
I n s o m e pa tie n ts , e n t e r ic Eosinopenia time, contaminants like coagulase-
fever may not p res ent in the Platelets: Low to normal negative staphylococci in the blood
typical manner described above. culture may cause a false-negative
Liver function tests:
Presentation of the disease depends report. Hence, the culture should
upon the host response, geographic Mildly abnormal be done with due caution. A clot
r e g io n , race f a c to r s , and the Serum transaminase levels 2 to culture is also being done. 2 The cost
infecting bacterial strain. 3 times the upper limit of normal of a blood culture in India ranges
Fev er: T he c harac teris tic Clinical jaundice is uncommon from `600 to `800.
Culture involves inoculation of
82 Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015

the specimen (blood, bone marrow or S. typhi and S. paratyphi A are not the greater will be the likelihood
stool) into an enrichment broth, and always culturable even if good of getting a positive result. Rectal
when a growth appears, making microbiological facilities are swabs can be obtained instead
subcultures on solid agar. available20 of stool samples but they are
Biochemical testing is done to Bone marrow culture: less successful in isolating the
identify the colonies obtained. This is organism. 3 A stool culture in India
Culture of the bone marrow
further confirmed by slide costs about `350 to ` 450.
aspirate is the gold standard for
agglutination with appropriate A ll th e pa ne l i s ts we r e in
the diagnosis of enteric fever, 3 and
antisera.19 agreement about the need to do
can yield positive results even if
Direct blood culture followed the patient has started antibiotics. 23 repeat stool cultures to detect
by microbiological identification carriers, as they tend to shed the
It is of particular value in the
r ema ins the gold s tanda rd in bacteria sporadically. Chefs, in
patients who have been treated
the diagnosis of enteric fever. 2 0 particular, should get their stool
previously, have a long history of
Blood culture shows growth of culture done to rule out carrier
illness and had a negative blood
the organ is m in 80% to 100% states, as they are likely to infect
culture with the recommended
of patients, 1 7 particularly those a large number of people when
volume of blood.3
with a history of fever for 7-10 cooking. 2
days. 3 However, patients who have This test has a sensitivity of 55-
Limitations in use
started antibiotics may not show 67% and a specificity of 30%.18 The
positivity rate can further be Sporadic shedding of the organism
any growth. 17
increased to almost 100% if FAN in stools potentially compromises the
The sensitivity range of blood stool culturing approach20
culture medium is used and growth
culture is estimated to be between
is monitored in automated culture Becomes positive only after the
40% and 80%. The sensitivity may
systems.23 first week of infection and has a
be low in endemic areas with high
Speaking about bone marrow much lower sensitivity than blood
rates of antibiotic use, making
culture, the participants declared culture (30% vs. 40-90%)18
it difficult to estimate the true
specificity. 18 that this investigation is never Sensitivity is low in developing
c a r r i ed o ut a t th e pr i m a ry countries18
Failure to isolate the organisms
healthcare level. Even otherwise, Not routinely used for follow- up18
can be due to delay in diagnosis,
it is avoided considering that it is
limitations of laboratory media, Urine culture:
costly as well as painful. The expert
widespread and irrational use
panelists informed that unlike Urine culture, according to
of antibiotics, and low volume
blood culture, bone marrow culture the experts, is not usually done.
of blood cultured, espec ia lly
remains positive even after the Po s i t i v i t y of u r i n e c u l t u r e
in children. 2 1 The probability of
administration of antibiotics. Thus, increases in carriers with urinary
recovering the organisms is directly
it is more suitable for hospitalized obstruction. 2
proportional to the volume of
and very sick patients. 2 Urine culture for enteric fever
blood drawn; hence, it is essential
to have an adequate volume of Limitations in use has variable sensitivity, the range
blood taken for culture. 20 Due to Although the most sensitive, it is being 0-58%. 18 In India, the cost of
the higher levels of bacteremia in an invasive procedure, and cannot be a urine culture varies from ` 350
children compared to that in adults, performed outside specialist to ` 450.
at least 10-15 ml of blood from settings20 Rose spot culture:
schoolchildren and adults, and 2-4 Has lim ite d c lin ic a l va lue, Punch-biopsy samples of rose
ml from toddlers and preschool e s p e c i a l l y i n a m b u l a t o ry spots may be cultured to yield
children should be taken to achieve management 18 a sensitivity of 63% and may be
optimal isolation rates. 3 positive even in patients who have
The specimen is difficult to obtain
Limitations in use reviewed antibiotics. 16
Stool culture:
Less sensitive for diagnosis Serum culture:
Stool culture can help in detecting
of infection among children as To conduct serum culture, 1-3
typhoid carriers. Stool should be
compared to adults 22 ml of blood is inoculated into a
collected from acute patients in a
Positive in only 40-60% of cases, sterile wide-mouthed plastic tube without anticoagulant. When
usually early in the course of the container and should preferably be the convalescent stage starts about
disease18 processed within two hours of 5 days later, a second sample
Expensive and requires specialist collection. The larger is the quantity is collected. After clotting, the
facilities and personnel20 of stool collected,
20
Journal of The Association of Physicians of India ■ Vol. 63 ■ November 201583

