Shigellosis : challenges & management issues

Dipika Sur, T. Ramamurthy, Jacqueline Deen* & S.K. Bhattacharya

National Institute of Cholera & Enteric Diseases, Kolkata & *International Vaccine Institute
Seoul, Korea

Received April 27, 2004

Infectious diseases kill about 11 million children each year while acute diarrhoeal diseases
account for 3.1 million deaths in children under 5 yr of age, of which 6,00,000 deaths annually
are contributed by shigellosis alone. Shigellosis, also known as acute bacillary dysentery, is
characterized by the passage of loose stools mixed with blood and mucus and accompanied by
fever, abdominal cramps and tenesmus. It may be associated with a number of complications of
which haemolytic uraemic syndrome is the most serious. Shigellosis is caused by Shigella spp.
which can be subdivided into four serogroups namely S.sonnei, S.boydii, S.flexneri and
S.dysenteriae. Organisms as low as 10-100 in number can cause the disease. Shigellosis can
occur in sporadic, epidemic and pandemic forms. Epidemics have been reported from Central
American countries, Bangladesh, Sri Lanka, Maldives, Nepal, Bhutan, Myanmar and from the
Indian subcontinent, Vellore, eastern India and Andaman and Nicobar islands. Plasmid profile
of shigellae in Kolkata has shown a correlation between presence of smaller plasmids and
shigellae serotypes- indicating epidemiological changes of the species. Diagnosis of shigellosis
is essentially clinical. Laboratory diagnosis includes stool culture and polymerase chain reaction
(PCR). Treatment includes use of an effective antibiotic, rehydration therapy (if there is
dehydration) and appropriate feeding during and after an episode of shigellosis. Hand-washing
is the single most important strategy for prevention of transmission of shigellosis from person
to person. A safe and effective vaccine should be developed against the more important circulating

strains i.e., S. dysenteriae type 1 and S. flexneri 2a.

Review Article

Indian J Med Res 120, November 2004, pp 454-462

Infectious diseases kill about 11 million children

each year and 99 per cent of these deaths occur in the
developing countries. Notably, of the 11 million
deaths, 4 million die within the first year of their
life

1

. Acute diarrhoeal diseases rank second amongst

all deaths due to infectious diseases accounting for
3.1 million deaths in under 5 children; 80 per cent of
these deaths occur in children below 2 yr of age.
Shigellosis is an important cause of diarrhoeal deaths.
It has been reported that no less than 140 million
cases of shigellosis occur worldwide with 600,000
deaths annually; 60 per cent of such deaths are seen
in under 5 children

2

. In this review, attempts have

been made to highlight the molecular epidemiology,
epidemic and pandemic potential, current case
management strategies including drug resistance
problem and preventive aspects of shigellosis.

Definition

Shigellosis, commonly known as acute bacillary

dysentery, is manifested by the passage of loose stools
mixed with blood and mucous and accompanied by
fever, abdominal cramps and tenesmus (a symptom
characterized by incomplete sense of evacuation with
rectal pain).

Key words Drug resistance - dysentery - shigellae - shigellosis

454

Clinical features

In some cases, there may not be any symptoms

(asymptomatic), while in others it may produce mild
to moderate dysentery or even fulminating dysentery
with fever, severe abdominal cramps and rectal pain.
Children may have high fever (104

0

F) with

convulsions, rectal prolapse and later develop
malnutrition. Shigella sonnei produces mild
dysentery. S.flexneri and S.dysenteriae type 1
typically produce severe dysentery, particularly the
latter.

Complications

Shigellosis may be associated with a large number

of mild to severe life-threatening complications

3

,

particularly due to S.dysenteriae type 1. Children may
have high fever, rectal prolapse and convulsions.
Arthritis and arthralgia are complained by some
patients. Intestinal perforation, haemorrhage, toxic
megacolon and protein loosing enteropathy may
complicate a shigellosis case. Leukemoid reaction
(WBC count > 50,000/ cmm) and haemolytic uraemic
syndrome (a triad of microangiopathic haemolytic
anaemia, thrombocytopaenia and renal failure) are
seen in S.dysenteriae type 1 infection and may be
fatal

4

.

