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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 Amarapurkar 5, 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

E nteric fever is a condition that


is taking its toll even now in
India, where its prevalence doesn’t
h e a l t h p r o b l e m i n I n d i a we r e
deliberated in this focused group
discussion. The practice patterns
to use the term ‘enteric fever’
instead of ‘typhoid fever,’ as the
former covers both typhoid and
seem to be decreasing in spite of f r o m a c r o s s t h e c o u n t r y we r e paratyphoid. In adults, enteric
the availability of antibiotics and compared, and the best clinical fever tends to cause constipation.
vaccines in the market. With the practices were pinpointed. Therefore, the presence of diarrhea
emergence of antibiotic resistant instead in such a case should
strains of the pathogenic organisms, Epidemiological Concerns raise suspicion of a co-infection.
the management of this disease of Enteric Fever in the Long-term use of proton pump
is becoming more challenging. inhib it ors (PPIs) increa ses t h e
Indian Scenario
Further, there are no standard incidence of EF because less or
India-specific guidelines to treat The term ‘enteric fever’ no acid in the stomach facilitates
this scourge. In order to bridge (EF) includes typhoid and the passage of bacteria without
this need gap and for the benefit of paratyphoid fevers. Typhoid destruction by the gastric acid. 2
primary care doctors, the ‘Enteric fever is caused by a Gram- Definitions3
Conclave,’ the first-of-its-kind, was n e g a t i ve o r g a n i s m ,   S a l m o n e l l a Confirmed enteric fever: Fever
conducted. This meeting was a very enterica subspecies enterica serovar ≥38°C for at least three days, with
innovative initiative that facilitated Typhi (Salmonella typhi), whereas a laboratory-confirmed positive
a frank exchange of opinions paratyphoid fever is caused by any culture (blood, bone marrow,
between gastroenterologists, of the three serovars of Salmonella bowel fluid) of S. typhi.
consulting physicians, and general enterica subspecies enterica, namely
practitioners, who had been Probable enteric fever: Fever ≥38°C
S. paratyphi A, S. schottmuelleri (also
brought together under a common for at least three days, with a
called  S. paratyphi B), and S.
roof to discuss the epidemiology, positive serodiagnosis or antigen
hirschfeldii (also called S. paratyphi
diagnosis, and management of detection test but without S. typhi
C). Type A is the most common
typhoid. While gastroenterologists isolation.
pathogen worldwide, whereas
usually get to see only complicated Type B predominates in Europe. Chronic carrier state: Excretion
forms of the disease, and consulting Type C is rare, and is seen only in of S. typhi in stools or urine (or
physicians mostly deal with cases the Far East. The overall ratio of repeated positive bile or duodenal
that are severe, majority of the the disease caused by S. typhi to string cultures) for longer than one
cases in India are taken care of by that caused by S. paratyphi is about year after the onset of acute enteric
primary care doctors. Thus, the 10 to 1. 1  fever; sometimes, S. typhi may be
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 serological 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
493.5
60
52.5 60 57
Typhoid incidence

500
50
50

% of resistant isolates
Typhoid prevalence
400 340.1
300 40

200 29.1 40
119.7 30
89.2
100 18.1 30
20
0
0-1 2-4 5-15 >= 16 10 6.9 20
Age (years)
0 10 7
0-1 2-4 5-15 >= 16 1.6
Fig. 1: Incidence of enteric fever in Age (years) 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. clinical and microbiological
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
wi t h se wa g e wa t er, h ave 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
i n c i d e n c e o c c u r s w h e r e wa t e r 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 contaminated with feces. 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 transmission 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 have the highest infection rates. 5 years). The high disease burden in
22 million new typhoid cases occur In 2008, Ochiai et al conducted pre-school children underscores
each year. The worst sufferers are a prospective population-based the importance of vaccines and
young children in poor, resource- survey in five Asian countries delivery systems in this age group,
limited areas, who make up the considered to be endemic for enteric, a s we l l a s o l d e r c h i l d r e n a n d
majority of the new cases and adolescents. 6
mortality figures (215,000 deaths
80
annually). Most of these deaths 65.54 ± 6.22
are due to S. typhi infection. The 70 62.08 ± 4.82
South-east Asian countries bear the 50.04 ± 9.61
Seropositivity (mean %)