15
serum is separated and tested little advantage in young (2 to 6 Due to its high sensitivity 83
and
immediately or stored for a week years old) children. specificity, nested PCR can serve as
without affecting the antibody titre. 3 Molecular diagnostics a useful tool to diagnose clinically
Duodenal aspirate culture: Polymerase c hain reaction suspected, culture negative cases of
enteric fever.27
S ha r in g th ei r e xpe r ie n c e s (PCR):
with regard to duodenal aspirate Benefits of nested PCR 27
PCR is a promising test, which
culture, the panelists explained that is as sensitive as blood culture, but • S e n s i t i v i t y of 1 0 0 % a nd
this investigation may have good less specific. 18 It has been found to specificity of 76.9%
sensitivity because bile directly be >90% sensitive and relatively • Higher case detection compared
enters the duodenum. However, they simple to perform. Moreover, it to blood culture even in the
added that this test is not practical can amplify DNA from dead or later stages of the disease (53.8
and is more of academic interest. A unculturable bacteria, providing vs. 46.1%)
culture of the duodenal aspirate in an additional sensitivity benefit. • Can be used as a diagnostic tool
chefs can help to detect carriers However, it seems to have limited in any stage of the disease
amongst them. Other materials which po te nti al for the d ia gn osi s of
can be cultured include bile, rose • Not a f f ec ted by e mp iric a l
enteric fever. In the absence of any
spot discharge, pus from a antibiotic therapy unlike blood
validated PCR test, the in-house
suppurative lesion, and CSF or culture. Hence, can serve as
s y s t e m s c u r r e n t l y in use are
sputum, if the patient has an effective diagnostic test
open to differing interpretation
complications. At autopsy, culture even after the initiation of
and do not meet the ri go ro us
from the liver, spleen, gall bladder, antimicrobial therapy.
q u a l i t y c o n t r o l s t a n d a r d s for
and mesenteric lymph nodes is also worldwide acceptance. 20 A PCR is Serological tests
positive.2 quite expensive, costing anything S ero lo gic al tes ts a re the
In a study24 of 36 patients with between `3800 and ` 4000 in mainstay of diagnosis of enteric fever
bacteriologically proven enteric India. in developing countries.21
fever, culture of duodenal contents The experts felt that PCR may S. typhi is known to express a
(obtained with string capsules) was not satisfy the criteria of a ‘gold number of immunogenic structures
found to be as sensitive in diagnosis standard’ for the diagnosis of on its surface. Among them, O
as bone marrow culture and more enteric fever in terms of sensitivity (liposaccharide), H (flagella), and the
effective than blood and stool and s p e c if ic i ty , since it does somewhat less immunogenic Vi
cultures in recovery of S. typhi. The not cover all the antigens of the capsule can be identified by
sensitivity of duodenal content disease. Only antigens 14, 15 and serological tests. S. typhi expressing
culture was not affected by the 18 are picked up by one PCR test. O (O9, O12), Vi, and H:d are
duration of illness or antibiotic Moreover, this test is not available abundantly present in most endemic
therapy. Even on the seventh day of in remote and peripheral areas. The areas.20 All the participating doctors
antibiotic treatment, the duodenal participants also echoed the same unanimously expressed the same
content culture was positive in eight sentiments, as they added that the view that although the Typhidot, IgM
of 17 patients, whereas stool culture PCR is hardly ever used for the Dipstick, and IDL Tubex tests are
was positive in only two of the same diagnosis of enteric fever in India. 2 promising tests, they are still not
patients. being used routinely in India.
Nested polymerase chain reaction:
Apart from good sensitivity, Widal test:
A nested polymerase chain
duodenal content culture is simple, According to the World Health
reaction is more sensitive than PCR
economical and can be performed Organization, Widal, the most
and uses H1-d primers to amplify
with minimal facilities.24 However, widely available test in India,
specific genes of S. typhi in the blood
this method is not widely performed should not be done before one
of patients.18 It involves two rounds
due to poor tolerance of the string week of the onset of fever. Even
of PCR using two primers with
device, particularly by children.25 if it is positive before one week, it
different sequences within the H1-d
According to a comparative study flagellin gene of S. typhi, offering the might be a false-positive. With the
25
of the various culture methods, best sensitivity and specificity.16 availability of other highly reliable
bone marrow cultures remain the tests, the importance of Widal has
It is a promising rapid diagnosis
most effective method for the declined. A single Widal has no
test, with potential to replace blood
recovery of S. typhi. Stool cultures value. It may be obsolete; but in
culture as the new gold standard.18 It
appear to be more effective in the absence of any other reliable
is so sensitive that it can detect even
children than in adults, while modality, it may be done. 2
one bacterium in a given sample
duodenal content cultures offer Wida l i s the m o s t wi de ly used
within a few hours.26
test in many regions as it is
20 Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015
15
84
relatively cheaper, easy to perform, The sensitivity, specificity,
and itself. Typhidot-M is done in cases of
and requires minimal training and predictive values differ in different acute infection.2 A Typhidot in India
equipment. The test is based on the geographic areas26 costs between `300 and `400.
demonstration of a rising titer of Negative in 30% of culture Limitations in use3
antibodies in paired samples 10 to proven cases of enteric fever3 IgG can persist for more than two
14 days apart. It uses O and H
Prior antimicrobial treatment may years after typhoid infection. Hence,
antigens of S. typhi, S. paratyphi A,
adversely affect the antibody detection of only IgG cannot
S. paratyphi B and S. paratyphi C to
response3 differentiate between acute and
detect antibodies in blood. 28 At least
False-positive results may be convalescent cases.
1 ml of blood should be collected to
obtain a sufficient amount of serum. obtained in other clinical conditions, Previous infection may lead to
Usually O antibodies take 6-8 days such as malaria, typhus, bacteremia false positive results.
to appear and H antibodies 10-12 and cirrhosis3 Typhidot- M:
days after the onset of disease. 3 May lead to overdiagnosis if Typhidot-M is a modified,
In acute enteric fever, therefore, relied upon solely in endemic areas 28 improved version of Typhidot,
the anti-O antibody titer is the first to Widal need not be performed obtained by inactivating total IgG in
rise, followed by a gradual increase if the diagnosis has already been the serum sample, which removes
in anti-H antibody titer. The anti-H confirmed by the isolation of S. competitive binding and allows
antibody response persists longer typhi from a sterile site. 3 While a access of the antigen to the specific
than the anti-O antibody.29 tube Widal in India costs around IgM, thereby enhancing diagnostic
According to a study conducted in `110 to `170, the slide Widal is accuracy. If specific IgM is detected
Nepal,29 a presumptive diagnosis of priced a bit higher between `150 and within three hours, it points towards
enteric fever can be made if `200. acute typhoid infection.3
significant titers are greater than 1:80 Typhidot: Advantages
for anti-O and greater than 1:160 for Typhidot is a rapid-dot enzyme Superior to culture method
anti-H. immunoassay (EIA) that takes in terms of sensitivity (> 93 %),
H o w e v e r , it is d i f f i c u l t to about three hours to perform. 3 It negative predictive value, and
pinpoint a definite cut-off for detects IgG and IgM antibodies to speed 3
a positive result since it varies a specific 50 kD outer membrane Can replace Widal when used
between areas and between times p r o t e in ( O M P ) a n t ig e n of S. along with culture method, for rapid
in given areas. 3 A fourfold rise in typhi. 21 Detection of IgM signifies and accurate diagnosis of enteric
antibody titer in a paired serum is acute enteric in the early phase of fever3
considered more diagnostic. 21 infection while detection of both
High negative predictive value
Widal has a sensitivity of 47-77% IgG and IgM indicates acute enteric
makes it useful in areas of high
and specificity of 50-92%.18 While a in the middle phase of infection. 3
endemicity.3
negative Widal test has a good The test becomes positive right
in the first week of fever and the Being rapid, easy to perform and
predictive value for the absence of
results are available within one reliable, it is suitable for enteric
the disease, a positive result is seen
hour. Thus, it is faster than blood endemic countries30
to have a low predictive value for its
presence.28 culture and Widal, in which results Latex agglutination test:
Advantages of Widal take 48 and 18 hours, respectively. Studies on the efficacy of the latex
In addition, this test is simpler and agglutination test (LAT) have shown
Inexpensive3
more reliable than Widal. 21 that:
Good for screening a large Its simplicity, speed, sensitivity With a sensitivity of 100%,
number of patients in endemic areas (95%), specificity (75%), cost- specificity of 97.6%, and positive
despite mixed results18 effectiveness, ability to detect and negative predictive values of
Use of slides instead of tubes antigens early, and high negative and 90.9% and 100%, respectively, LAT
gives results faster — in only a few positive predictive values make can be used for the presumptive
minutes19 Typhidot an efficient diagnostic tool diagnosis of enteric fever in remote
Limitations in use in resource-poor countries.3 health centers31
Standardization and quality Typhidot, the experts felt, is an LAT could detect the antigen in
assurance of reagents may be alternative to Widal, but is far more 100% of the sera of patients with
required18 reliable. It is available even in tier 3 negative blood culture and positive
Moderate sensitivity and cities, so it can be easily prescribed. Widal, indicating better sensitivity as
specificity3 It becomes positive in the first week compared to blood culture32
20
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15
Table 2: Investigations according to week of presentation 85
tests are indicated after all the other
Week of illness Feasible tests Non-feasible tests febrile conditions have been ruled
1st week Hematological tests Eosinopenia17,18 Bone marrow culture3 out.
Blood culture20 PCR20 Newer tests
Typhidot/Typhidot-M3 Duodenal aspirate culture 25 Newer tests in the pipeline include
Widal (basal)28 Dipstick3 salivary IgM test, molecular
2nd week Hematological tests Leukocytosis17,18 Bone marrow culture3 immunology-based tests and
Blood culture20 Rose spot culture16 nanotechnology-based tests.2
Stool culture18 PCR20
Screening for Carriers
Typhidot/Typhidot-M3 Tubex3
Widal (basal or repeat – to see rising titer)28 Duodenal aspirate culture 25 E n t e r i c fe ve r c o n t i n u e s to
Dipstick3 have a high incidence due to the
3rd week Hematological tests17,18 Bone marrow culture3 dissemination of the disease via
USG abdomen (hepatosplenomegaly) 2 PCR20 carriers. 2 2 This calls for urgent
Blood culture20 Tubex3 measures to detect carriers as
Stool culture18 Duodenal aspirate culture 25 they are a silent threat to the
Widal (very high titer)28 Dipstick3 community. 20 An ideal test for
Typhidot/Typhidot-M3 carriers should be rapid, specific,
4th week Hematological tests17,18 Bone marrow culture3 as well as sensitive. 2 2 One such
USG abdomen2 PCR20 measure is monitoring S. typhi
Blood culture20 Tubex3 in the stool. However, this may
Stool culture18 Duodenal aspirate culture 25 be hamstrung by low level or
Widal (very high titer)28 Dipstick3 sporadic shedding and the fact
Typhidot/Typhidot-M3 that routine stool sampling may
be expensive, time consuming
LAT can be used for rapid other serotypes, such as S. paratyphi and unpopular. Another option
diagnosis of enteric fever though A3
is based on the observation that
it cannot replace conventional IgM dipstick test: enteric fever carriers may produce
blood culture required for isolation
IgM dipstick test is based on the higher levels of Vi antibodies over
of organism to report the antibiotic
detection of S. typhi-specific IgM extended periods compared to
sensitivity 33
antibodies in serum or whole blood acutely infected patients. Hence,
IDL Tubex test: samples. Specific antibodies appear development of simple, cheap, and
Tubex is an antibody-detection a week after onset of symptoms and non-invasive Vi antibody assays
test that is user-friendly and can signs — this fact should be kept in may be of great help in identifying
be used at the point of care. 19 This mind while interpreting a negative carriers. 20
simple one-step rapid test can be serological test. 3
performed in just two minutes. 3 Advantages3
Current Approaches in the
The test is as simple and fast as
Requires no formal training,
Treatment of Enteric Fever
the slide latex agglutination tests
specialized equipment, electricity or in India
but has been modified to improve
cold storage facilities
the sensitivity and specificity to With time, the treatment of
75-85% and 75-90%, respectively. 19 Results are available the same enteric fever is not only becoming
The O9 antigen used in the test is day, enabling prompt initiation of more complicated, but also costly,
extremely specific, and can detect treatment because of increased resistance to
IgM O9 antibodies within minutes. Fast and simple to perform the commonly used antibiotics in
A positive result is a definite Ideal for places with no culture the Salmonella enterica species. 3 4
indicator of a Salmonella infection. 3 facilities C h a r a c t e r i z e d by a l e n g t h y
As Tubex detects only IgM incubation period, nonspecific
Table 2 giv es the list of tests
antibodies and not IgG, it is highly sy mpto ms that are diverse in
according to the week of
useful for the diagnosis of current nature, and complications that
presentation. The tests have been
infections, and performs better than could threaten life, the disease
categorized as feasible and non-
Widal, both in terms of sensitivity only adds to the financial burden
feasible. The non-feasible tests
and specificity.3 of individuals and maintains the
include those that are expensive, not
poverty cycle. It is estimated that
Limitation in use easily available, require specialized
nearly 22 million new cases of
Negativ e results may be obtained equipment, or are not tolerated.
enteric fever develop every year,
in patients infected by It must be borne in mind that the mortality rate being higher in
20 Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015
15
86 3: Treatment of enteric fever
Table 2