Epidemiology

Shigellosis is a highly contagious disease caused

by Shigella spp. and humans are the principal
reservoir of infection. The organism is acid resistant
and can easily pass the gastric acid barrier. The
infective dose is as low as 10-100 organisms only.
The disease is transmitted faeco-orally, the
commonest modes being person-to-person contact
and contaminated food and water. Infected food
handlers can spread the disease. Sometimes
consumption of raw vegetables harvested in fields
where sewage is used as fertilizer can cause
contamination. Flies can breed in infected faeces and
contaminate food. Washing clothes and bathing in
ponds, which is a common practice in rural India,
can also enhance transmission of the disease if the

water is contaminated with excreta of an infected
person. It is a disease of overcrowding, insanitary
conditions and poor personal hygiene, and affects
mostly children of developing countries. However,
travelers visiting endemic areas may be affected by
this disease if they do not take proper precautionary
hygienic measures.

Incubation period of the disease is 1-4 days which

is usually followed by sudden onset of acute
symptoms. In mild cases the disease may be self
limiting but severe disease requires appropriate
medication. The disease is communicable as long as
an infected person excretes the organisms in the stool
and this can extend up to 4 wk from the onset of
illness. However, timely antibiotic therapy can reduce
the period of communicability. Secondary attack rates
can be as high as 40 per cent especially among
household contacts.

Epidemics and pandemics

During 1967-70, bacillary dysentery was first

reported in Central American countries

5

. Since then,

spread of this infection has been reported from many
Asian countries such as Bangladesh (1972-78, 2003),
Sri Lanka (1976), Maldives (1982), Nepal (1984-85),
Bhutan (1984-85) and Myanmar (1984-85)

6-9

. In

India, epidemics were mainly encountered in southern
India (Vellore - 1972-73, 1997-2001)

10,11

, eastern

India (1984)

12,13

and Andaman and Nicobar islands

(1986)

14,15

. Recent outbreaks (2002-03) of multi drug

resistant S.dysenteriae type 1 have been reported from
Siliguri, Diamond Harbour, Kolkata, and Aizwal and
Bangladesh

16-19

.

Microbiology

Shigellosis is caused by Shigella spp. which can

be subdivided into four serogroups - S.sonnei,
S.boydii, S.flexneri and S.dysenteriae. Each of them
has a number of serotypes, e.g., S.dysenteriae type
1-12, S.sonnei phase I and II, S.boydii type 1-18,
S.flexneri type 1-6. However, three predominant
strains are responsible for majority of shigellosis
cases viz., S.sonnei, S.flexneri 2a and S.dysenteriae

SUR et al: SHIGELLOSIS

455

456

INDIAN J MED RES, NOVEMBER 2004

type 1. Of these, S.sonnei is encountered mostly in
industrialized countries, S.flexneri 2a in developing
countries and S.dysenteriae type 1 is the only
epidemic as well as pandemic strain. S.dysenteriae
type 1, which produces severe disease, may cause
life-threatening complications, is usually multi drug
resistant and can cause large epidemics and even
pandemics with high morbidity and mortality.

Shigellae are facultative non motile, Gram

negative bacilli. They are pathogenic primarily due
to their ability to invade intestinal epithelial cells.
The virulence factor is a smooth lipopolysaccharide
cell wall antigen which is responsible for the invasive
features and a toxin (shiga toxin) which is both
cytotoxic and neurotoxic and causes watery diarrhoea.

Shigella organisms invade and multiply within the

colonic epithelial cells causing cell death and mucosal
ulcers but rarely invade the blood stream. Histological
findings include cellular infiltration with mixed round
cells, neutrophilic in majority and disorganization of
crypts with branching and dilatation. The
inflammatory process extends to muscularis mucosae
and submucosae with resultant oedema. In
S.dysenteriae type 1 infection, changes in the colonic
mucosa are more severe than those by the other
serogroups

20,21

.