brunt of the disease, particularly 60


children and 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
Year
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
Antibiotic Patients Responded Resistant Effervescences 50 people (three fatally), highlights
(No.) (N%) (N%) period* the 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
Ciprofloxacin 42 34 (80.5%) 8 (19.5%) 5.5 state is the single most important
Ofloxacin 14 12 (85.71%) 2 (14.28%) 5.0 risk factor for development of
Amikacin 9 8 (88.8%) 1 (11.9%) 5.0
hepatobiliary carcinomas, as
Cefixime 6 6 (100%) - 6.5
salmonella carriers with gallstones
Cefotaxime 5 4 (80%) 1 (20.0%) 6.5
h a ve b e e n s h o w n t o c a r r y a n
Ceftriaxone 38 38 (100%) - 5.0
8.47-fold higher risk of developing
Chloramphenicol 2 - 2 (100%) -
cancer of the 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 multidrug-resistant 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
Nalidixic acid resistance being an antibody titers to O and H antigens
the first few years of life, peaking
indirect marker of fluoroquinolone of S. typhi over a period of ten
in school-aged children and young
resistance; indicates high resistance years (1998-2002 and 2007-2011)
adults and then falling in middle
to fluoroquinolone.6 Since in Indian patients of different age
age. Older adults are relatively
fluoroquinolones are empirical groups, who had been diagnosed
resistant, probably due to frequent
therapy of choice in enteric fever, 7 with enteric fever. This study found
boosting of immunity.
increasing rates of antibiotic that the overall seropositivity rates
over the 10-year study period had Season
resist ance may necessitate the
replacement of inexpensive increased significantly, as shown In endemic areas, peaks of
antibiotics with newer, expensive in 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,
patients. This also highlights favor the growth of the organism.
Salmonella typhi crosses 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 multidrug resistance (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 vendors; drinking contaminated
About 3 to 5% of infected people
doubled between 1999 and 2005 water; and eating vegetables and
become carriers, particularly those
(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 Other
are often asymptomatic and can
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 Poor socioeconomic status
groups, typhimurium, and paratyphi
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
Recent consumption of 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 and troughs rise progressively over
Transmission of enteric fever
of hospitalization. Almost similar time (Figure 6).
has also been attributed to flies,
observations have been made in Gastrointestinal manifestations
laboratory mishaps, unsterile
other studies from other parts of
instruments, and anal intercourse. Diffuse abdominal pain and
the country. The costs increased
MDR Enteric Fever tenderness; sometimes, fierce
several times due to increased
colicky pain in right upper
In 1972, chloramphenicol- hospitalizations and growing
quadrant.
resistant S. typhi was first reported, 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
(MDREF) has been reported during individuals and their families. 15 and narrowing of bowel lumen,
outbreaks from many parts of the resulting 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
Dull frontal headache
well. MDREF is associated more Isolation of S. typhi from
commonly with hepatomegaly blood, bone marrow, or a specific Delirium
and splenomegaly. Resistance anatomical lesion is the only Stupor
to ceftriaxone and cefixime has d e f i n i t i v e wa y o f d i a g n o s i n g Malaise
been seen in many studies, as is enteric fever. 3 The presence of
Second week
resistance to quinolones, indicating characteristic clinical symptoms
that Salmonella develops resistance or the demonstration of a specific Progression of above signs and
rapidly against quinolones and antibody response is suggestive of symptoms
hence, existing quinolones, the disease, but not definitive. Fever plateaus at 39-40°C
like sparfloxacin, levofloxacin, Clinical Features Rose spots
gatifloxacin and moxifloxacin, The panelists were of the opinion Salmon-colored, blanching,
should be used very rationally that a good clinical history and maculopapules on the chest,
(Table 1). 14 physical examination are very abdomen, and back, may not be
Economic Implications of Enteric Fever important for the diagnosis of visible in dark-skinned individuals
Management of enteric fever in enteric fever. In fact, the presence 1-4 cm in width, less than 5 in
India is a costly affair. According to of fever with hepatosplenomegaly number, present in up to 25% of
a prospective surveillance carried should make one think of this patients
out in an urban slum in Delhi, condition as one of the differential
They resolve within 2-5 days.
the direct and indirect costs per diagnoses. The participants were
Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015 81

Represent bacterial emboli to stepladder fever pattern is seen Significant hepatic dysfunction
the dermis in 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
Relative bradycardia — The specificity of a blood culture
children in AIDS and one-third
temperature elevations not is 100%. At least 25-30 ml of blood
of immunocompetent adults with
accompanied by a physiological should be collected for a good
enteric fever
increase in the 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 Only fever ideal time of doing a blood culture
first S e v e r e h e a d a c h e s is when the patient is having
mimicking meningitis chills (and not when the fever
Third week
spikes, as is commonly thought).
Fever persists Acute lobar pneumonia
Blood for culture should be taken
Increase in toxemia Arthralgias before giving the first dose of
Anorexia Urinary symptoms antibiotics. However, in clinical
Severe jaundice practice, antibiotic therapy is
Weight loss
initiated based on the diagnosis,
Conjunctivitis Neurological symptoms in
and a blood culture is advised. It
some patients, especially in India
Thready pulse is always better to do an antibiotic
and Africa, such as delirium,
Tachypnea sensitivity test along with the
Parkinsonian symptoms or
culture, as this will help to select
Crackles over lung bases Guillain-Barré syndrome
the most appropriate antibiotic.
Severe abdominal distension Pancreatitis Culture should be repeated after
Sometimes, foul, green-yellow, Meningitis an hour and then after 24 hours.
liquid diarrhea (pea-soup diarrhea) Orchitis A single culture should not be
Typhoid state — characterized encouraged. (The participants,
Osteomyelitis
by apathy, confusion, psychosis on the other hand, revealed that
Abscesses they seldom did a blood culture
Bowel perforation and peritonitis
Laboratory Evaluation in a primary healthcare setup, as
due to necrosis in Peyer’s patches
The expert panelists opined it was expensive for the patients.
Death may occur due to severe They usually depended on the
that a very toxic-looking patient
toxemia, myocarditis or intestinal findings of the Widal test and the
with low counts should raise
hemorrhage complete blood cell count, which
suspicion of enteric fever or a viral
Fourth week infection. Increased counts usually shows eosinopenia and relative
Gradual improvement in fever, signify sepsis or perforation, with lymphocytosis). The positivity of
mental state, and abdominal eosinopenia being an important the blood culture is as follows:
distension over a few days finding. Monocytosis is also a 1 st week – 90%
Untreated patients may suffer usual finding. The presence of both 2 nd week – 75%
from intestinal and neurological eosinopenia and thrombocytopenia
3 rd week – 60%
complications is strongly suggestive of enteric
fever. 2 4 th week – 25%
Weight loss and debilitating
Hematological tests17,18 The positivity of blood culture
weakness (may last for months)
Complete blood count decreases due to the administration
Asymptomatic carrier state in of antibiotics; however, the blood
some patients, who can transmit Hemoglobin: Mild anemia
culture will continue to test
the bacteria indefinitely Total leucocytic count (TLC): positive in resistant cases. Many a
Atypical presentation16 Low to normal time, contaminants like coagulase-
In some patients, enteric Eosinopenia negative staphylococci in the blood
fever may not present in the Platelets: Low to normal culture may cause a false-negative
typical manner described above. report. Hence, the culture should
Liver function tests:
Presentation of the disease depends be done with due caution. A clot
upon the host response, geographic Mildly abnormal culture is also being done.2 The cost
region, race factors, and the Serum transaminase levels 2 to of a blood culture in India ranges
infecting bacterial strain. 3 times the upper limit of normal from ` 600 to `800.
Fever: The characteristic Clinical jaundice is uncommon Culture involves inoculation of
82 Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015