Susceptibility Patient Antibiotic Dosage


Uncomplicated enteric fever
Quinolone Adult Responders: Fluoroquinolones, namely Ciprofloxacin or Ofloxacin 15 mg/kg body weight/day × 10 days
sensitivity areas OR 3rd Generation Cephalosporin like Cefixime 15-20 mg/kg body weight/day × 10 days
Nonresponders: Chloramphenicol OR 50-75 mg/kg body weight/day × 14 days
Amoxicillin 75-100 mg/kg body weight/day × 14 days
Child Responders: 3rd Generation Cephalosporin like Cefixime 15-20 mg/kg body weight/day × 10 days
Nonresponders: Chloramphenicol OR 50-75 mg/kg body weight × 14-21 days
Amoxicillin 75-100 mg/kg body weight × 14 days
Quinolone Adult Responders: Cefixime 20 mg/kg body weight/day × 14 days
resistance areas Nonresponders: Azithromycin 10-20 mg/kg body weight/day × 7 days
Child Responders: Azithromycin 10-20 mg/kg body weight/day × 7 days
Nonresponders: Cefixime 15-20 mg/kg body weight/day × 14 days
Complicated enteric fever
Quinolone Adult Responders: 3rd and 4th Generation Cephalosporins like
sensitivity areas Ceftriaxone 60 mg/kg body weight/day IV × 14 days
Cefotaxime 80 mg/kg body weight/day IV × 14 days
OR Fluoroquinolone like Ciprofloxacin or Ofloxacin 15 mg/kg body weight/day IV × 14 days
Nonresponders: Chloramphenicol 100 mg/kg body weight/day IV × 14-21 days
Ampicillin 100 mg/kg body weight/day IV × 14 days
Child Responders: Ceftriaxone or Cefotaxime 50-75 mg/kg body weight/day IV × 14 days
Nonresponders: Chloramphenicol 100 mg/kg body weight/day IV × 14-21 days
Amoxicillin 100 mg/kg body weight/day IV × 14 days
Quinolone Adult Responders: Ceftriaxone or 60 mg/kg body weight/day IV × 14 days
resistance areas Cefotaxime 80 mg/kg body weight/day IV × 14 days
Nonresponders: Fluoroquinolone 20 mg/kg body weight/day IV × 14 days
Child Ceftriaxone or Cefotaxime 50-75 mg/kg body weight/day IV × 14 days
bid: twice daily; qid: four times daily; tid: three times daily; IV: intravenously; PO: orally; TMP-SMX: trimethoprim-sulfamethoxazole
Adapted from
1. Bhutta ZA. Current concepts in the diagnosis and treatment of typhoid fever. BMJ 2006; 333:78-82.
2. World Health Organization (WHO) Department of Vaccines and Biologicals. Background document: The diagnosis, prevention and treatment
of typhoid fever. Geneva: WHO; 2003:19-23. Available at: http://www.who.int/vaccine_research/documents/en/typhoid_diagnosis.pdf; and
3. Kundu R, Ganguly N, Ghosh TK, Yewale VN, Shah RC, Shah NK. IAP Task Force Report: Diagnosis of enteric fever in children. Indian Pediatr
2006; 43:884-7.

