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MANAGEMENT OF ENTERIC FEVER IN 2012

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Falguni S. Parikh, Mumbai


Enteric fever is a severe systemic illness characterized by fever and abdominal pain that is caused
by dissemination of S. typhi and S. paratyphi. Patients with immunosuppression, biliary and urinary
tract abnormalities, hemoglobinopathies, malaria, schistosomiasis, bartonellosis, histoplasmosis and
Helicobacter co infections are at increased risk of severe disease. Typhoid and paratyphoid fever
continue to be important causes of illness and death particularly among children and adolescents
in south-central and south-east Asia due to poor sanitation and unsafe food and water supply. The
incidence is 102-2219 cases per 1,00,000 population. The growing importance of S. paratyphi A in
Asia is concerning.
Classic presentation is rising fever in first week of illness accompanied by relative bradycardia. In
second week, abdominal pain develops and `rose spots may be seen. Diarrhoea or constipation may
occur. During the third week, hepatosplenomegaly, intestinal bleeding and perforation with secondary
bacteremia and peritonitis may develop. Less commonly neurologic symptoms may be observed.
Focal extraintestinal manifestations have been described as a result of bacteremic seeding. Chronic
salmonella carriage is defined as excretion of the organism in stool or urine more than 12 months
after acute infection. Chronic carriers frequently have high serum antibody titres against Vi antigen
which is clinically useful test for rapid identification of such patients.
In post antibiotic era the average case fatality rate is estimated to be less than 1% but this may be
10-20 fold higher in most resource limited settings.
A center for disease control (CDC) compilation of 10 hospital based typhoid fever series reported a
mean case fatality rate of 2% (range 0 14.8%) which included very severe hospitalized cases with
access to care.
Diagnosis
Blood culture is the gold standard for diagnosis of typhoid fever. Cultures are positive in 40 80% of
patients. Stool, urine, rose spots or duodenal contents may also be cultured. Bone marrow culture may
remain positive up to 5 days after starting antibiotics. The cost, non availability of laboratory facilities,
failure to do culture and prior antibiotic use often cause underutilization of valuable diagnostic
method. Advantage of doing cultures is availability of antibiotic susceptibility of the isolate which is
of paramount therapeutic importance.
Widal test is commonly used. A fourfold or greater increase in titer (when paired acute and convalescent
samples are compared) is considered positive. However, seropositivity amongst healthy blood donors
in a study performed in Central India was 8 14%. Hence clinical utility is doubtful in endemic areas
as positive results may represent previous infection.
Newer serologic assays using Elisa and dipstick methods have still not been approved for routine
diagnostic use in view of variable sensitivity and specificity.
Other laboratory findings may include anemia, leucopenia, absolute eosinopenia and abnormal liver
function tests. Often salmonella hepatitis and acute viral hepatitis may coexist posing a diagnostic
challenge.

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Management of Enteric Fever in 2012

Treatment of typhoid fever

chloramphenicol where it showed similar efficacy. However,


on basis of its shorter treatment duration, fewer adverse events
and lower cost, authors recommend it as preferred treatment
of enteric fever.

Antimicrobial resistance is a major public health problem


in both S. typhi and S. paratyphi and timely treatment with
appropriate antimicrobial agents is important for reducing the
mortality of enteric fever. Chloramphenicol was the drug of
choice for several decades after its introduction in 1948 but
was set aside due to emergence of plasmid mediated resistance
and rare but fatal occurrence of bone marrow aplasia.
Trimethoprim sulfmethoxazole and ampicillin used in 1970s
met a similar fate. In 1980s, ceftriaxone and ciprofloxacin
were shown to be effective against the multidrug resistant
strains and became drugs of choice. In the past decade strains
of bacteria with decreased ciprofloxacin susceptibility have
emerged and rendered older fluoroquinolones ineffective.
Azithromycin was tested in 1990s and can now be regarded
promising alternative.

Cephalosporins
Trials of ceftriaxone show that fever defervescence takes
longer and relapses occur in patients treated for shorter
duration. It is recommended for 14 days. This antibiotic is
safe and achieves good clinical cure.
Chloramphenicol
The reduced use of chloramphenicol has increased sensitivity
to chloramphenicol. Reversal may be due to loss of plasmids
encoding resistance to chloramphemicol. It is making a
comeback in developing countries.
Prevention

Azithromycin

The availability of full genome sequences for S. typhi and


S. A confirms their place as monomorphic human adapted
pathogens vulnerable to control measures if efforts for the
same can be intensified.

Nine prospective clinical trials have been done. Drug


was received by a total 453 patients including children.
Azithromycin was used in dose of 500mg 1 gm /day for
5-7 days.

Interventions to improve availability of safe water, food and


basic sanitation measures are underway in most countries.
The identification and management of S. carriers particularly
those involved with food handling has proved to be important
strategy for control.

No relapses were recorded in 267 patients treated with


azithromycin followed up for 1 month after therapy where as
relapses were recorded in 16 of 276 patients (5.8%) treated
with ceftriaxone, ofloxacin or gatifloxacin.
Bacteriological responses were very good with only 1.5%
patients whose blood was recultured after treatment showed
salmonella.

Vaccines
While Ty 21a and Vi polysaccharide vaccines are effective,
development of cheap, safe vaccines with efficacy among
infants which can provide protective immunity after single
does is required. The growing importance of S. A as a cause
of enteric fever is of great concern particularly due to lack of
effective vaccine available. CDC has issued special guidelines
for typhoid vaccination in travelers to endemic countries.

Azithromycin is capable of achieving very high intracellular


concentrations and its ability to achieve intracellular
concentrations 50-100 times greater than serum levels
explains its efficacy against salmonella species. It has half life
of 2-3 days. Raised MICS of azithromycin have been reported
in S. and paratyphi A. Recently azithromycin resistance and
treatment failure in patient with S. paratyphi A infection has
been reported.

Conclusions
Enteric fever continues to be important cause of illness with
estimated global burden of greater than 27 million cases per
annum with a clinical relapse rate of 5% to 20%. In India there
have been increasing reports of Salmonella enterica serotype
A causing enteric fever in addition to serotype. Typhoid
vaccine does not offer protection against paratyphi

Fluoroquinolones
Quinolones including ciprofloxacin and ofloxacin were drugs
of choice for most cases of enteric fever. However reports of
resistance to fluoroquinolones in the form of nalidixic acid
resistance which correlates with decreased ciprofloxacin
susceptibility (DCS) was reported in 1990s. In Asian countries
this gave rise to them being rendered ineffective therapy.
Gatifloxacin gave good results in 2 trials that used 7 day
courses, had low MIC (minimum inhibitory concentration)
for bacterial strains with DCS and is suggested to be more
effective than older fluoroquinolones owing to better results
of time-kill experiments but its use was associated with more
relapses than with azithromycin. In a recent paper in the Lancet
infectious disease from Nepal Gatifloxacin was compared to

Antimicrobial resistance has rendered many drugs particularly


older fluoroquinolones useless as therapy for typhoid. There is
greater use of third generation cephalosporins. Azithromycin
and newer fluoroquinolone Gatifloxacin have showed
promise in the treatment of multidrug resistant typhoid. Safe
water supply and improvement in sanitation facility will go
a long way in the control of typhoid especially in developing
countries.

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Medicine Update 2012 Vol. 22

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