the specimen (blood, bone marrow S. typhi and S. paratyphi A are the greater will be the likelihood
or stool) into an enrichment broth, n o t a l wa y s c u l t u r a b l e e ve n i f of getting a positive result. Rectal
and when a growth appears, good microbiological facilities are swabs can be obtained instead
making subcultures on solid agar. available 20 of stool samples but they are
Biochemical testing is done to Bone marrow culture: less successful in isolating the
identify the colonies obtained. organism. 3 A stool culture in India
Culture of the bone marrow
This is further confirmed by slide costs about ` 350 to ` 450.
aspirate is the gold standard for
agglutination with appropriate All the panelists were 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
remains the gold standard in bacteria sporadically. Chefs, in
patients who have been treated
the diagnosis of enteric fever. 20 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 organism in 80% to 100% states, as they are likely to infect
culture with the recommended
of patients, 17 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
Limitations in use
started antibiotics may not show 55-67% and a specificity of 30%. 18
The positivity rate can further be Sporadic shedding of the
any growth. 17
increased to almost 100% if FAN org anism in st ools pot en t i a l l y
The sensitivity range of blood compromises the stool culturing
culture medium is used and growth
culture is estimated to be between approach 20
is monitored in automated culture
40% and 80%. The sensitivity may
systems. 23 Becomes positive only after the
be low in endemic areas with high
Speaking about bone marrow first week of infection and has a
rates of antibiotic use, making
culture, the participants declared much lower sensitivity than blood
it difficult to estimate the true
that this investigation is never culture (30% vs. 40-90%) 18
specificity. 18
carried out at the primary Sensitivity is low in developing
Failure to isolate the organisms
healthcare level. Even otherwise, countries 18
can be due to delay in diagnosis,
it is avoided considering that it is Not routinely used for follow-
limitations of laboratory media,
costly as well as painful. The expert up 18
widespread and irrational use
panelists informed that unlike
of antibiotics, and low volume Urine culture:
blood culture, bone marrow culture
of blood cultured, especially Urine culture, according to
remains positive even after the
in children. 21 The probability of the experts, is not usually done.
administration of antibiotics. Thus,
recovering the organisms is directly Positivity of urine culture
it is more suitable for hospitalized
p r o p o r t i o n a l t o t he volum e of increases in carriers with urinary
and very sick patients. 2
blood drawn; hence, it is essential obstruction. 2
to have an adequate volume of Limitations in use
Urine culture for enteric fever
blood taken for culture. 20 Due to Although the most sensitive, it is
has variable sensitivity, the range
the higher levels of bacteremia in an invasive procedure, and cannot
being 0-58%. 18 In India, the cost of
children compared to that in adults, be performed outside specialist
a urine culture varies from ` 350
at least 10-15 ml of blood from settings 20
to ` 450.
schoolchildren and adults, and 2-4 H a s l i m i t e d c l i n i c a l va l u e ,
ml from toddlers and preschool Rose spot culture:
especially in ambulatory
children should be taken to achieve management 18 Punch-biopsy samples of rose
optimal isolation rates. 3 spots may be cultured to yield
T he s pecimen is difficult t o
Limitations in use a sensitivity of 63% and may be
obtain
positive even in patients who have
L e s s s e n s i t i ve f o r d i a g n o s i s Stool culture: reviewed antibiotics. 16
of infection among children as
Stool culture can help in Serum culture:
compared to adults 22
detecting typhoid carriers. Stool
Positive in only 40-60% of cases, To conduct serum culture, 1-3
should be collected from acute
usually early in the course of the ml of blood is inoculated into a
patients in a sterile wide-mouthed
disease 18 tube without anticoagulant. When
plastic container and should
the convalescent stage starts about
Expensive and requires specialist preferably be processed within
5 days later, a second sample
facilities and personnel 20 two hours of collection. The larger
is collected. After clotting, the
is the quantity of stool collected,
Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015 83