young children from low-resource effectiveness. However, decreased cephalosporins (specifically those of
areas.4 ciprofloxacin susceptibility (DCS) is the third and fourth generation) are
History of Antibiotic Therapy in Enteric now being seen. Since the 1990s, recommended for use as the first-line
Fever azithromycin has been showing good therapeutic agents.2
C h lo ra m p h e n ic o l was th e results and is a promising alternative Table 3 lists the drugs
drug of choice for the treatment to fluoroquinolones and recommended by the panelists for
of enteric fever since 1948, but cephalosporins.35 various patient populations, based
plasmid-mediated resistance and Drugs Recommended by the Expert on the severity of their condition,
its rare side-effect of bone marrow Panel for the Management of Enteric r es po n s e to tre a tm e n t, a n d
Fever possibility of antibiotic resistance
aplasia put it behind on the shelf.
This was followed by the use of After going through treatment in them. They emphasized on the
trimethoprim-sulfamethoxazole recommendations by the World need for doctors to titrate the dose
and a m p i c i l l i n in the 1 9 7 0 s ; Health Organization (WHO), the of the antibiotics in every case,
however, their rampant use led Association of Physicians of India based on the patient’s age and
the pathogen to get resistant to (API), and the Indian Association body weight. All of them agreed to
them. In the 1980s, ceftriaxone of Pediatrics (IAP), the expert the fact that it is better to slightly
and ciprofloxacin proved to be advisory panel concluded that overdose the patient rather than
effective against multidrug - there was a need to sim p lif y underdose the patient, when trying
resistant (MDR) strains of S. typhi, the choice of the drugs in the to adjust the dose of the antibiotic
and were therefore the drugs of treatment of enteric fever. They for the patient, bearing in mind the
choice. Ciprofloxacin and ofloxacin unanimously declared that the strengths available in the market.
were p re fer red to ce f tr ia xo n e f l u o r o q u in o l o n e s ( e s p e c ia l ly , Thus, if the dose requirement
due to their oral use and cost- ciprofloxacin and ofloxacin) and calculated for a patient amounts to
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15
Table 4: List of red flag symptoms in Table 5: Azithromycin in 87
typhi isolated (n = 40) was <4 μg/mL
enteric fever36 uncomplicated enteric fever42 (range 2-8 μg/mL); and for cefixime
Involvement Symptoms Parameter tested Result was 0.5 μg/mL (range 0.25-1.0 μg/
Central nervous Headache, vomiting, Cure rate (%) 93.5 mL).39
system seizures, altered states of Mean day of response 3.45 ± 1.97 Fluoroquinolones:
consciousness, papilledema,
Blood culture positive (%) 15.5
and focal neurological The Wor l d Healt h
deficits Good global wellbeing (%) 95
Organization (WHO) recommends
Cardiovascular Chest pain, palpitations, fluoroquinolones in areas with
system new murmur or change in
two are given parenterally. The
favorable pharmacokinetic profile of known resistance to the older first-
characteristics of a previous
murmur, cardiac cefpodoxime proxetil allows for its line antibiotics. A Cochrane study
arrhythmias twice daily dosing. In past studies, revealed that fluoroquinolones have
Respiratory Chills, cough (with or all the 50 strains responsible for f e w e r c l i n i c a l f a i l u r e s in
system without sputum), pleuritic c o m p a r i s o n w ith a m p i c i l l i n ,
pain, coarse crackles, and enteric fever were found to be
bronchial breathing sensitive to ceftriaxone, amoxicillin, chloramphenicol, and
Musculoskeletal Local tenderness, rigidity, cefixime, and cefpodoxime.37 The co-trimoxazole; with no clinical
system and pain giving rise to minimum inhibitory concentration or microbiological failures having
a loss of functionality in (MIC) of a drug can help to predict been seen with seven-day courses
the affected limb; acute of ciprofloxacin or ofloxacin, which
swelling and pain in joints its efficacy. When a drug is given in
with or without an effusion an appropriate dosage on the have been found to be superior to
Gastrointestinal Jaundice, nausea, vomiting, basis of sound pharmacokinetic older antibiotics.40 In uncomplicated
system and abdominal pain and pharmacodynamic principles, enteric fever caused by nalidixic
Genitourinary Dysuria, frequency, and a clinical cure is facilitated by acid-resistant Salmonella enterica
system suprapubic or pelvic serovars typhi and paratyphi A,
e r a d ic a tio n of the pa thogen ’s
discomfort giving ofloxacin (20 mg/kg/day) in
carrier status and prevention of
600 mg/day, it is advisable to give resistance to the antimicrobial two divided doses for 7 days led
him 750 mg instead of 500 mg. 2 drug. 3 8 A study that tested the to prompt fever clearance within
e f f ic ac y of c e p h a lo s p or in s in 4.7 hours, on an average.41 The
When factors such as intolerance
the treatment of enteric fever panelists reminded that the use of
to oral drugs, dehydration, extremes
found that the MIC 50 and MIC 9 0 quinolones should be avoided in
of age, and associated comorbid
of cefotaxime, a parenteral third- children, elderly, pregnant women,
conditions are present, parenteral
generation cephalosporin, was the and those who cannot tolerate this
treatment should be instituted. Once
least in comparison to the oral third- class of antibiotics. In such patients,
the condition of the patient stabilizes,
generation cephalosporin cefixime alternative treatment regimens
s/he should gradually be de-escalated
and the parenteral fourth-generation should be followed. Also, if culture
from parenteral therapy to oral drugs.
cephalosporin cefipime.37 and antibiotic sensitivity shows the
With the defervescence period
presence of nalidixic acid-resistant
usually being about 5 days, any Cefpodoxime and cefixime have
Salmonella typhi (NARST), the use
patient who is not responding been used extensively in enteric
of quinolones must be avoided, as
adequately may be switched to a fever. Although cefpodoxime has
there is a great probability of the
different drug after stopping the first, wide applications in pediatric
pathogen being resistant to this
or the second drug may be added to in f e c t io u s d i s e a s e s , it ha sn ’ t
antibiotic class.2
the first one.2 However, at any point b e e n u s e d m u c h in e n t e r i c
during the course of the illness, f e v e r ; t h o u g h it is s im i l a r Azithromycin:
patients may develop symptoms of pharmacologically to cefixime Azithromycin is safe and
developing complications, which and cheaper than cefixime. In 140 efficacious for the management of
should serve as red flags for the children assessed for suspected uncomplicated enteric fever. An
treating doctor. The important red e n te r ic f e v e r , a c o m p a r a t i v e open-label, non-comparative study,
flag symptoms have been listed in study showed that cefpodoxime which evaluated the efficacy and
Table 4.36 reduced treatment cost by 33% safety of azithromycin for the
Cephalosporins: in comparison to cefixime, and is treatment of uncomplicated enteric
also a safer oral option in children. fever, found that azithromycin (20
Cefixime, cefpodoxime proxetil,
The two groups showed a similar mg/kg/day for 6 days) cured 93% of
ce f ipim e, and c e f tr ia xo ne are
clinical response with comparable the subjects, with a mean day of
expanded-spectrum cephalosporins
periods to defervescence in days response of 3.5 as seen in Table 5.
that have been very promising
and clinical cure rates. The MIC for No serious adverse event was
in the m a nagemen t of enteric 42
cefpodoxime against all Salmonella observed. The panelists
fever. While the former two are
recommended a course of not more
administered orally, the latter
20 Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015
15
88
100 as in children, pregnant women, and a quinolone or cephalosporin);
quinolone-resistant cases of enteric and 40.3% cases received 2 drugs
90
fever.44 simultaneously. The duration of
Cure rate (%)

