2. MICROBIOLOGY
The term enteric fever includes typhoid fever caused b Salmonella. enterica var typhi and paratyphoid fever
caused by S. enterica var paratyphi A, B or C.
Paratyphoid infections constitute about 20% of all cases of enteric feve worldwide.
Enteric fever is a disease transmitted by the feco-oral route.
S. enterica serotype typhi/paratyphi is a gram-negative, non-lactose fermenting, flagellate bacterium.
The somatic or 0 antigen is shared among various salmonellae; the flagellar or H antigen is specific to the
serovar. S. enterica var typhi also possesses a Vi polysaccharide capsule.
The infective dose of typhoid/paratyphoid bacillus varies from 103 to 106 organisms.
3. PATHOGENESIS
The organism must survive the gastric barrier to reach the small intestine
conditions which reduce gastric acidity, such as antacids, H2 receptor blockers and proton pump inhibitors
reduce the infective dose.
On reaching the small intestine, the organism penetrates the mucosa and infects lymphoid follicles and
subsequently the draining mesenteric nodes and the liver and spleen.
It multiplies in the reticuloendothelial system
After incubation period varying from 7-14 days spills into the bloodstream and is widely disseminated,
especially to liver, spleen, bone marrow, gallbladder and Peyer patches of the terminal ileum.
4. CLINICAL FEATURES
The hallmark of enteric fever is fever which starts as a low grade fever and then shows stepwise increase
peaking to as high as 103-104°C by the end of the first week.
This pattern differentiates it from viral fever where the peak is usuaIIy at the onset of fever.
With fever, there is associated malaiSed, 1 . e dull headache, anorexia, nausea, poorly loca iz abdominal
discomfort, mild cough and malaise.
There may be diarrhea; constipation in children is rare.
Physical findings are unremarkable with the exception of a coated tongue, tumid abdomen and sometimes
hepatosplenomegaly.
The rash described in Western textbooks is seldom seen in indian subjects.
Infants and young children with enteric fever may have diarrhea as a predominant manifestation or a short-
lasting undifferentiated febrile illness.
In the absence of treatment, fever may continue for ~ weeks followed by natural remission or by development
of complications.
5. COMPLICATIONS
The commonest intestinal complications are bleeding or perforation seen in the 2nd or 3rd week of illness in
10-15% of adult patients, but less frequently in children.
Bleeding is due to erosion of a necrotic Peyers patch through the wall of a vessel and is usually mild but can,
sometimes, be life-threatening,
Perforation is a dreaded complication manifesting as acute abdomen, with high mortality unless
appropriately treated.
The term severe or complicated enteric fever is used for patients presenting with neurological complications
such as delirium, coma, obtundation, stupor or shock and is associated with mortality rates as high as 50%.
Other complications of include hepatic and splenic abscesses, hepatitis, cholecystitis, pneumonia,
disseminated intravascular coagulation, psychosis, ataxia or meningitis.
The case fatality rate is less than 1 % in appropriately treated cases but may be 10-20% in inadequately
treated or complicated cases.
6. RELAPSE
Relapse may occur in 5-15% of treated cases.
Usually due to the organism with the same susceptibility as the original attack and is relatively a milder illness.
Rate of relapse is dependent on choice of drug therapy.
It is higher with beta lactams such as cefixime or ceftriaxone as compared to quinolones and azithromycin.
7. CARRIER STATE
Although 5-10% adult patients may shed Salmonella in stool following an acute attack for up to 3 months.
Only 1-4% excrete bacilli for more than 1 year.
These individuals are potential sources of infection for family members and contacts and for the community, if
they are in occupations that involve food processing.
There is no data on carrier prevalence m children.
Routine examination of stool following recovery from enteric fever is not recommended.
8. DIAGNOSIS
Leukocyte counts may be normal to low with absolute eosinopenia and neutrophilic predominance.
Anemia and thrombocytopenia may occur in advanced illness.
There may be mild elevation of transaminases to 2-3 times normal (SGOT being higher than SGPT).
A very high C reactive protein sometimes helps to differentiate enteric from viral fevers, especially dengue.
Ultrasound abdomen shows mesenteric adenitis with splenomegaly.
The gold standard for diagnosis is blood culture.
9. DIAGNOSIS CONTINUED
The sensitivity is greatest in the first week at around 90% but drops to 40% in the 4th week. Its overall sensitivity is
60%, which reduces to 20-40% after antibiotics.
Salmonella is an easy organism to culture and use of bile broth media and automated culture systems such as
BACTEC improve recovery.
Sufficient blood should be collected (10 ml in adults and 5 ml in children) and a blood: media ratio of 1:5 should be
maintained.
The use of clot culture methods does not significantly improve recovery rates.
Bone marrow cultures have higher yield as compared to peripheral blood cultures as Salmonella is a pathogen of
the reticuloendothelial system and should be sent, if a bone marrow examination is done as part of work-up for
pyrexia of unknown origin.
Owing to very low recovery rates, stool cultures and urine cultures are not recommended. Antimicrobial susceptibility
testing of the isolate is important in the era of multidrug resistance.