serum is separated and tested little advantage in young (2 to 6 Due to its high sensitivity and
immediately or stored for a week years old) children. specificity, nested PCR can serve as
without affecting the antibody Molecular diagnostics a useful tool to diagnose clinically
titre. 3 suspected, culture negative cases
Polymerase chain reaction
Duodenal aspirate culture: of enteric fever. 27
(PCR):
Sharing their experiences Benefits of nested PCR 27
PCR is a promising test, which
with regard to duodenal aspirate is as sensitive as blood culture, but • S e n s i t i v i t y o f 1 0 0 % a n d
culture, the panelists explained that less specific. 18 It has been found to specificity of 76.9%
this investigation may have good be >90% sensitive and relatively • Higher case detection compared
sensitivity because bile directly simple to perform. Moreover, it to blood culture even in the
enters the duodenum. However, can amplify DNA from dead or later stages of the disease (53.8
they added that this test is not unculturable bacteria, providing vs. 46.1%)
practical and is more of academic an additional sensitivity benefit. • Can be used as a diagnostic tool
interest. A culture of the duodenal However, it seems to have limited in any stage of the disease
aspirate in chefs can help to detect potential for the diagnosis of
carriers amongst them. Other • N o t a f f e c t e d b y e m p i r i c a l
enteric fever. In the absence of any
materials which can be cultured antibiotic therapy unlike blood
validated PCR test, the in-house
include bile, rose spot discharge, culture. Hence, can serve as
systems currently in use are
pus from a suppurative lesion, and an effective diagnostic test
open to differing interpretation
CSF or sputum, if the patient has even after the initiation of
and do not meet the rigorous
complications. At autopsy, culture antimicrobial therapy.
quality control standards for
from the liver, spleen, gall bladder, worldwide acceptance. 20 A PCR is Serological tests
and mesenteric lymph nodes is also quite expensive, costing anything Serological tests are the
positive. 2 between ` 3800 and ` 4000 in India. mainstay of diagnosis of enteric
In a study 24 of 36 patients with The experts felt that PCR may fever in developing countries. 21
bacteriologically proven enteric not satisfy the criteria of a ‘gold S. typhi is known to express a
fever, culture of duodenal contents standard’ for the diagnosis of number of immunogenic structures
(obtained with string capsules) was enteric fever in terms of sensitivity on its surface. Among them, O
found to be as sensitive in diagnosis and specificity, since it does (liposaccharide), H (flagella), and
as bone marrow culture and more not cover all the antigens of the the somewhat less immunogenic
effective than blood and stool disease. Only antigens 14, 15 and Vi capsule can be identified by
cultures in recovery of S. typhi. 18 are picked up by one PCR test. serological tests. S. typhi expressing
The sensitivity of duodenal content Moreover, this test is not available O ( O 9 , O 1 2 ) , Vi , a n d H : d a r e
culture was not affected by the in remote and peripheral areas. The abundantly present in most endemic
duration of illness or antibiotic participants also echoed the same areas.20 All the participating doctors
therapy. Even on the seventh day of sentiments, as they added that the unanimously expressed the same
antibiotic treatment, the duodenal PCR is hardly ever used for the view that although the Typhidot,
content culture was positive in diagnosis of enteric fever in India. 2 IgM Dipstick, and IDL Tubex tests
eight of 17 patients, whereas stool are promising tests, they are still
Nested polymerase chain
culture was positive in only two of not being used routinely in India.
reaction:
the same patients. Widal test:
A nested polymerase chain
Apart from good sensitivity, According to the World Health
reaction is more sensitive than PCR
duodenal content culture is simple, Organization, Widal, the most
and uses H1-d primers to amplify
economical and can be performed widely available test in India,
specific genes of S. typhi in the
with minimal facilities. 24 However, should not be done before one
blood of patients. 18 It involves two
this method is not widely performed week of the onset of fever. Even
rounds of PCR using two primers
due to poor tolerance of the string if it is positive before one week, it
with different sequences within
device, particularly by children. 25 might be a false-positive. With the
the H1-d flagellin gene of S. typhi,
Acco r di n g t o a c o mp a r a t i ve offering the best sensitivity and availability of other highly reliable
s t u d y 2 5 o f t h e va r i o u s c u l t u r e specificity. 16 tests, the importance of Widal has
methods, bone marrow cultures declined. A single Widal has no
It is a promising rapid diagnosis
remain the most effective method value. It may be obsolete; but in
test, with potential to replace blood
for the recovery of S. typhi. Stool the absence of any other reliable
culture as the new gold standard. 18
cultures appear to be more effective modality, it may be done. 2
It is so sensitive that it can detect
in children than in adults, while Widal is the most widely
even one bacterium in a given
duodenal content cultures offer used test in many regions as it is
sample within a few hours. 26
84 Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015

relatively cheaper, easy to perform, The sensitivity, specificity, and itself. Typhidot-M is done in cases
and requires minimal training and predictive values differ in different of acute infection. 2 A Typhidot in
equipment. The test is based on geographic areas 26 India costs between ` 300 and ` 400.
the demonstration of a rising titer N e g a t i ve i n 3 0 % o f c u l t u r e Limitations in use 3
of antibodies in paired samples 10 proven cases of enteric fever 3 IgG can persist for more than
to 14 days apart. It uses O and H
Prior antimicrobial treatment two years after typhoid infection.
antigens of S. typhi, S. paratyphi A,
may adversely affect the antibody Hence, detection of only IgG cannot
S. paratyphi B and S. paratyphi C to
response 3 differentiate between acute and
detect antibodies in blood.28 At least
False-positive results may convalescent cases.
1 ml of blood should be collected to
obtain a sufficient amount of serum. be obtained in other clinical Previous infection may lead to
Usually O antibodies take 6-8 days conditions, such as malaria, typhus, false positive results.
to appear and H antibodies 10-12 bacteremia and cirrhosis 3 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 improved version of Typhidot,
the anti-O antibody titer is the areas 28 o b t a i n e d b y i n a c t i va t i n g t o t a l
first to rise, followed by a gradual Widal need not be performed IgG in the serum sample, which
increase in anti-H antibody titer. if the diagnosis has already been removes competitive binding and
The anti-H antibody response confirmed by the isolation of S. allows access of the antigen to the
persists longer than the anti-O typhi from a sterile site. 3 While a specific IgM, thereby enhancing
antibody. 29 tube Widal in India costs around diagnostic accuracy. If specific
According to a study conducted ` 110 to ` 170, the slide Widal is IgM is detected within three hours,
in Nepal,29 a presumptive diagnosis priced a bit higher between ` 150 it points towards acute typhoid
of enteric fever can be made if and ` 200. infection. 3
significant titers are greater than Typhidot: Advantages
1:80 for anti-O and greater than Typhidot is a rapid-dot enzyme Superior to culture method
1:160 for anti-H. i m m u n o a s s a y ( E I A) t h a t t a k e s in terms of sensitivity (>93%),
However, it is difficult 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 protein (OMP) antigen of S. along with culture method, for
in given areas. 3 A fourfold rise in typhi. 21 Detection of IgM signifies rapid and accurate diagnosis of
antibody titer in a paired serum is acute enteric in the early phase of enteric fever 3
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 in the middle phase of infection. 3
endemicity. 3
a 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 countries 30
to have a low predictive value for
its presence. 28 culture and Widal, in which results Latex agglutination test:
take 48 and 18 hours, respectively. Studies on the efficacy of the
Advantages of Widal
In addition, this test is simpler and latex agglutination test (LAT) have
Inexpensive 3 more reliable than Widal. 21 shown that:
Good for screening a large Its simplicity, speed, sensitivity Wi t h a s e n s i t i v i t y o f 1 0 0 % ,
number of patients in endemic (95%), specificity (75%), cost- specificity of 97.6%, and positive
areas despite mixed results 18 effec tiveness, ab ilit y t o det ect and negative predictive values of
Use of slides instead of tubes antigens early, and high negative 90.9% and 100%, respectively, LAT
gives results faster — in only a few and positive predictive values make can be used for the presumptive
minutes 19 Typhidot an efficient diagnostic diagnosis of enteric fever in remote
Limitations in use tool in resource-poor countries. 3 health centers 31
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
required 18 reliable. It is available even in tier 3 negative blood culture and positive
cities, so it can be easily prescribed. Widal, indicating better sensitivity
Moderate sensitivity and
It becomes positive in the first week as compared to blood culture 32
specificity 3
Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015 85