80 Single vs. Multiple Drug Regimens fever from the beginning of the
60 The expert panelists declared that illness to the time of defervescence
there are no clear-cut guidelines for was 13.54 days and 13.84 days in
40 the single-drug and multiple-drug
the employment of monotherapy
20 and combination therapy. Since groups, respectively. The mean
it is not possible to tell whether a duration for defervescence after
0
Azithromycin Ceftriaxone
patient is going to respond to the initiation of antimicrobial therapy
Antibiotic used
treatment or not on the very first in the single-drug group was 5.24
days; and in the multidrug group,
Fig. 7: Azithromycin vs. day, it is advisable for the clinician
it was 4.32 days. There was no
ceftriaxone in enteric to use his experiences with other
fever43 patients in and around the area to significant difference in the total
presume resistance or sensitivity to duration of fever or the time taken
than 7 days with azithromycin, a particular drug. Although culture for defervescence after initiation
because this drug has stronger of therapy in the single-drug and
and antibiotic sensitivity would be
tissue penetration and accumulates multidrug groups. This reinforces
desirable in all cases, most doctors
in the gall bladder. Thus, while a the traditional recommendation
depend on the clinical signs and
5-day course of azithromycin may of treatment of enteric fever with
symptoms when treating patients
be considered to be an equivalent one drug at a time. Treatment
of enteric fever and refer them to
to a 10-day course of any other with a single drug is sufficient in
a tertiary care center, whenever
antibiotic, a 7-day course of the enteric fever, and administration of
the development of complications
same is as good as another drug multiple drugs should be restricted
is suspected. If a patient does
given for 14 days. 2 to unresponsive cases. 45
not seem to be r espond ing to
When compared to intravenous the first-line drugs by day 5 of Role of Surgery
ceftriaxone (75 mg/day; maximum treatment, an alternative treatment Enteric fever per fora tion is
2.5 g /d a y ) d a ily for 5 d a y s , op tio n shou ld be co n s id e r e d . a common surgical emergency
oral azithromycin (20 mg/kg/day; C o m b in a t io n th er apy may be in d e v e lo p in g c o u n t r ie s , but
maximum 1000 mg/day) achieved considered when monotherapy optimal operative management
an almost similar cure rat (97% fails. Usually, a fluoroquinolone is debatable. 46 Primary ileostomy
vs. 94%) (Figure 7). No patient is the first drug of choice. If the has been shown to be a better
on azithromycin had a relapse, response is found to be inadequate, surgical option in comparison
whereas few relapses were seen the oral cephalosporin, cefixime, with others and can be a life-
with ceftriaxone. 43 is added. If the improvement in saver, particularly in patients
Azithromycin and ofloxacin were the patient is still not satisfactory, who present late in the course of
compared for safety and efficacy in the former drug is withdrawn illness with rapidly deteriorating
40 patients with uncomplicated and azithromycin is added. A health. 47 Enteric perforation should
enteric fever. number of do cto rs use fixed - always be treated surgically, and
dose combinations these days; timely surgery within 24 hours,
G r o up I: P a tie n ts r e c e iv e d
however, the panel of experts did with adequate and aggressive
ofloxacin 200 mg orally twice
not encourage their use, as these resuscitation, decreases morbidity
daily for 7 days. Nineteen out of 20
lack flexibility in dosing. 2 The and mortality. 48 The panelists also
patients from group I were cured
emergence of MDR S. typhi and addressed the issue of the type
with a mean fever clearance time
concerns about a delayed response of surgery that should ideally
of 3.68 days
to quinolones has resulted in a be adopted to operate on such
Group II: Patients rece ived lot of anxiety among treating a perforat ion. They concluded
azithromycin orally 1 g on day 1 p h y s i c i a n s . T h e r e have been that if CT imaging has helped to
and then 500 mg daily from day 2 several takes on the usage of detect the exact site of perforation,
to day 6. All 20 patients from group single versus multiple therapies. l a p a r o s c o p i c s u r g e r y can be
II were cured with a mean fever While some advocate it, others performed; however, if the site has
clearance time of 3.65 days. recommend their usage only in not been identified, then an open
Ofloxacin and azithromycin are unresponsive cases. A comparative surgery is advisable. 2
almost equally efficacious and safe Indian analysis was done in 62 Antibiotic Resistance
in enteric fever, and azithromycin cases of enteric fever proven by As seen earlier, the mainstay of
could be used as an alternative when blood culture, out of which 59% enteric fever management is the use
ofloxacin is contraindicated, received a single drug (either of antibiotics for empiric or
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Journal of The Association of Physicians of India ■ Vol. 63 ■ November 201589

15
Table 6: Relapse rate categorized by bacterial drug resistance and antimicrobials peritonitis, pneumonitis, 89
severe
used52 dehydration, and shock. Other rare
Initial therapy of exclusively Partial or full initial therapy complications that serve as red flags
ampicillin, chloramphenicol, with cephalosporins or include apathy, presence of basal
or TMP-SMX quinolones crepitations, coma, endocarditis,
Resistance profile Cases of relapse/total number of cases (%) p value Guillian-Barré syndrome, neuritis,
Pan-sensitive 47/559 (8.4) 25/377 (6.6) 0.32 meningitis, osteomy elitis,
Partial drug resistance 3/71 (4.2) 4/86 (4.7) 1a pancreatitis, pericarditis, psychosis,
Multidrug resistance 5/31 (16.1) 23/506 (4.5) 0.018a
pyelonephritis, and unexplained
All patients 55/661 (8.3) 52/969 (5.4) 0.018
tachypnea. It is also advisable to refer
a
Fisher’s exact
the patient in case of any
directed therapy. Improper use enteric fever due to the advent diagnostic confusion or when s/he
of antibiotics, especially broad- of antibiotics, relapses continue fails to respond to the primary or
sp ectrum an tib io tic s can lead to occur in up to 10% of the secondary line of treatment with
to emergence of resistance. The patients, even though they are antibiotics.55
commonest factors that lead to immunocompetent. Patients with Treatment of Carriers
antibiotic resistance are the misuse drug-resistant enteric fever who A person is said to be a chronic
and overuse of these drugs. 4 9 A received ineffective therapy have carrier if s/he is asymptomatic,
re-emergence of chloramphenicol a relapse rate, which is almost but his or her stool or rectal swab
susceptibility in S. enterica serovar twice that of those infected with c u ltu r e s test p os itive for the
typhi isolates has been witnessed pan-sensitive strains (Table 6). presence of S. typhi, a year after
in some regions of India, where the Diarrhea is associated with lower recovery. 22 There are basically
susceptibility has been found to be relapse rates in children infected three types of carriers, namely
as high as 95%. Investigators have with pan-sensitive enteric fever. convalescent carriers, who continue
suggested using chloramphenicol, Those infected with MDR strains to shed bacilli in their feces for
along with the third-generation have a higher relapse rate when 3 weeks to 3 months; temporary
cephalosporins in enteric fever due presenting with constipation or carriers, who sheds bacilli for
to ciprofloxacin-resistant S. enterica starting specific therapy within more than 3 months up to a year;
serovar typhi infection. 50 Resistance 14 days of fever onset. The use and chronic carriers, who shed
to fluoroquinolones has led to an of quinolones or cephalosporins bacilli for more than a year. 56 The
increased use of azithromycin and as part of the treatment course Vi (virulence) antibody test is of
third-generation cephalosporins. p r o t e c ts a g a i n s t s u bs e q u e n t value when screening for carriers.
There are worldwide reports of relapse. In those areas where MDR The WHO recommends the use of
high level resistance to expanded- enteric fever caused by S. typhi is ciprofloxacin 750 mg twice daily
spectrum cephalosporins prevalent, empirical treatment of for 4 months or 52 weeks. It is not
( e . g . c e f t r i a x o n e ) . S pr e a d of patients with a cephalosporin or recommended for use in pregnant
such resistance would further quinolone should be considered, women. It may be used in children
g r e a t l y l i m i t t h e av a i l a b l e until infection is caused by a drug- only if the benefits outweigh the
therapeutic options, with only sensitive strain. 52 risks. If there is cholelithiasis,
reserv e a n tim ic ro b ials like Role of Corticosteroids c ho le cy s tec tom y is ind ica ted.
c a r b a p e n e m and t ig e c y c l in e The expert panelists emphatically Schistosomiasis, if present, should
being left as possible treatment stated that steroids should be used be treated. 54
op tio ns. 50 It is s ugge sted that strictly under supervision by Management Guidelines
quinolones and third-generation qualified physician.2
cephalosporins should be used as The IAP task force has made the
When to Refer following statements:53
first-line antimicrobials in enteric
fever. The use of fourth-generation Patients with fever that lasts for The timely and appropriate
cephalosporins should be restricted more than 7 days should be m a n a g e m e n t of en te r ic fever
to complicated or resistant cases. 51 investigated for enteric fever, and reduces morbidity and mortality.
Relapse of Enteric Fever their blood counts and renal function
General supportive measures
should be evaluated. Referral to a
There are several factors, which such as the use of antipyretics,
tertiary care center must be done
are associated with relapse of m a i n t e n a n c e of h y d r a t i o n ,
when there is any evidence of
culture-proven enteric fever as appropriate nutrition, and prompt
complications such as
seen over 15 years in 1,650 children r e c o g n it io n and tr e a t m e n t of
encephalopathy, gastrointestinal
in MDR strains in South Asia. complications ensure a favorable
hemorrhage, glomerulonephritis, m
Despite the drop in the morbidity outcome.
yoc ard itis , perfo ratio n,
and mortality associated with In areas of endemic disease, 90%
20 Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015
15
90 7: Five key steps to safer food
Table 54
should be used to guide the choice of
Key step Explanation antibiotics.
Keep clean Why? Dangerous microorganisms are widely found in soil, water, F l u o r o q u i n o l o n es a re the
animals, and people. These are carried on the hands, cloth used optimal choice for the treatment
for wiping, utensils, and cutting boards; and the slightest contact
of enteric fever in all age groups.
can transfer them to food and cause foodborne diseases.
How? Hands should be washed before handling food, during food In areas where the bacterial
preparation, and after using the toilet. All surfaces and equipment species is still sensitive to traditional
used for food preparation should be washed and sanitized. first-line drugs (chloramphenicol,
Kitchen areas and food should be protected from insects, pests,
and other animals. ampicillin, amoxicillin, or
Separate raw Why? Raw food, especially meat, poultry, and seafood, and their juices, trimethoprim-sulfamethoxazole),
and cooked can contain dangerous microorganisms that might be transferred and fluoroquinolones are not
food onto other foods during food preparation and storage. available or affordable, these drugs
How? Raw meat, poultry, and seafood should be separated from other remain appropriate for treating
foods. Equipment and utensils such as knives and cutting boards
enteric fever.
should be kept separate for handling raw foods. Food should be
stored in containers to avoid contact between raw and prepared Supportive measures like oral or
foods. intravenous hydration, antipyretics,
Cook Why? Cooking food to a temperature of 70°C kills almost all dangerous appropriate nutrition, and blood
thoroughly microorganisms and ensures that it is safe for consumption. Foods
that require special attention include minced meats, rolled roasts,
transfusions are also important.
large joints of meat, and whole poultry. Electrolyte imbalances, anemia, and
How? Food should be cooked thoroughly, especially meat, poultry, eggs, thrombocytopenia also need to be
and seafood. Soups and stews should be boiled till 70°C. Meat and corrected.
poultry should not be pink. Ideally, the use of a thermometer is
advocated. People infected with enteric
Keep at safe Why? Microorganisms can multiply very quickly if food is stored at fever, or exposed to someone
temperatures room temperature. By keeping the temperature below 5°C or infected with enteric fever, MUST
above 60°C, the growth of microorganisms is slowed down or NOT be permitted to work if their
stopped. Some dangerous microorganisms still grow below 5°C.
work involves food handling or
How? Cooked food should not be kept at room temperature for more
caring for children, patients or the
than 2 hours, and should be refrigerated promptly. Cooked
and perishable food should be preserved preferably below 5°C. elderly, and should not prepare food
Cooked food should be kept piping hot (more than 60°C) prior to for others.
serving. Food should not be refrigerated for too long and frozen
food should not be thawed at room temperature.
As enteric fever can be carried
Safe water Why? Safe water should be used or it should be treated to make it safe.
on the hands it is very important to
and raw Fresh and wholesome foods and pasteurized milk should be wash hands thoroughly after using
materials consumed. Fruits and vegetables should be washed properly, the toilet and before handling food.
especially if eaten raw. Do not use food beyond its expiry date. Hands should be washed with soap
How? Raw materials, including water and ice, may be contaminated and water for at least 15 seconds,
with dangerous microorganisms and chemicals. Toxic chemicals
may be formed in damaged and moldy foods. Care in the rinsed and dried well.
selection of raw materials and simple measures such as washing Prevention of Enteric Fever
and peeling may reduce the risk.
or more of enteric fever cases can be ceftriaxone is the most convenient to Primary as well as secondary
managed at home with proper oral use. Oral third-generation strategies need to be adopted in
antibiotics and good care. cephalosporins need to be given in the prevention of enteric fever and
Close follow-up is necessary to higher doses to treat enteric fever. its complications. While secondary
detect complications or failure to Azithromycin is a preferred prevention stratagems attempt to
therapy. alternative agent in uncomplicated reduce the morbidity and mortality
N ali di xi c ac i d- r e s is tan t S. enteric fever. associated with the disease, the
typhi (NARST) species usually Aztreonam and imepenem are primary prevention approaches
demonstrate reduced susceptibility potential second-line drugs. entail measures that help to avoid
to fluoroquinolones. getting infected completely or
For life-threatening infections
at least prevent overt clinical
Third-generation cephalosporins resistant to all other recommended
manifestations of the disease. 57
are recommended for first- line antibiotics, fluoroquinolones may be
treatment. While cefixime and used. Secondary Prevention
cefpodoxime proxetil are Following are recommendations The aim of secondary prevention
administered orally, ceftriaxone, by the WHO:54 is to decrease the clinical severity of
cefotaxime, and cefoperazone are enteric fever and its complications,
Culture and sensitivity tests
given parenterally. Of these, so that it doesn’t prove to be fatal.
Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015 91

