Original

Article

EFFECTIVENESS OF ANTI-TYPHOID DRUGS

CURRENTLY USED IN PAKISTAN
QAMAR RIZVI
Department of Pharmacology & Therapeutics, Hamdard College of Medicine & Dentistry, Karachi
ABSTRACT
Objective: To study the effectiveness of Anti-Typhoid drugs in the Pakistani population.
Design & Duration: Prospective comparative study conducted from Jan. 2003 to Jan. 2004.
Setting: Department of Surgery, S. S. Hospital, Karachi.
Patients: Diagnosed cases of Typhoid fever on Blood or Faeces Culture, Widal test and / or Dot Enzyme Immunosorbant
Assay (Dot EIA or Typhi Dot), above 12 years of age.
Methodology: Patients were randomly assigned to one of the five treatment groups named after the antibiotic used
i.e. Ciprofloxacin (48), Ofloxacin (45), Cefixime (46), Chloramphenicol (44) and Co-trimoxazole (44).Treatment was
administered for 7 or 14 days, and the results of the clinical and investigational assessment of patients, before and
after the treatment, were compiled and tabulated.
Results: Out of the total 227 patients included in the study, there were 112 males and 115 females, with a mean age
of 31.78.2 years. There was no significant difference between the treatment groups with respect to demography.
Apart from fever, abdominal pain (79%), splenomegaly(34%), hepatomegaly(21%), diarrhoea (51%), vomiting (12%),
dehydration (15%) and rose spots on the skin (18%) were the main clinical features. Salmonella typhi was isolated
from the blood of 184 and stool of 24 patients, while S. paratyphi was isolated from the blood of 15 and stool of three
patients. In 159 patients the Typhi-dot and in 87 the Widal test was +ve. The mean duration of fever or fever clearance
time was 31 days with ciprofloxacin, 2.51 days with ofloxacin, 3.51.5 with cefixime, 62 days with chloramphenicol
and 6.52 days with co-trimaxazole. There were no serious side effects or mortality in this series.
Conclusion: Ciprofloxacin, Ofloxacin and Cefixime has an excellent (100%) cure rate and efficacy, whereas Chloramphenicol has an 80% and Co-trimoxazole a 70% cure rate only.
KEY WORDS: Typhoid Fever, Enteric Fever, Salmonella Typhi, Salmonella Paratyphi, Anti-Typhoid Drugs

INTRODUCTION

rose-colored eruption, diarrhoea, abdominal tenderness

and enlargement of the spleen, but these symptoms are
extremely inconstant and even the fever varies in its
character. This concise yet complete description is certainely adequate today1. In other words typhoid and
paratyphoid fevers may be described as systemic infections caused respectively by Salmonella typhi and Salmonella paratyphi A, B and C, Gram-negative bacteria
belonging to the Enterobacteriaceae family. They are
sometimes collectively termed as Enteric fever; although infection follows invasion of the intestinal mucosa
and reinfection of the intestine subsequently occurs,
dissemination in the blood leads to more wide spread
systemic effects2. Occasionally, Salmonella typhi-murium
also appears as an aetiological agent3. Typhoid and the
paratyphoid fevers are endemic in many countries, though the former is more common2,4.

In 1982 Dr. William Osler first described typhoid as

an infectious disease, characterized anatomically by
hyperplasia and ulceration of the lymph follicles of the
intestines, swelling of the mesenteric glands and spleen,
and parenchymal changes in other organs. The bacillus
of Eberth now named S. Typhi is constantly present in
the lesion. Clinically the disease is marked by fever, a

Correspondence:
Dr. Qamar Rizvi, Assistant Professor,
Department of Pharmacology & Therapecutics,
Hamdard College of Medicine & Dentistry, Karachi.
Phones: 4642383, 0333-2216131.
E-mail: dr_qamar@hotmail.com

In Pakistan unfortunately imported drugs are not sub57

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Effectiveness of Antityphoid Drugs currently used in Pakistan

jected to clinical trials. Hence, it is not safe to believe
that those regimens which are determined for foreign
populations will be applicable locally also. The factors
for any probable discrepancy may include climate, dietary habits, racial factors, poor compliance of the patients,
etc. Hence, this study was carried out to check the efficacy of the commonly used current antityphoid drugs
in our local population, and to look for any undesirable
effects.