Table 2: Investigations according to week of presentation tests are indicated after all the
Week of illness Feasible tests Non-feasible tests other febrile conditions have been
1st week Hematological tests Eosinopenia17,18 Bone marrow culture3 ruled out.
Blood culture20 PCR20 Newer tests
Typhidot/Typhidot-M3 Duodenal aspirate culture25 N e we r t e s t s i n t h e p i p e l i n e
Widal (basal)28 Dipstick3 include 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 culture25 Enteric fever continues 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. 22 This calls for urgent
Blood culture20 Tubex3 measures to detect carriers as
Stool culture18 Duodenal aspirate culture25 they are a silent threat to the
Widal (very high titer)28 Dipstick3 c o m m u n i t y . 20 A n i d e a l t e s t f o r
Typhidot/Typhidot-M3 carriers should be rapid, specific,
4th week Hematological tests17,18 Bone marrow culture3 as well as sensitive. 22 One such
USG abdomen2 PCR20 measure is monitoring S. typhi
Blood culture20 Tubex3 in the stool. However, this may
Stool culture18 Duodenal aspirate culture25 b e h a m s t r u n g b y l o w l e ve l o r
Widal (very high titer)28 Dipstick3 sporadic shedding and the fact
Typhidot/Typhidot-M3 that routine stool sampling may
b e e x p e n s i ve , t i m e c o n s u m i n g
L AT c a n b e u s e d f o r r a p i d 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 Advantages 3
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 in India
specialized equipment, electricity
but has been modified to improve
or cold storage facilities
the sensitivity and specificity to Wi t h t i m e , t h e t r e a t m e n t o f
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 p o s i t i ve r e s u l t i s a d e f i n i t e Ideal for places with no culture the Salmonella enterica species. 34
indicator of a Salmonella infection. 3 facilities Characterized by a lengthy
A s Tu b e x d e t e c t s o n l y I g M incubation period, nonspecific
Ta b l e 2 g i v e s t h e l i s t o f
antibodies and not IgG, it is highly s y m p t o m s t h a t a r e d i ve r s e i n
tests 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,
poverty cycle. It is estimated that
Limitation in use not easily available, require
nearly 22 million new cases of
Negative results may be specialized equipment, or are not
enteric fever develop every year,
obtained in patients infected by tolerated.
the mortality rate being higher in
It must be borne in mind that
86 Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015

Table 3: Treatment of enteric fever2


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
areas. 4 ciprofloxacin susceptibility (DCS) of the third and fourth generation)
History of Antibiotic Therapy in Enteric is now being seen. Since the 1990s, are recommended for use as the
Fever azithromycin has been showing first-line therapeutic agents. 2
Chloramphenicol was the good results and is a promising Ta b l e 3 l i s t s t h e d r u g s
drug of choice for the treatment alternative 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 response to treatment, and
aplasia put it behind on the shelf. Fever possibility of antibiotic resistance
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 ampicillin in the 1970s; 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- t h e r e wa s a n e e d t o s i m p l i f y underdose the patient, when trying
resistant (MDR) strains of S. typhi, the c hoice of t he drug s in t he 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.
we r e p r e f e r r e d t o c e f t r i a x o n e fluoroquinolones (especially, Thus, if the dose requirement
due to their oral use and cost- ciprofloxacin and ofloxacin) and calculated for a patient amounts to
Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015 87