Drug resistance

When sulphonamides were first introduced in the

early 1940s, all the Shigella strains were sensitive to
this drug, which became the drug of first choice. In
late 1940s, tetracycline followed by chloramphenicol,
were recommended for the treatment of shigellosis
because sulphonamides became ineffective. Soon,
resistance to these two drugs was observed.
Ampicillin and co-trimoxazole came to the rescue

22,23

.

They were found to be clinically highly effective.
However, during the epidemic in eastern India in
1980s, the isolated S. dysenteriae type 1 strains were
found to be resistant to most of the antibiotics

24

except

nalidixic acid which was found to be clinically highly
effective

25

. But later, S. dysenteriae type 1 strains

isolated from an outbreak in Tripura were even
resistant to nalidixic acid

26

. In the late 1980s,

fluoroquinolones (norfloxacin, ciprofloxacin and

ofloxacin) were introduced and were found to be very
effective in the treatment of shigellosis cases

27-31

including those caused by multi drug resistant S.
dysenteriae type 1 strain. Recent outbreak
investigations in India (Siliguri, Diamond Harbour,
Kolkata, and Aizwal) and Bangladesh showed high
level of resistance even to norfloxacin, ciprofloxacin
and ofloxacin

16-19

. Only ceftrioxone and azithromycin

are now clinically effective

32,33

for the treatment of

multi drug resistant shigellosis. However, ceftrioxone
has to be administered parenterally and is expensive.
In Bangladesh, pivmecillinum

34

has been found to

be useful.

Mechanisms of antibiotic resistance

Treatment of shigellosis has been confounded by

wide spread resistance to the commonly used
antibiotics such as ampicillin, co-trimoxazole,
tetracycline, nalidixic acid and recently to norfloxacin
and ciprofloxacin. The transmissibility of resistance
can take place by clonal spread of particular strains
as observed in S. dysenteriae type 1

35

. Horizontal

transfer of resistance determinants by plasmids,
transposon-mediated conjucation and/or chromosome
also occurs

36,37

. Presence of integrons in shigella with

multi drug resistant genes and the ability to spread
in epidemic form necessitates intervention at the
public health level. Studies conducted with S. sonnei
isolated in Ireland showed the prevalence of class 1
and class 2 integrons carrying aadA cassettes along
with sat1 and dhfr1

38

. In Australia, it was shown

that most of the S. sonnei strains harboured class 2
integron with a gene cassette array analogous to that
found in transposon (Tn7), namely dfrA1, sat1, and
aadA1 conferring resistance to trimethoprim,
streptothricin and streptomycin/spectinomycin,
respectively

39

. These antibiotics were introduced in

the 1950s as alternative treatment for sulfonamide
resistant Shigella and were extensively used in
Australia and Ireland. S. sonnei strains readily acquire
resistance to ampicillin through conjugative
resistance-plasmids carrying the resistance cassettes
bla

TEM-1

and bla

TEM-52

40

.

Tetracyclines have been used extensively since the

late 1940s as broad spectrum inexpensive antibiotics.
However, resistance to tetracycline has increased

457

dramatically since the first appearance of resistance
in 1953 in S. dysenteriae

41

. Most tetracycline

resistance determinants, defined as genetic units,
which contain both structural and regulatory genes,
involved in resistance have been found on resistance
plasmids or transposons, making gene transfer the
likely method of acquiring resistance. An
investigation carried out using about 600 strains
collected from six countries demonstrated that the
tetracycline resistance in Shigella is due to both clonal
spread and horizontal gene transfer

42

.

Quinolones were highly effective drug for the

treatment of shigellosis. Resistance to this group of
drugs by Shigella spp is essentially due to
chromosomal mutations

43,44

. Mutations that confer

quinolone resistance principally affect the DNA
gyrase and topoisomerase IV of type II. Both the
enzymes are heterotetramers consisting of two types
of subunits GyrA and GyrB for DNA gyrase and ParC
and ParE for topoisomerase IV. DNA gyrase is
primarily engaged in the control of negative super
coiling of DNA and topoisomerase is involved in the
decatenation of the interlinked daughter chromosome.
The mutation recorded due to quinolone resistance
was Sero 83 to Leu in S. dysenteriae type 1, S. flexneri
and S. sonnei

40,43,44

.

