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Original Article

Multidrug - Resistant Typhoid Fever


Rajiv Kumar, Nomeeta Gupta and Shalini1
Department of Pediatrics, Batra Hospital & Medical Research Centre, New Delhi and 1Department of
Pharmacology, Maulana Azad Medical College, New Delhi, India.

ABSTRACT
Objective. To study the epidemiological pattern, clinical picture, the recent trends of multidrug-resistant typhoid fever (MDRTF),
and therapeutic response of ofloxacin and ceftriaxone in MDRTF.
Methods. The present prospective randomized controlled parallel study was conducted on 93 blood culture-proven Salmonella
typhi children. All MDRTF cases were randomized to treatment with ofloxacin or ceftriaxone.
Results. Of 93 children, 62(66.6%) were MDRTF. 24 cases were below 5 years, 26 between 5-10 years and 12 were above
10 years. Male to female ratio was 1.85: 1. Majority of cases came from lower middle socio-economic classes with poor
personal hygiene. Fever was the main presenting symptom. Hepatomegaly and splenomegaly was present in 88% and 46%
cases respectively. 19(30.6%) cases developed complications. Mean defervescence time with ceftriaxone and ofloxacin was
4.258 and 4.968 days respectively.
Conclusion. MDRTF is still emerging as serious public and therapeutic challenge. Ceftriaxone is well-tolerated and effective
drug but expensive whereas ofloxacin is safe, cost-effective and therapeutic alternative in treatment of MDRTF in children with
comparable efficacy to ceftriaxone. [Indian J Pediatr 2007; 74 (1) : 39-42] E-mail: drrajivkumar@hotmail.com

Key words : Multidrug-resistant; Typhoid fever; Salmonella typhi; Ceftriaxone and Ofloxacin

Typhoid fever is a distinctive acute multi-systemic febrile


disease caused primarily by Salmonella typhi. It is
recognized as a major cause of morbidity globally with
over 21.6 million cases annually worldwide, and an
estimated 216500 deaths.1 Almost 80% of cases and deaths
are in Asia. The attack rate as high as 1100 cases per
100000 populations have been documented in developing
countries.2 It remains a serious publichealth in developing
countries.
The recent explosive emergence and spread of MDRTF
with resistance to the conventionally used antibiotics for
the treatment of typhoid fever, namely chloramphenicol,
ampicillin and co-trimoxazole has caused significant
therapeutic and public health problem. The problem is
also compounded by the fact that a large number of cases
of MDRTF occur in childhood with significantly higher
morbidity and mortality.
MDRTF in childhood is frequently associated with a
more severe clinical illness and higher rates of toxicity,
hepatomegaly, hypotensive shock, and death.3 There is an

Correspondence and Reprint requests : Dr. Rajiv Kumar,


Department of Pediatrics, Batra Hospital & Medical Research Centre,
New Delhi 110 062, India. Fax: 91-11-29957661.