Table 4: List of red flag symptoms in Table 5: Azithromycin in 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 World Health
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 known resistance to the older first-
characteristics of a previous
murmur, cardiac of cefpodoxime proxetil allows line antibiotics. A Cochrane study
arrhythmias for its twice daily dosing. In revealed that fluoroquinolones have
Respiratory Chills, cough (with or past studies, all the 50 strains fewer clinical failures in
system without sputum), pleuritic comparison with ampicillin,
pain, coarse crackles, and responsible for enteric fever were
found to be sensitive to ceftriaxone, amoxicillin, chloramphenicol, and
bronchial breathing
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
with or without an effusion in 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
eradication of the pathogen’s serovars typhi and paratyphi A,
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. 38 A study that tested the to prompt fever clearance within
efficacy of cephalosporins in 4.7 hours, on an average. 41 The
When factors such as intolerance
t h e t r e a t m e n t o f e n t e r i c f e ve r panelists reminded that the use of
to oral drugs, dehydration, extremes
found that the MIC 50 and MIC 90 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 and those who cannot tolerate this
treatment should be instituted.
the least in comparison to the oral class of antibiotics. In such patients,
Once the condition of the patient
third-generation cephalosporin alternative treatment regimens
stabilizes, s/he should gradually
cefixime and the parenteral should be followed. Also, if culture
be de-escalated from parenteral
fourth-generation cephalosporin and antibiotic sensitivity shows the
therapy to oral drugs. With the
cefipime. 37 presence of nalidixic acid-resistant
defervescence period usually being
Salmonella typhi (NARST), the use
about 5 days, any patient who is Cefpodoxime and cefixime have
of quinolones must be avoided, as
not responding adequately may be been used extensively in enteric
there is a great probability of the
switched to a different drug after fever. Although cefpodoxime has
pathogen being resistant to this
stopping the first, or the second wide applicat ions in pediat ric
antibiotic class. 2
drug may be added to the first one. 2 infectious diseases, it hasn’t
However, at any point during the been used much in enteric Azithromycin:
course of the illness, patients may fever; though it is similar Azithromycin is safe and
develop symptoms of developing pharmacologically to cefixime efficacious for the management
complications, which should serve and cheaper than cefixime. In 140 of uncomplicated enteric fever.
as red flags for the treating doctor. children assessed for suspected An open-label, non-comparative
The important red flag symptoms enteric fever, a comparative study, which evaluated the efficacy
have been listed in Table 4. 36 study showed that cefpodoxime and safety of azithromycin for the
Cephalosporins: reduced  treatment  cost by 33% treatment of uncomplicated enteric
in comparison to cefixime, and is fever, found that azithromycin (20
Cefixime, cefpodoxime proxetil,
also a safer oral option in children. mg/kg/day for 6 days) cured
cefipime, and ceftriaxone are
The two groups showed a similar 93% of the subjects, with a mean
expanded-spectrum cephalosporins
clinical response with comparable day of response of 3.5 as seen in
that have been very promising
periods to defervescence in days Table 5. No serious adverse event
in the management of enteric
and clinical cure rates. The MIC for wa s o b s e r ve d . 4 2 T h e p a n e l i s t s
fever. While the former two are
cefpodoxime against all Salmonella recommended a course of not more
administered orally, the latter
88 Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015

100 as in children, pregnant women, a quinolone or cephalosporin);


and quinolone-resistant cases of and 40.3% cases received 2 drugs
90
enteric fever. 44 simultaneously. The duration of
80 fever from the beginning of the
Cure rate (%)

Single vs. Multiple Drug Regimens


60 illness to the time of defervescence
The expert panelists declared that
was 13.54 days and 13.84 days in
40 there are no clear-cut guidelines for
the single-drug and multiple-drug
the employment of monotherapy
20 groups, respectively. The mean
and combination therapy. Since
duration for defervescence after
0 it is not possible to tell whether a
Azithromycin Ceftriaxone initiation of antimicrobial therapy
patient is going to respond to the
Antibiotic used in the single-drug group was 5.24
treatment or not on the very first
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
significant difference in the total
fever43 patients in and around the area to
duration of fever or the time taken
presume resistance or sensitivity to
than 7 days with azithromycin, for defervescence after initiation
a particular drug. Although culture
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 responding 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 E n t e r i c f e ve r p e r f o r a t i o n i s
2.5 g/day) daily for 5 days, option should be considered. a common surgical emergency
oral azithromycin (20 mg/kg/day; Combination therapy may be in developing countries, 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, w i t h o t h e r s a n d ca n b e a l i f e -
with ceftriaxone. 43 is added. If the improvement in s a ve r , p a r t i c u l a r l y i n p a t i e n t s
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 doctors use fixed- always be treated surgically, and
dose combinations these days; timely surgery within 24 hours,
G r o u p I : Pa t i e n t s r e c e i v e d
however, the panel of experts did w i t h a d e q u a t e a n d a g g r e s s i ve
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
G r o u p I I : Pa t i e n t s r e c e i ve d lot of anxiety among treating a perforation. They concluded
azithromycin orally 1 g on day 1 physicians. There have been that if CT imaging has helped to
and then 500 mg daily from day 2 s e ve r a l t a k e s o n t h e u s a g e o f detect the exact site of perforation,
to day 6. All 20 patients from group single versus multiple therapies. laparoscopic surgery 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 blood culture, out of which 59%
enteric fever management is the
when ofloxacin is contraindicated, r e c e i ve d a s i n g l e d r u g ( e i t h e r
use of antibiotics for empiric or
Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015 89

Table 6: Relapse rate categorized by bacterial drug resistance and antimicrobials peritonitis, pneumonitis, 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, osteomyelitis,
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
a
Fisher’s exact
refer 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
spectrum antibiotics 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. 49 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 cultures test positive 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. protects against subsequent 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. ceftriaxone). Spread 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
greatly limit the available 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,
reserve antimicrobials like Role of Corticosteroids cholecystectomy is indicated.
carbapenem and tigecycline Schistosomiasis, if present, should
The expert panelists emphatically
being left as possible treatment be treated. 54
stated that steroids should be
o p t i o n s . 50 I t i s s u g g e s t e d t h a t
used strictly under supervision by Management Guidelines
quinolones and third-generation
qualified physician. 2 The IAP task force has made the
cephalosporins should be used as
When to Refer following statements: 53
first-line antimicrobials in enteric
fever. The use of fourth-generation Patients with fever that lasts The timely and appropriate
cephalosporins should be restricted for more than 7 days should be management of enteric fever
to complicated or resistant cases. 51 i n ve s t i g a t e d f o r e n t e r i c f e ve r , reduces morbidity and mortality.
Relapse of Enteric Fever and their blood counts and renal
General supportive measures
f u n c t i o n s h o u l d b e e va l u a t e d .
There are several factors, which such as the use of antipyretics,
Referral to a tertiary care center
are associated with relapse of maintenance of hydration,
must be done when there is any
culture-proven enteric fever as appropriate nutrition, and prompt
evidence of complications such as
seen over 15 years in 1,650 children recognition and treatment of
encephalopathy, gastrointestinal
in MDR strains in South Asia. complications ensure a favorable
hemorrhage, glomerulonephritis,
Despite the drop in the morbidity outcome.
myocarditis, perforation,
and mortality associated with In areas of endemic disease, 90%
90 Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015