Plasmid profile

Multiple antibiotic resistant S.dysenteriae type 1

isolates from the 1984 epidemic in Eastern India
showed identical plasmid patterns

45

. During the

period 1995-2000, the plasmid profile of shigella
strains isolated in Kolkata, revealed the presence of
large plasmid of 220kb in majority of the strains
(except S.sonnei) and there was a correlation between
the presence of smaller plasmids and Shigellae
serotypes – indicating epidemiological changes of
Shigellae species in Kolkata, India

46

.

Clonality of recent multidrug resistant strains of
S. dysenteriae type 1

Outbreaks of multi drug resistant S. dysenteriae

type 1 occurred in several parts of eastern India
including northern and southern parts of West Bengal
in 2002 and Mizoram in 2003

47

and also from Matlab,

Bangladesh

9

. Sporadic cases were also admitted to

the Infectious Diseases Hospital and Dr B.C.Roy
Childrens’ Hospital, Kolkata during the same time.
Antimicrobial resistance pattern, plasmid DNA and
pulsed field gel electrophoresis (PFGE) profiles of
both epidemic and sporadic cases revealed their
genetic similarity. Chronologically the new clone was
detected first during 2002 from epidemic cases
followed by sporadic cases in Kolkata and later from
Mizoram. The recently emerged S. dysenteriae type
1 strains are different from the previous outbreak
strains isolated during 1988

48

.

Diagnosis

Diagnosis of shigellosis is made clinically by the

typical features of bacillary dysentery with blood and
mucus in stool although some cases may present with
mild to moderate watery diarrhea initially.
Dehydration is usually not a conspicuous feature.
Microscopic examination of faecal smear stained with
iodine shows presence of plenty of faecal leucocytes
(> 10/high power field). Confirmation is made by
stool culture, serological and biochemical tests

49

.

Collection, transportation and culture of stool
specimen

Specific diagnosis of shigella in stool specimens

depends on the appropriate collection and
transportation to the laboratory. Fresh stool samples
collected from patients before initiation of therapy
are preferred for microbiological tests because the
chances of recovering the organisms are higher. For
microbiologic cultures, fresh stool is preferred to
rectal swabs in which the pathogens are less in
number. Samples that cannot be cultured immediately
should be kept in buffered glycerol-saline transport
medium. Cary-Blair medium is the second option.
Direct inoculation of culture plates at the bedside is
the most efficient means of isolating shigella from
the dysentery patients.

Stool specimens for isolation of shigella should

be plated on both moderately selective medium such
as MacConkey or deoxycholate citrate agar (DCA),
and a highly selective medium such as xylose-lysin

SUR et al: SHIGELLOSIS

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INDIAN J MED RES, NOVEMBER 2004

deoxycholate (XLD), Hektoen enteric (HE) or
Salmonella-Shigella (SS) agar. Since the Shigella
isolates growing in these plates do not change the
colour of the pH indicator due to its inability to
ferment lactose, it is easy to pick up the typical
colonies.

Further identification can be made by using triple

sugar iron (TSI) agar or Kligler iron agar (KIA), on
which Shigellae are non-motile, produce an alkaline
slant and acid butt due to inability to ferment lactose
aerobically in the slope and the anaerobic
fermentation of glucose in the butt, and fail to produce
hydrogen sulphide or other gas. After tentative
identification, strains can be speciated by serological
methods, using grouping antisera. Rapid methods for
the diagnosis of S. dysenteriae type 1 by means of
fluorescent antibody staining have been established

50

.

Till date, no reliable rapid method is commercially
available and none are in use routinely anywhere.

Detection using polymerase chain reaction (PCR)

Most of the PCR methods established for the

identification of shigella are targeted towards either
invasive-associated locus (ial) gene or invasive
plasmid antigen (ipa) H locus, which are also present
in the enteroinvasive Escherichia coli (EIEC)

51-55

. An

immunocapture PCR was established which employs
amplification to detect bacteria captured by specific
antibodies coupled either to the beads or polystyrene
plates

56,57

. The use of IS630-specific primers along

with serotype specific primers derived from the rfc
genes in the multiplex PCR was reported to be useful
for the detection of many serotypes of Shigella

58

.