Table 8: Comparison of the Vi-PS and Ty21a vaccines59 safer food, which have been listed in
Parameter Vi-PS Ty21a Table 7.54
Type of vaccine Polysaccharide Live attenuated Identifying and treating chronic
Route of Parenteral Oral carriers:
administration
Chronic carriers of the pathogen
Formulations Liquid for injection Enteric-coated tablets and suspension
responsible for the development of
Content per dose 25 μg of the antigen 2 × 109 bacteria
enteric fever can cause localized or
Number of doses Single dose 3 doses every other day
sporadic cases of the disease,
Protective efficacy 60% to 70% within 3 years 62% and 70% after 7 years of vaccination
and around 50% after 3 years with the enteric-coated tablets and liquid particularly if they handle food
of vaccination suspension, respectively that is consumed by others. Once
Storage 2-8°C 2-8°C identified, they should be taken
Thermostability 6 months at 37°C 14 days at 25°C away from these situations. Since
2 years at 22°C nearly 90% of chronic carriers
Clinical tolerability Well tolerated; other than Side-effects include fever, rash, headache, demonstrate high titers of serum
local swelling, no major abdominal pain, nausea, diarrhea, vomiting,
side-effects such as fever and
myalgia, sepsis, pain, urticaria, anaphylactic
Vi antibodies, serological tests to
erythema reaction, weakness, and demyelinating detect the same can be useful for
disease screening. Doing stool cultures
Safety Safe even in HIV patients Best avoided in HIV patients repeatedly after inducing strong
Contraindications Children under 2 years of Children under 6 years of age, pregnant purgation can also serve this purpose.
age women, and immunocompromised state. Several weeks of oral ciprofloxacin
Cost Cheaper Costlier
or norfloxacin therapy has b een
Interactions None reported Reduced efficacy on concurrent use with
antibiotics or IgG and increased efficacy
shown to eradicate the carrier state in
when given to a patient being treated up to 90% of the cases, without the
with mefloquine; interferes with the need for cholecystectomy, which
diagnostic effect of tuberculin test; alcohol used to be advocated in the past. 57
consumption to be avoided within 2 hours
of taking the vaccine. Vaccination:
Booster dose Every 2 years for people who Every 3 years for people living in endemic
remain at risk areas; yearly for people traveling to The use of affordable vaccines
endemic regions
seems to be the most lucrative
The judicious use of efficacious and uncontaminated consumables: prophylactic intervention. In spite
antimicrobials early in the disease Chlorination of drinking water of the fact that the first vaccine for
is the most important component at home should be advocated. The typhoid was introduced by Wright
of secondary prevention. When treated water should preferably way back in 1896, its effectiveness
prescribing antibiotics for patients be stored in a narrow-mouthed was established through controlled
who have acquired the infection vessel and drawn out by tilting the field trials nearly seven decades
from regions where S. typhi species container or using a tap to avoid later. Vaccination against typhoid
are m u ltid r u g r e s is ta nt, it is contamination. People should be as a routine is not required in
advisable to select the drug, based encouraged to use latrines at home countries where high sanitation
on the most current reviews. 57 and the disposal of wastes must be standards are in place. However,
Primary Prevention done in closed sewerage systems. its administration is recommended
E n v iro n me n ta l mea sure s to Raw fruits and vegetables should for individuals travelling to areas
ensure the supply of treated water be washed thoroughly, and the of the world where typhoid is
along with proper sa nita tio n , latter should preferably be cooked endemic, people who are in close
identification of chronic carriers before consumption. Hygienic contact with a chronic carrier of
of enteric fever to break the chain practices should be adopted in the typhoid, and laboratory staff that
of transmission of the disease, and storage of milk and the preparation handle samples containing S. typhi
vaccination of susceptible hosts o f m i l k pr o d uc ts . S tu d i e s bacteria. The standard old typhoid
in order to make them immune should be done by the public vaccines included a monovalent
to the organism, constitute the health department to ascertain vaccine (containing only S. typhi),
three main approaches for primary the quality of dr ink ing water a bivalent vaccine (containing S.
prevention. Unfortunately, owing being supplied to the community. typhi and S. paratyphi A) and the
to cost implications, many parts of Surveillance by hospitals can help traditional typhoid paratyphoid A
developing countries continue to to evaluate the effectiveness of such and B (TAB) vaccine (containing S.
have poor sanitation facilities and interventions. 58 typhi, S. paratyphi A, and S. paratyphi
drink water that is not potable. 57 The World Health Organization B). As of now, only two types of
(WHO) has suggested some tips for typhoid vaccines are available in
Need for adequate sanitation
92 Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015