Table 7: Five key steps to safer food54 should be used to guide the choice
Key step Explanation of antibiotics.
Keep clean Why? Dangerous microorganisms are widely found in soil, water, Fluoroquinolones are 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
foods. oral or intravenous hydration,
Cook Why? Cooking food to a temperature of 70°C kills almost all dangerous antipyretics, appropriate nutrition,
thoroughly microorganisms and ensures that it is safe for consumption. Foods
that require special attention include minced meats, rolled roasts,
and blood transfusions are also
large joints of meat, and whole poultry. important. Electrolyte imbalances,
How? Food should be cooked thoroughly, especially meat, poultry, eggs, anemia, and thrombocytopenia also
and seafood. Soups and stews should be boiled till 70°C. Meat and need to be 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 f e ve r , o r e x p o s e d t o s o m e o n e
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
Cooked food should be kept piping hot (more than 60°C) prior to food 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
and peeling may reduce the risk. Prevention of Enteric Fever
or more of enteric fever cases can be ceftriaxone is the most convenient Primary as well as secondary
managed at home with proper oral to 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
Nalidixic acid-resistant 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
a t l e a s t p r e ve n t o ve r t c l i n i c a l
Third-generation cephalosporins resistant to all other recommended
manifestations of the disease. 57
are recommended for first- antibiotics, fluoroquinolones may
line treatment. While cefixime be used. Secondary Prevention
and 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 enteric fever and its complications,
Culture and sensitivity tests
are 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
Parameter Vi-PS Ty21a in 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
Number of doses Single dose 3 doses every other day
or 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,
myalgia, sepsis, pain, urticaria, anaphylactic
side-effects such as fever and 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 p u r g a t i o n c a n a l s o s e r ve t h i s
age women, and immunocompromised state.
purpose. Several weeks of oral
Cost Cheaper Costlier
ciprofloxacin or norfloxacin
Interactions None reported Reduced efficacy on concurrent use with
antibiotics or IgG and increased efficacy
therapy has been shown to
when given to a patient being treated eradicate the carrier state in up to
with mefloquine; interferes with the 90% of the cases, without the need
diagnostic effect of tuberculin test; alcohol for cholecystectomy, which used to
consumption to be avoided within 2 hours
of taking the vaccine.
be advocated in the past. 57
Booster dose Every 2 years for people who Every 3 years for people living in endemic Vaccination:
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 multidrug resistant, 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
Environmental measures 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 sanitation, 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 of milk products. Studies 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 t h e q u a l i t y o f d r i n k i n g wa t e r 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
n a m e l y t h e Vi p o l y s a c c h a r i d e of patients, the vaccine evoked a early, so that the development of
(Vi-PS) vaccine and the Ty21a oral seroconversion of 98% in infants major complications can be averted,
vaccine. A comparison of the two between 6 and 24 months of age, and the associated mortality can
vaccines has been done in Table 8. 59 99% in children aged 2 to 15 years, be decreased. Physicians also
Since both these vaccines are and 92% in individuals belonging need to look for certain age or
safe and do not produce major to the 15-45 year age group. It has gender specific complications;
side-effects, they are good for been shown to be superior to the for example, bronchitis is seen
public health and school-based Vi-PS typhoid vaccines and also more often in children, whereas
immunization programs. The has a good safety profile, being intestinal perforations are more
e m p l o y m e n t o f t h e s e va c c i n e s tolerated by people of all the tested common in males. 2
has been recommended by the age groups. 59 Intestinal Complications
WHO for children residing in The gastrointestinal
areas where typhoid is endemic
Complications of Enteric
complications of enteric fever can
and antibiotic-resistant strains of Fever range from something as benign
S. typhi are present. In 2013, the as glossitis or an esophageal ulcer
When patients of enteric fever
Vi-PS vaccine was licensed for to a problem that can prove fatal
are left untreated, its complications
clinical use in lndia by the Drug such as intestinal perforation or
mostly tend to occur in the third
Controller General of India (DCGI). bleeding. Gastrointestinal bleeding,
and fourth weeks of infection,
The seroconversion rate reported seen in 10% of the patients, is the
the complication rate being as
with this vaccine has been 98.05%, commonest complication; and in 2%
high as 15%. The most important
but a significant fall in the antibody of these cases, there may be a need
complications met with in clinical
titers has been observed after 18 for blood transfusions. 60 Severe
practice include gastrointestinal
months, indicating the need for a untreated cases of enteric fever are
bleeding, intestinal perforation,
booster dose. The exact time frame associated with the development of
bronchitis, encephalopathy with
for administration of the booster intestinal as well as extraintestinal
confusion as a result of toxemia,
dose can be established only on complications. Surgical
a n d t o x i c m y o c a r d i t i s . 60 T h e
following-up for a long period. 59 interventions may be required
panelists felt that it is important for
Although enteric fever is to manage certain complications
the treating physician to recognize
common in lndia, and there are involving the small gut, acalculous
the various complications of enteric
concerns about the prevalence cholecystitis, perforation of the
fever early and plan his or her
of multidrug resistant strains, g a l l b l a d d e r , o r g a n g r e n e . 61
line of management accordingly,
t h e t y p h o i d va c c i n e i s b e i n g Salmonella cholecystitis, a rare
because a number of complications
grossly underutilized. The use of complication of Salmonella typhi
need to be managed in a tertiary
vaccines appears to be very cost- infection, presents with high-
medical care center and hence
effective, considering the financial grade fever, jaundice and right-
call for timely referral followed
implications of diagnosing typhoid sided abdominal pain (Charcot’s
by the medical management with
by blood culture, the expenditures triad). Tender hepatomegaly and a
appropriate antibiotics along with
on hospitalization and medicines, distended gallbladder are the usual
any surgical interventions, if found
and the loss of daily productive examination findings. 62
to be necessary. 2
working hours, as a result of the Intestinal Perforation
They were of the opinion that the
illness. Therefore, the expert group The most serious complication
complications of enteric fever are
recommends the use of these two of enteric fever is intestinal
not very commonly seen in primary
t y p h o i d va c c i n e s r o u t i n e l y i n perforation, as the morbidity and
care setups and at the family
unvaccinated adults, especially mortality rates associated with
p h y s i c i a n l e ve l . S o m e d o c t o r s
those who are at high risk. 59 it are high. An indicator of the
see only one or two complicated
The Vi-TT conjugate vaccine c a s e s i n a ye a r a t t i m e s , w i t h endemicity of enteric fever, the
is a fourth generation typhoid children and elderly patients incidence of intestinal perforation
vaccine that has been indigenously being the ones who are more varies geographically, the
developed by an Indian likely to develop complications perforation rate ranging between
biotechnological company. After in comparison with individuals 0.6% and 4.9% worldwide. The
being tested and analyzed for from other age groups. They felt rate of enteric perforation in India
efficacy and safety in more than a that there is a need for doctors to is higher, owing to factors such as
thousand individuals belonging to identify red flag symptoms like drought, illiteracy, poverty, and
different age groups, this vaccine dehydration, toxemia, altered proliferation of bacterial strains
was launched in Hyderabad in sensorium, and abdominal rigidity that are multidrug resistant.
2013. As evident from the fourfold Youngsters in their second or third
Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015 93