In most of these studies, PCR was found to be

more sensitive and specific technique than the
conventional culture methods and has the potential
to be employed in routine diagnosis. In addition, in
most of the Shigella strains there is a spontaneous
loss of the virulence genes, and hence direct stool
PCR based detection system is preferred than the
DNA probe hybridization technique in which the
strains should be cultured several times.

Management

Diagnosis of shigellosis can be made clinically

by the typical features of the disease. Sometimes

laboratory confirmation is necessary especially for
antimicrobial resistance pattern as it varies from place
to place and from time to time.

In case management of shigellosis antibiotics play

a central role. Use of appropriate antibiotic hastens
recovery, shortens the duration of excretion of
pathogen in stool and possibly prevents
complications. However, these should be chosen
carefully considering the sensitivity pattern of the
circulating strains. Presently in India, the antibiotics
of choice are norfloxacin (400 mg) or ciprofloxacin
(500 mg) or ofloxacin (200 mg) twice daily for 3-5
days

59

. These drugs are not yet recommended for

children and pregnant women although their use has
shown that they are probably safe in children

60

.

Although dehydration is not a common feature of

shigellosis infection, but if it occurs or the stools are
watery, patients should be given the oral rehydration
salt (ORS) recommended by WHO /UNICEF. In
severe dehydration, intravenous fluids preferably
Ringer’s lactate solution is recommended. However,
clinical experience indicates that ORS is beneficial
in all cases of shigellosis if given as routine fluid
intake.

Anorexia poses a major problem for feeding

especially in children. They should be encouraged to
take small, frequent and easily digestible meals. This
is easily achieved after an effective antibiotic is
started when appetite improves and the patient is able
to take food.

Prevention and control

Since the main route of transmission of shigellosis

is through water, food and also person-to-person
contact, the prevention and control strategies
essentially include provision of safe water supply and
adequate sanitation facilities, maintenance of good
personal hygiene and food safety. Hand washing with
plenty of water and soap is the most important single
effective preventive strategy against shigellosis

61

. It

is emphasized that hands should be washed before
eating, before feeding children, after defeacation and
after disposal of children’s excreta. These measures

459

are further reinforced in epidemic situations, when
because of the very low infective dose of the organism
and its potential for rapid spread, stringent control
measures need to be instituted through simple but
effective health education messages to the common
masses.

Vaccines

In view of the difficulties in implementing the

preventive and control measures, the high prevalence
of multi drug resistant S.dysenteriae type 1 strains
and their propensity to cause large epidemics and even
pandemics, development of safe and effective
vaccines against S.dysenteriae type 1 and S. flexneri
2a is an attractive proposition. WHO has given high
priority for shigella vaccine development programme.

Protection against clinical infection is the rationale

of a shigella vaccine. However, interference with
establishment of infection and colonization is also
beneficial. Since shigellosis can be caused by at least
three predominant strains, a trivalent vaccine would
be most effective. Presently several candidate
vaccines are in the pipeline including a parenteral
conjugate vaccine consisting of S.sonnei detoxified
lipopolysaccharide (LPS) linked to a Pseudomonas
aeroginosa carrier protein and a nasally administered
shigella-proteosome vaccine consisting of shigella
LPS non-covalently linked to protein of group B
Neisseria meningitides. Among other potential
vaccines, a combination of live attenuated S.flexneri
2a strain CVD 1207 and S.dysenteriae type 1 strain
CVD 1253 has proved to be safe and immunogenic.
Another live attenuated S.flexneri 2a strain SC 602
vaccine has successfully undergone phase I and II
trials in the USA and Bangladesh

62

.

Conclusion

Shigellosis is an important public health problem

with high morbidity and also mortality mainly among
children in developing country situations where
overcrowding and poor personal hygiene are rampant.
Of all the Shigellae spp, S. dysenteriae type 1 is
notorious for producing not only large scale
epidemics but also pandemics which are characterized

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P-33, CIT Road, Scheme XM, Beliaghata, Kolkata 700010, India
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