the Indian market for use clinically, increase in the serum IgA responses and guarding in these patients early,
namely the Vi p oly saccha r ide of patients, the vaccine evoked a so that the development of major
(Vi-PS) vaccine and the Ty21a oral seroconversion of 98% in infants complications can be averted, and the
vaccine. A comparison of the two between 6 and 24 months of age, associated mortality can be
vaccines has been done in Table 8. 59 99% in children aged 2 to 15 years, decreased. Physicians also need to
Since both these vaccines are and 92% in individuals belonging to look for certain age or gender
safe and do not produce major the 15-45 year age group. It has been specific complications; for example,
side-effects, they are good for shown to be superior to the Vi-PS bronchitis is seen more often in
public health and school-based typhoid vaccines and also has a good children, whereas intestinal
i m m u n i z a t io n p r o g r a ms . The safety profile, being tolerated by perforations are more common in
employment of these vaccines people of all the tested age groups. 59 males.2
has been recommended by the Intestinal Complications
WHO for children residing in
Complications of Enteric
The gastrointestinal
areas where typhoid is endemic Fever complications of enteric fever can
and antibiotic-resistant strains of range from something as benign
When patients of enteric fever are
S. typhi are present. In 2013, the Vi- as glossitis or an esophageal ulcer
left untreated, its complications
PS vaccine was licensed for clinical to a problem that can prove fatal
mostly tend to occur in the third and
use in lndia by the Drug Controller such as intestinal perforation or
fourth weeks of infection, the
General of India (DCGI). The bleeding. Gastrointestinal bleeding,
complication rate being as high as
seroconversion rate reported with seen in 10% of the patients, is the
15%. The most important
this vaccine has been 98.05%, but a commonest complication; and in 2%
complications met with in clinical
significant fall in the antibody titers of these cases, there may be a need
practice include gastrointestinal
has been observed after 18 months, for blood transfusions. 6 0 Severe
bleeding, intestinal perforation,
indicating the need for a booster untreated cases of enteric fever are
bronchitis, encephalopathy with
dose. The exact time frame for associated with the development of
confusion as a result of toxemia, and
administration of the booster dose intestinal as well as extraintestinal
toxic myocarditis. 60 The panelists
can be established only on following- complications. Surgical
felt that it is important for the
up for a long period.59 interventions may be required
treating physician to recognize the
A lt h o u g h ent e r i c f e v e r is to manage certain complications
various complications of enteric
common in lndia, and there are involving the small gut, acalculous
fever early and plan his or her line of
concerns about the prevalence cholecystitis, perforation of the
management accordingly, because a
of multidrug resistant strains, g a ll b l a d d e r , or g a n g r e n e . 6 1
number of complications need to be
the ty p ho id va cc ine is be ing Salmonella cholecystitis, a rare
managed in a tertiary medical care
grossly underutilized. The use of complication of Salmonella typhi
center and hence call for timely
vaccines appears to be very cost- infe ction, presents with high -
referral followed by the medical
effective, considering the financial grade fever, jaundice and right-
management with appropriate
implications of diagnosing typhoid sided abdominal pain (Charcot’s
antibiotics along with any surgical
by blood culture, the expenditures triad). Tender hepatomegaly and a
interventions, if found to be
on hospitalization and medicines, distended gallbladder are the usual
necessary.2
and the loss of daily productive examination findings. 62
They were of the opinion that the
working hours, as a result of the Intestinal Perforation
complications of enteric fever are not
illness. Therefore, the expert group The most serious complication
very commonly seen in primary care
recommends the use of these two of e n te r ic f eve r is in t e s t in a l
setups and at the family physician
typho id vaccines routine ly in perforation, as the morbidity and
level. Some doctors see only one or
unvaccinated adults, especially mortality rates associated with
two complicated cases in a year at
those who are at high risk. 59 it are high. An indicator of the
times, with children and elderly
The Vi-TT conjugate vaccine patients being the ones who are more endemicity of enteric fever, the
is a fourth generation typhoid likely to develop complications in incidence of intestinal perforation
vaccine that has been indigenously comparison with individuals from v a rie s g e o g r a p h i c a l l y , the
d e v e l o p e d by an Indian other age groups. They felt that there perforation rate ranging between
biotechnological company. After is a need for doctors to identify red 0.6% and 4.9% worldwide. The
being tested and analyzed for flag symptoms like dehydration, rate of enteric perforation in India
efficacy and safety in more than a toxemia, altered sensorium, and is higher, owing to factors such as
thousand individuals belonging to abdominal rigidity drought, illiteracy, poverty, and
different age groups, this vaccine proliferation of bacterial strains
was launched in Hyderabad in that are m u ltid r u g r e s is ta n t.
2013. As evident from the fourfold Youngsters in their second or third
20
Journal of The Association of Physicians of India ■ Vol. 63 ■ November 201593