Indian Journal of Pediatrics, Volume 74January, 2007

urgent need to keep the possible emergence of untreatable


strains to a minimum, by prudent use of existing drugs
and by resting the temptation to use yet more antibiotics.
We undertook this study with the aim of documenting the
clinical picture, complications, and sensitivity patterns of
S. typhi isolates, epidemiological pattern, recent trends of
MDRTF, and therapeutic response to ofloxacin and
ceftriaxone.
MATERIAL AND METHODS
The present prospective randomized controlled parallel
study was conducted on 93 children up to 12 years
admitted in our hospital between May 2002 and April
2004 with clinical presentation of typhoid fever without
any localizing signs, and a positive blood culture for S.
typhi.
All those children were excluded who had a history of
an effective antibiotic therapy within one week prior to
admission in the hospital, a known allergy to penicillin,
chloramphenicol, quinolones or cephalosporins, and a
history of immunization with typhoid vaccine. The
informed written consent was obtained from the parents
of the children prior to the inclusion of the children in this
study.
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Rajiv Kumar et al
A detailed epidemiological and clinical history, a
thorough clinical examination and laboratory
investigations at the time of admission and during the
course of hospital stay were performed in all cases and
the findings were recorded in the pre-made proforma.
Epidemiological and clinical history: In addition to
patients name, age, sex, address, socio-economic status,
hygiene and sanitation, some epidemiological
information like education, occupation, family income,
number of family members, level of personal hygiene
(practice of hand washing with soap by family members
after defecation and before eating and preparing food),
source of drinking and portable water supply, and habit
of defecation (use of sanitary latrine, open pit latrine) by
family members were also obtained from parents. Socio
economic status of the parents was estimated by
Kuppuswamys classification. On admission, a detailed
clinical history was taken in each case.
Clinical examination: A detailed general and systemic
examination was done in all cases. In general
examination, authors took note of general condition, toxic
look, level of consciousness, temperature, pulse rate,
pulse character, respiratory rate, blood pressure, pallor,
jaundice, icterus, rash, petechiae and lymphadenopathy.
In systemic examination, children were thoroughly
examined for throat congestion, altered sensorium,
rhonchi, meningismus, abdominal distension, abdominal
tenderness, hepatomegaly and splenomegaly. All
associated findings and complications were noted in all
children.
Laboratory investigations: A blood sample for complete
hemogram, serum bilirubin, liver enzymes, serum urea,
serum creatinine, serum sodium, serum potassium, Widal
test and blood culture was obtained in all children on
admission and thereafter if the childrens condition
warranted it. Stool and urine samples were also sent for
culture examination. The chest and abdominal X-rays
were done in children where it was indicated.
Treatment : The patients with a presumptive clinical
diagnosis of typhoid fever were initially treated with
chloramphenicol (75 mg/Kg/day) by oral or intravenous
route. The mid-course modification of therapy was done
after the availability of blood culture and sensitivity
report. All MDRTF cases were randomized to treatment
with ofloxacin (20 mg/Kg/day) or ceftriaxone (100 mg/
Kg/day). The clinical course was closely monitored and
the period of defervescence was recorded. The time to
defervescence is defined as the time interval from starting
an appropriate antimicrobial chemotherapy until the
documentation of normal body temperature. The clinical
response to therapy was considered inadequate if there
was deterioration or no clinical improvement within 7-10
days of starting specific therapy. The drug efficacy was
judged primarily by the patients clinical response with
particular attention being given to the number of days of
40

treatment required make the patient afebrile.


The patients were carefully observed for possible
complications. The children were followed up for three
months to detect relapse or complications.
Data Analysis : The epidemiological, clinical, laboratory
and therapeutic data were collected from each patient and
recorded on a specially designed proforma. The various
tests of significance e.g. Chi-square, Standard error of
difference between means and p-value where applied to
assess the probability and significance of the data. The
statistical computing was performed and the data were
analyzed statistically by using Epi Info Version 6.04d
(Centers for Disease Control and Prevention, USA).