10. DIAGNOSIS CONTINUED 2
The Widal test detects presence of IgG and IgM antibodies to H (flagellar antigen) of S. enterica var typhi and
paratyphi A and B, and 0 (somatic antigen) common to typhi and paratyphi A and B.
Anti-0 titers are both IgG and IgM that rise and decline early, while anti-His primarily IgG that rise and
decline late in course of the disease.
The conventional method of interpretation of the Widal test has been to demonstrate fourfold rise in
antibody titers in two samples.
Since this is often not practical, a single titer of at least 1:160 for both 0 and His considered positive.
Even with this compromise, the Widal test has several limitations. Sensitivity is low in the first week of illness
and in patients treated with prior antibiotics.
Specificity is low owing to anamnestic reactions, prior vaccination, cross-reactivity with other
Enterobacteriaceae and subclinical infections in endemic areas.
11. IN PATIENT VS HOME TREATMENT
Most cases of enteric fever can be managed at home with oral antibiotics and
advice to seek medical follow-up in case of failure to respond to therapy or
development of complications.
Children with persistent vomiting, poor oral intake, severe diarrhea or abdominal
distension usually require intravenous (IV) antibiotics and IV fluids, necessitating
admission to hospital.
12. ANTIMICROBIAL SENSITIVITY
The antimicrobial sensitivity of S. typhi/paratypHi has shown changes over the decades.
Though resistance to chloramphenicol was first noted soon after its first use in 1940s, it was not until 1972 that
chloramphenicol-resistant typhoid fever became a major problem.
Multidrug-resistant typhoid fever (MDRTF) became a common occurrence by the end of 1990s, with emergence of S. typhi
simultaneously resistant to all the drugs that were used as first-line treatment (chloramaphenicol, trimethoprim,
sulfamethoxazole and ampicillin).
Fluoroquinolones were introduced in the late 1980s and early 1990s and produced very good results initially.
But the past decade has seen a progressive increase in the minimum inhibitory concentrations (MIC) of ciprofloxacin in S. typl1i
and paratypl1i and resistance rates to fluoroquinolones/nalidixic acid now approach 90%.
Alongside the rise in resistance to quinolones, there has been return in sensitivity to first-line antibiotics such as
cltloramphenicol, cotrimoxazole and ampicillin.
However, concerns of toxicity and inconsistent reports of sensitivity preclude their widespread use.
There are recent sporadic reports of resistance to ceftriaxone due to production of novel type of beta lactamases.
Salmonella may show in vitro susceptibility to aminoglycosides and second-generation cephalosporins, but these are not
effective in vivo, and should not for treatment.
13. CHOICE OF EMPIRICAL THERAPY
Where enteric fever is clinically suspected but cultures have not been sent for, reports are awaited or are sterile,
empirical therapy may be started.
Choice for empirical therapy is guided by various factors including the severity of the illness, inpatient/outpatient
therapy, presence of complications and local sensitivity patterns.
For uncomplicated enteric fever, oral cefixime at a dose of 20 mg/kg/day (ceiling dose of 1200 mg) is the drug of
choice.
Azithromycin (10-20 mg/kg/day) is a good second choice agent; chloramphenicol (5O mg/kg/day), amoxicillin and
cotrimoxazole are other second-line agents.
Clinical efficacy is more or less the same with all these drugs with each drug having its own advantages and limitations.
The choice of medication depends on individual preference, experience, and level of comfort and cost considerations.
Once culture results are available, therapy can be modified.
There is no data at present to support use of combination therapy in enteric fever.
14. SEVERE ILLNESS TREATMENT
For severe illness and where complications are present, intravenous ceftriaxone and cefotaxime are used a dose of 100
mg(kg/day and 200 mg/kg/day, respectively.
In patients with history of penicillin or cephalosporin allergy, aztreonam, chloramphenicol (in higher than usual doses)
and cotrimoxazole (in higher than usual doses) are used as second-line agents.
Parenteral treatment is continued until defervescence has occurred, oral intake has improved and complications
resolved.
Thereafter, therapy can be switched to oral cefixime to complete a total duration of 14 days.
Other oral drugs that may be used for switch over therapy include azithromycin, cotrimoxazole and amoxicillin.
In culture proven enteric fever, if defervescence does not occur by day 7, causes such as drug fever, thrombophlebitis,
hepatic or splenic abscesses, hemophagocytic syndrome and coinfections need to be excluded.
If cultures are negative and defervescence has not occurred by day 7 a thorough search for alternative etiology for
fever be made and ceftriaxone continued.
15. TREATMENT OF RELAPSE
Relapse rates vary with the type of drugs and are most common with beta lactams
( ceftriaxone, Cefixime) especially if shorter duration of therapy.
Although relapses may be satisfactorily treated with same drug as used for
primary therapy, azithromycin is the preferred drug since it is associated with very
low relapse rates.
16. PREVENTION
The most effective and desirable method for prevention of enteric fever is by
improving hygiene and sanitation.
It will yield additional dividends of reduction in the burden of other water-borne
illnesses.
Vaccination