15
Table 9: Clinical features of enteric Table 10: Extraintestinal complications of enteric fever36 93
perforation63
Organ system Prevalence Complications
Symptom Frequency CNS 3-35% Encephalopathy, cerebral edema, subdural empyema, cerebral
Fever 100% abscess, meningitis, ventriculitis, transient Parkinsonism, motor
Abdominal pain 100% neuron disorders, ataxia seizures, Guillain–Barré syndrome,
psychosis
Distention 78.06%
Cardiovascular 1-5% Endocarditis, myocarditis, pericarditis, arteritis, congestive
Dehydration 76.12%
heart failure
Constipation 73.54%
Pulmonary 1-6% Pneumonia, empyema, bronchopleural fistula
Vomiting 30.96%
Bone and joint < 1% Osteomyelitis, septic arthritis
Shock 28.38%
Hepatobiliary 1-26% Cholecystitis, hepatitis, hepatic abscesses, splenic abscess,
Chest infection 22.58% peritonitis, paralytic ileus
decade of life are more likely to Genitourinary < 1% Urinary tract infection, renal abscess, pelvic infections, testicular
abscess, prostatitis, epididymitis
develop this complication, as they
Soft tissue 17 reported* Psoas abscess, gluteal abscess, cutaneous vasculitis
tend to eat street food more often,
Hematological 5 reported * Hemophagocytosis syndrome
practice poor hand hygiene, and *
Minimum number of cases reported in English literature
neglect their health.63
Ileal perforation is witnessed timely and appropriate surgical site, followed by the ileocecal
more frequently in remote areas interventions, safe anesthesia, proper valve, the ascending colon, and the
due to a lack of good medical operative care, and the use of wide- transverse colon. The ulcers seen
facilities. Factors associated with spectrum antibiotics with low in such cases are usually multiple
an increased risk of perforation resistance.63 and punched out in appearance,
include male gender, leukopenia, Gastrointestinal Bleeding and their margins are slightly
short disease duration, presence of elevated. 64
Gastrointestinal bleeding
bacterial strains that are multidrug
generally occurs in the third week Extraintestinal Complications
resistant, and incomplete antibiotic
as a result of ulceration, which S. typhi infection may at times
therapy. The treating surgeon
occurs due to necrosis in the small manifest with extraintestinal
usually finds it difficult to manage
bowels. About 20% of the patients infectious complications, which can
such cases, as the patients present
with enteric fever test positive involve various systems and organs
themselves or are diagnosed late
for the presence of occult blood of the body, as shown in Table
after being initially treated by
in their stool. Massive bleeding is 10. It is important to recognize these
quacks. 63
very rarely seen, although gross complications, specifically in
T he i ndi s c r i mi na te us e o f bleeding may be observed in 10% patients who have just been to an
glucocorticoids, lack of awareness, of the patients. The first signs of endemic region and are returning
poverty, and poor medical and bleeding are a sudden decrease home. This can help to prevent a
transportation facilities complicate in the blood pressure and body delay in the diagnosis of enteric
matters further. While the mortality temperature, the former dropping fever.36
a ssoc ia ted with enteric fever- to 80-90 mmHg or even lower and Hematological Complications
related perforation ranges from 0 the patient going into a state of V arious hematological
to 2% in the developed nations, shock. Before chloramphenicol complications have been witnessed
it is much higher (9 to 22%) in was discovered and used for the in patients suffering from enteric
the developing countries, due treatment of enteric fever, the fever, such as hemolytic anemia,
to reasons such as the want of incidence rate of perforations was h e m o l y t i c u r e m ic s y n d r o m e ,
intensive care, poor resuscitation higher. While perforations usually and disseminated intravascular
facilities, antibiotic resistance, occur in the third week of infection, coagulation (DIC). In these patients,
regional taboos, delay in surgery, with the distal part of the ileum the hemoglobin level and platelet
more perforations, fecal peritonitis, being involved most of the times, count may be normal or low, but
and increased disease duration. 63 they can occur even in the first 2 their leukocytic count can be low,
The clinical features of enteric weeks in fulminant cases. 60 normal, or high. Generally, there
perforation and their incidence Bleeding in the gastrointestinal is evidence of eosinopenia, and
r a t e s , as was r e p o r t e d by a tract can occur in the form of either prolongation of the prothrombin
retrospective study of 155 patients occult blood in stool or melena. In time is also detected. 60
who were operated for intestinal enteric fever, this happens due to Neurological Complications
perforation due to enteric fever in erosion of Peyer’s patches into an
a Central Indian district hospital, The neurological complication
intestinal vessel. On colonoscopy,
have been listed in Table 9. It is rates in enteric fever vary (5-35%) in
it is seen that the terminal ileum
advisable to manage such cases with accordance with the extent of
is the most commonly involved
20 Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015

15
9445 42.8 appropriate use of drugs such as
40 fluoroquinolones, cephalosporins,
35 and azithromycin; however, the
Prevalence rate (%)

30 indiscriminate use of antibiotics has


25
25 led to an increase in the incidence of
19.44 19.44
20 drug-resistant enteric fever. While
13.89 the condition is usually treated
15

10
8.33 medically, surgical interventions may
5.56
5 be required at times to manage
0 certain complications. Strategies to
Delirium Encephalitis Psychiatric Cerebellar ataxia Meningitis Polyneuropathy Extrapyramidal reduce the disease burden include
manifestations symptoms
supply of purified water, thoughtful
Fig. 8: Prevalence rates of various neurological manifestations in patients with disposal of sewage and other wastes,
neurological complications in enteric fever65 practice of hygienic food habits,
identification and treatment of
90 82.8 80 chronic carriers of enteric fever, and
80
vaccination of susceptible hosts. The
70 62.7
Prevalence rate (%)

Vi-PS and Ty21a vaccines are


60
50.8 available for typhoid prophylaxis in
50
India; however, a comparison of the
40
31.2 two types of vaccines shows that the
30 former is safer and more cost-
20 effective, as compared to the latter.
10 The indigenously developed Vi-TT
0
Restlessness Confusion Incoherent speech Disorientation Carphology
conjugate vaccine seems to be
Fig. 9: Prevalence rates of the clinical features of delirium associated with showing much promise and may
enteric fever be the vaccine of choice in the days
ahead.
drug resistance. M eningismus the delirium state associated with
and acute confusion are the most enteric fever and their prevalence Acknowledgement
frequent manifestations. Confusion rates in the delirious patients among Dr. M.A. Kharadi, Ahmedabad;
may have an intermittent character the study population have been Dr. Rashmin Prajapati, Ahmedabad;
and appears as apathy in many shown in Figure 9.65 Dr. V i ja y S h a r m a , A m r i t s a r ;
patients. 60 An Indian study found
that 27.1% of the patients suffering Conclusion Dr. A j i t K u m a r , B a n g a l o r e ;
Dr. Bharath Kumar, Bangalore;
from enteric fever had neurological Dr. Sanjeev Murthy, Bangalore;
Enteric fever is very common in
manifestations, and the mortality Dr. M.B. Seshachandra, Bangalore;
the Asian countries, especially in
rate was 6.35%. This only goes
India; and it progresses quite rapidly D r . R a m e s h S. C h a k s o t a ,
to show how important the early Bhiwandi; Dr. Ruby Bansal, Delhi;
to present with complications
detection of such complications D r . R . K . L u t h a ri a , D el h i ;
that can be both intestinal and
is during the course of enteric Dr . I . K . K a s t u r i a , De l h i ;
e x tr a in te s t in a l. D e lir iu m and
fev er. F ig u re 8 g r a p h i c a l l y D r . R a j e s h K u m a r , D el hi ;
neurological complications may
shows the common neurological Dr. V inod K u mar , D e l h i ;
also be e n c o u n te r e d in some
complications of enteric fever, Dr. Hardeep Singh Ruproi, Delhi;
patients. Hence, there is a need
which were also observed in this Dr. Venkata Arella, Hyderabad;
for the treating doctors to stay
study population. 65 Dr. Vij a y Go pa l , H y d e r a b a d ;
alert when managing such cases.
In this study, delirium was found The early identificatio n of red Dr. Kodali Vijay Kumar, Hyderabad;
to be the earliest neurological flag symptoms, which herald the D r . K .K . R e d d y, H y d e r a b a d;
symptom and occurred 2-18 days development of complications and D r . B ah u b a l i J a i n , I n d o r e ;
(mean 5.9 days) after the onset of impending danger, can go a long D r . P r a b h a t J a i n , I nd o r e ;
fever. The mean duration was 7.3 way in ensuring that the patient Dr. K .S . S a b h a r w a l , I n d o r e ;
days (3-14 days); and following the is treated appropriately and at the D r . P r a b h a t J a i n , I nd o r e ;
initiation of appropriate therapeutic right time, thereby reducing the Dr. R . N. T ri p a th y, Ka n p u r ;
measures, the mean time of morbidity and mortality associated Dr. A b h a y ku m a r , K o l ka ta ;
resolution was 3.3 days (1-7 days). with the disease. The condition can Dr. Nirmal Mukherjee, Kolkata;
The clinical features of be very effectively treated with the Dr. S.K . N a s i r u d i n , K o l k a t a ;
20
Journal of The Association of Physicians of India ■ Vol. 63 ■ November 201595

15
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Infections: Clinical, Immunological and comparative study of Widal test with blood
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“The initiative of ‘Enteric Conclave’ is supported by Abbott Healthcare Private Limited (through its Truecare division) in the quest of widening therapy
knowledge in Enteric fever by bringing together experts and primary care physicians on one platform for the benefit of patients and medical fraternity.”