RESULTS
Of 93 blood culture-proven S. typhi cases, 62(66.6%) were
MDRTF. The incidence was highest (30.6%) seen in the
age group of 2 5 years. The second peak (25.8%) was
observed among age group of 7 10 years. It was seen
only in a one infant. 22(35.5%) cases were females and
40(64.5%) cases were males. Therefore, male: female ratio
was 1.85: 1.
MDRTF cases were seen throughout the year but the
rate of both hospitalization of cases and isolation of S.
typhi were relatively low during the months of October
and December. The majority of children belonged to
lower middle socio-economic classes with poor personal
hygiene. A history of travel away from the community
was not observed in any of the children. Most of the
affected families consumed either municipal supplied
water or water from tube wells. Majority (88.7%) of the
families and their children used sanitary latrines.
Fever was the main presenting symptom in all the
cases. High-grade fever was observed in 75.8% cases. The
duration of fever was of more than seven days in the
majority (72.6%) of cases at the time of admission. The
pattern of fever was intermittent in majority (71%) of
cases. Only 6 (9.6%) cases had fever with chills and rigors.
Headache was associated with fever in 34(54.8%) cases.
Other features seen were diarrhea (74.2%), abdominal
pain (62.9), vomiting (61.2%), malaise (48.3%), anorexia
(33.8%), nausea (32.2%), cough (32.2%), constipation
(14.5%) and GIT bleeding (12.9%).
46(74.1%) cases were toxic at time of presentation.
Relative bradycardia and coated tongue were seen in
7(11.2%) and 22(35.4%) cases respectively. Hypotension
was noted in 4 (6.4%) cases, one patient was unconscious
and two patients had loose motions and vomiting at the
time of admission. Clinically pallor and icterus was
present in 26(41.9%) and 18(29%) cases respectively.
Hepatomegaly and splenomegaly was present in 88% and
46% cases respectively.
Laboratory examination of blood revealed that anemia
Indian Journal of Pediatrics, Volume 74January, 2007

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Multidrug-Resistant Typhoid Fever


(hemoglobin < 10.0 gm/dl) was noted in 16(25.8%) cases
and leucopenia (< 4000/cmm) in 3% cases. Transient
thrombocytopenia was documented in 3(4.8%) cases.
Raised level of serum bilirubin was seen in 13 (20.9%)
cases. About 13% cases had raised SGPT level above 100
U/L. The sensitivity, specificity, positive predictive value
and negative predictive value of Widal test were 68.57%,
37.08%, 43.11 and 62.92 respectively. The antimicrobial
susceptibility patterns to commonly used antibiotics are
shown in Table 1.
TABLE 1. Sensitivity* of S. typhi
Drugs

Ampicillin
Co-trimoxazole
Chloramphenicol
Amoxicillin
Amikacin
Gentamicin
Norfloxacin
Ciprofloxacin
Ofloxacin
Ceftriaxone
Cefotaxime
*

Present
study
(n=93)

Kabra
et al4
(n=100)

Mishra
et al5
(n=50)

25.8
31.1
33.4
29.0
91.3
90.3
51.6
74.1
92.8
97.8
76.3

16
2
8
16
85
85
100
100
100

36
50
42
36
100
100
100
100
100

Agarwal
et al6
(n=68)
54.4
38.2
55.8
97.0
97.0
92.64
100
89.7
88.23

Figures of sensitivity are in percentage

19(30.6%) of children developed complications. The


main complications observed by us were hepatitis
(14.5%), intestinal bleeding (4.8%) and pleural effusion
(1.6%). Intestinal perforation occurred in one child during
the second week of illness and he required surgery plus
antibiotic and metronidazole therapy. The mean
defervescence time was 4.258 days in case of ceftriaxone
and 4.968 days in case of ofloxacin. The difference in mean
defervescence time between ceftriaxone and ofloxacin
was statistically significant. (P-value< 0.05) All patients
recovered completely and none had clinical relapse of
fever or complications within the follow period of three
months after discharge from the hospital.
DISCUSSION
In this study, 66.6% of the isolated strains of S. typhi were
MDRTF. We observed maximum MDRTF cases in the age
group of 2 5 years (30.6%) which was similar to other
studies.4,5 The incidence of MDRTF among children below
one year of age is very rare. It is evident that children
between 2 - 5 years of age are most susceptible age group
and thereby are the highest risk group against MDRTF.
The maximum number of cases was found from April to
August in both the years, thus highlighting the seasonal
variation in the incidence of MDRTF cases.
Fever was the commonest presentation in all the cases.
Fever was observed in 100% of cases in most of the
Indian Journal of Pediatrics, Volume 74January, 2007