Table 9: Clinical features of enteric Table 10: Extraintestinal complications of enteric fever36
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 sit e, followed b y t he i l eoceca l
more frequently in remote areas in tervent ions, safe anest hesia, valve, the ascending colon, and the
due to a lack of good medical proper operative care, and the use transverse colon. The ulcers seen
facilities. Factors associated with of wide-spectrum antibiotics with in such cases are usually multiple
an increased risk of perforation low 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 Extraintestinal Complications
generally occurs in the third week
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
quacks. 63
very rarely seen, although gross these complications, specifically in
The indiscriminate use of 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 s s o c i a t e d w i t h e n t e r i c f e ve r - to 80-90 mmHg or even lower and Hematological Complications
related perforation ranges from 0 the patient going into a state of
Va r i o u s h e m a t o l o g i c a l
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
t h e d e ve l o p i n g c o u n t r i e s , d u e treatment of enteric fever, the
fever, such as hemolytic anemia,
to reasons such as the want of incidence rate of perforations was
hemolytic uremic syndrome,
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
rates, as was reported 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%)
it is seen that the terminal ileum
advisable to manage such cases with in accordance with the extent of
is the most commonly involved
94 Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015

45 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
5.56
5 may be required at times to manage
0 certain complications. Strategies
Delirium Encephalis Psychiatric Cerebellar ataxia Meningis Polyneuropathy Extrapyramidal to reduce the disease burden
manifestaons symptoms
include supply of purified water,
Neurological condions
Fig. 8: Prevalence rates of various neurological manifestations in patients with thoughtful disposal of sewage and
neurological complications in enteric fever65 other wastes, practice of hygienic
food habits, identification and
90 82.8 80 treatment of chronic carriers of
80
enteric fever, and vaccination of
70 62.7 susceptible hosts. The Vi-PS and
Prevalence rate (%)

60
50.8 Ty21a vaccines are available for
50
t y p h o i d p r o p h yl a x i s i n I n d i a ;
40
31.2 however, a comparison of the two
30 types of vaccines shows that the
20 former is safer and more cost-
10 effective, as compared to the latter.
0 The indigenously developed Vi-TT
Restlessness Confusion Incoherent speech Disorientaon Carphology
conjug at e vaccine seems t o be
Clinical features of delirium
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. Meningismus 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 Dr. M.A. Kharadi, Ahmedabad;
may have an intermittent character among the study population have Dr. Rashmin Prajapati, Ahmedabad;
and appears as apathy in many been shown in Figure 9. 65 Dr. Vijay Sharma, Amritsar;
patients. 60 An Indian study found Dr. Ajit Kumar, Bangalore;
that 27.1% of the patients suffering Conclusion
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 Dr. Ramesh S. Chaksota,
India; and it progresses quite rapidly
to show how important the early Bhiwandi; Dr. Ruby Bansal, Delhi;
to present with complications
detection of such complications Dr. R.K. Lutharia, Delhi;
that can be both intestinal and
is during the course of enteric Dr. I.K. Kasturia, Delhi;
extraintestinal. Delirium and
fever. Figure 8 graphically Dr. Rajesh Kumar, Delhi;
neurological complications may
shows the common neurological Dr. Vinod Kumar, Delhi;
also be encountered 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. Vijay Gopal, Hyderabad;
alert when managing such cases.
I n t h i s s t u d y , d e l i r i u m wa s The early identification of red Dr. Kodali Vijay Kumar, Hyderabad;
found to be the earliest neurological flag symptoms, which herald the Dr. K.K. Reddy, Hyderabad;
symptom and occurred 2-18 days development of complications and Dr. Bahubali Jain, Indore;
(mean 5.9 days) after the onset of impending danger, can go a long Dr. Prabhat Jain, Indore;
fever. The mean duration was 7.3 way in ensuring that the patient Dr. K.S. Sabharwal, Indore;
days (3-14 days); and following is treated appropriately and at the Dr. Prabhat Jain, Indore;
the initiation of appropriate right time, thereby reducing the Dr. R.N. Tripathy, Kanpur;
therapeutic measures, the mean morbidity and mortality associated Dr. Abhay kumar, Kolkata;
time of resolution was 3.3 days with the disease. The condition can Dr. Nirmal Mukherjee, Kolkata;
(1-7 days). The clinical features of be very effectively treated with the Dr. S.K. Nasirudin, Kolkata;
Journal of The Association of Physicians of India ■ Vol. 63 ■ November 2015 95

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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.”