studies by other authors. 3,6,7 The classical continuous


stepladder rise of temperature was not seen in any of the
cases and the majority (75.8%) of the cases had high grade
fever. Bhutta et al reported high-grade fever in 90% cases.8
There was a significant difference in the incidence of
gastrointestinal complaints abdominal pain (62.9%
versus 30% Agarwal et al3); diarrhea (74.2% versus 47.1%
Rasaily et al9 versus 3% Koul et al10); GIT bleeding (12.9%
versus 7% Koul et al10). All these differences simply reflect
the protean manifestations of MDRTF and may well
reflect the regional differences. Encephalopathy (8%) was
the commonest CNS manifestation noted in our study,
continuing the observation of others.2,11
Hepatomegaly was seen in 88% cases in this study
similar to that reported by Chandra et al12. Bhutta et al 8
and Koul et al10 reported hepatomegaly in 33% of cases.
Splenomegaly was seen in 46% of cases in our study
which was similar to that reported by Kabra et al6. Though
higher incidence of splenomegaly have been reported by
other authors. 11, 12
Most of the patients in this study had normal leukocyte
count although leucopenia is said to be the common
hematological finding in typhoid fever.13 Leucopenia was
seen in 3% cases, continuing the observation of others.8,10,13
The total culture positivity rate was 41%, continuing the
observation of others.14
The commonest complications are GIT bleeding,
intestinal perforation and typhoid encephalopathy. Earlier
reports suggest a complication rate of 10-40% in
MDRTF. 9,10 Intestinal perforation, a well known
complication of typhoid fever in adults is less frequent in
children and its presence in only one child suggests that it
is very rare in children.
Osler first reported hepatic complications of typhoid
fever in 1899. 15 Since then, several reports of typhoid
hepatitis have been described in adults. However, very
few reports detailing the spectrum of hepatic injury in
typhoid fever exist in the pediatric literature. The reported
incidence of typhoid hepatitis varies from 0.4% - 6%.
Several patient series have previously reported
biochemical evidence of hepatic dysfunction in 23% - 60%
of cases.16
We observed pneumonia in 3.2% cases. Similar results
have been reported by others.8, 12 Pleural effusion was seen
in only one case whereas Biswal et al17 reported more
frequent incidence of pleural effusion in MDRTF. Other
complications reported in literature include parotitis,
paralytic ileus, arthritis, chorea and cerebellar ataxia, 8,10
splenic abscess, subphrenic abscess and pancreatitis, rose
spots, cutaneous ulcers and subcutaneous abscesses 18
were not observed by us.
The patients treated with ceftriaxone had a slightly
shorter time to defervescence than did those treated with
ofloxacin. The difference of mean was significant and both
results were within time frames reported in previous
clinical trials for treatment of MDRTF.19
The effectiveness of ceftriaxone in the treatment of
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Rajiv Kumar et al
typhoid fever in children is a particularly important
finding because ofloxacin, which constitute the other
group of drugs being used as alternative treatment for
MDRTF. Ofloxacin is not recommended in children due
to arthropathic toxicity in growing animals. The
examination of available clinical data to date provides no
absolute evidence that ofloxacin induces significant
arthropathy in children, in contrast to data reported in
some animal species. However, literature does say that
ofloxacin should be used with caution in children below
12 years of age. Ofloxacin has been used with good
clinical response without significant side effects in
typhoid fever20 and cystic fibrosis21.
CONCLUSION
MDRTF is still emerging as serious public and therapeutic
challenge. Ceftriaxone is well-tolerated and effective drug
for MDRTF in children but expensive. Ofloxacin is safe,
cost-effective and therapeutic alternative in treatment of
MDRTF with comparable efficacy to ceftriaxone.
However, further studies in a larger group of patients are
needed to validate our findings. The rapid spread of
MDRTF over a large geographic area presents multiple
challenges, especially in developing countries where
access to newer and more expensive antimicrobial agents
may be limited. Therefore, research efforts must be
continued to focus on oral agents with chances of high
cure rate.
REFERENCES
1. Wasfy MO, Oyofo BA, David JC et al. Isolations and antibiotic
susceptibility of Salmonella, Shigella, and Campylobacter from
acute enteric infections in Egypt. J Health Popul Nutr 2000; 18:
33-38.
2. Ivanoff B, Levine MM, Lambert PH. Vaccination against
typhoid fever: present status. Bull World Health Organ 1994;
72 : 957-971.

42

3. Agarwal K S, Singh S K, Kumar N et al. A study of current


trends in enteric fever. J Commun Dis 1998; 30(3): 171-174.
4. Sood S, Kapil A, Das B, Jain Y, Kabra SK. Re-emergence of
chloramphenicol-sensitive Salmonella typhi. Lancet 1999; 353 :
1241-1242.
5. Sinha A, Sazawal S, Kumar R et al. Typhoid fever in children
aged less than 5 years. Lancet 1999; 354 : 734-737.
6. Kabra S K, Kabra M, Talati A, Soni N, Patel S, Modi R R.
Multidrug-resistant typhoid fever. Trop Doct 2000; 30: 195-197.
7. Wongsawat J, Pancharoen C, Thisyakorn U. Typhoid fever in
children: Experience in King Chulalongkorn Memorial
Hospital. J Med Assoc Thai 2002; 85: 1247-1250.
8. Bhutta ZA, Naqvi SH, Razzaq ZA et al. Mutidrug-resistant
typhoid in children: Presentation and Clinical features. Rev
Infect Dis 1991; 13: 832-836.
9. Rasaily R, Dutta P, Saha MR, Mitra U et al. Multidrug-resistant
typhoid fever in hospitalized children: clinical, bacteriological
and epidemiological profiles. Eur J Epidemiol 1994; 10: 41-46.
10. Koul P B, Murali M V, Sharma P P, Ghai O P, et al. Multidrug
resistant Salmonella typhi infection: clinical profile and therapy.
Indian Pediatr 1991; 28: 352-356.
11. Garg K, Mangal N, Mathur HC. Clinical profile of multidrug
resistant typhoid fever in Jaipur city. Indian Pediatr 1994; 31:
191-193.
12. Chandra R, Srinivasan S, Nalini P, Rao RS. Multidrug-resistant
enteric fever. J Trop Med Hyg 1992; 95: 284-287.
13. Johnson AOK, Aderele WI. Enteric fever in childhood. J Trop
Med Hyg 1981; 84: 29-35.
14. Vallenas C, Hernandez H, Kay B et al. Efficacy of bone
marrow, blood, stool and duodenal contents culture for
bacteriologic confirmation of typhoid fever in children. Pediatr
Infect Dis 1985; 4 : 496-498.
15. Osler W. Hepatic complication of typhoid fever. Johns Hopkins
Hosp Rep 1899; 8 : 373-387.
16. Ramchandaran S, Godfrey JJ, Perera MVF. Typhoid hepatitis.
J Am Med Assoc 1974; 230: 236-240.
17. Biswal N, Mathai B, Bhatia B D, Srinivasan S et al. Enteric fever:
A changing perspective. Indian Pediatr 1994; 31: 813-819.
18. Burnett J W. Uncommon bacterial infections of skin. Arch
Dermat 1962; 86 : 597-607.
19. Smith MD, Duong NM, Hoa NT et al. Comparison of ofloxacin
and ceftriaxone for short-course treatment of enteric fever.
Antimicrob Agents Chemother 1994; 38: 1716-1720.
20. Asperilla MO, Smego RAJr, Scott LK. Quinolone antibiotics in
the treatment of Salmonella infections. Rev Infec Dis 1990; 12:
873-879.
21. Ramsey BW. Management of pulmonary disease in patients
with cystic fibrosis. N Eng J Med 1996; 335: 179-188.

Indian Journal of Pediatrics, Volume 74January, 2007