Group 5 - Co-trimox Group receiving oral Co-trimoxazole 960mg twice daily for 14 days.
Assessments
All patients were hospatalised for 24 hours for the purpose of observation and collection of relevant samples.
Patients subsequently attended the clinic for assessment
at days 2,3,5,7 and 14. Post-treatment follow-up was
conducted at day 28 ( 2 days). Blood and stool samples
were collected for bacterial culture at the days 0,3,5,7,14
and 28. Where day 0 denotes the baseline test.

PATIENTS & METHODS

This study was conducted on patients taken from the
Outpatient department (OPD) of Social Security Hospital, Karachi. They were required to be above the age
of 12 years with clinically and bacteriologically proven
diagnosis of Typhoid fever, either on positive blood or
stool culture or by positive Typhi-Dot test.

At each visit, every patient was inquired specifically to

ensure whether he/she had been complying adequately
with his/her medication regimen. If the subject was taking less than the recommended dose of the drug, the
patient was warned about his/her compliance. All the
patients missing more than one days therapy were excluded from the study for non-compliance.

Patients with signs and symptoms similar to those of

typhoid fever but proved bacteriologically to be caused
by other organisms were excluded from the study. Similarly patients with salmonellosis caused by organisms
other than S. Typhi and S. Paratyphi were not included.
Pregnant women and patients with previously known
hypersensitivity to any of the trial drugs were also not
included.

Bacteriological Evaluation
The bacteriological outcome for each patient was classified into the following categories:
Bacteriological Cure
Means that the initially susceptible pathogen was eliminated from blood or stool on day 7 or as per term of treatment with that drug and did not reappear within three
weeks after the end of treatment.

All the patients were evaluated to determine whether

they met the selection criteria. The assessment of clinical
signs and symptoms included: temperature, pulse, blood
pressure, state of conciousness, abdominal tenderness,
number of stools within the last 24 hours, dehydration,
vomiting, body weight and possible complication. The
presence of splenomegaly, hepatomegaly and rose spots
(not usually so evident in dark-skinned people) were
also assessed. Additionally other signs and symptoms,
and co-morids if present, were also noted. Blood and
stool culture, Widal test and Typhi-Dot tests were carried
out in all cases apart from routine CP and ESR, Urine
DR, X-rays chest and abdomen, and ultrasonography.

Bacteriological Failure
Means persistence of S. Typhi and S. Paratyphi on day
7 or 14 or recurrence of the initial pathogen at the end
of treatment.
Bacteriological Relapse
Means elimination of pathogen within 7 or 14 days, but
reappearence in blood and / or stool within three weeks
after the end of treatment.
Clinical Assessment of Efficacy
This was based on the disappearance of clinical signs
and symptoms on clinical assessment. All cases were
classified into one of the following categories:

Treatment
The patients were randomly assigned to one of the following treatment groups, and the drugs administered
for 7 or 14 days:

Clinical Cure
Reduction of maximum daily temperature equal to or
<37oC and /or and disappearance of clinical signs and
symptoms at the end of treatment with no clinical
evidence of infection during further follow-up.

Group 1 - Cipro Group receiving oral Ciprofloxacin

500mg twice daily for 7 days.
Group 2 - Oflox Group receiving oral Ofloxacin 200mg
twice daily for 7 days.
Group 3 - Cefixime Group receiving oral Cefixime
200mg twice daily for 7 days.
Group 4 - Chloram Group receiving oral Chloramphenicol 750mg 6 hourly for 14 days.

Clinical Improvement
All clinical signs and symptoms subsiding significantly
within 7 and 14 days, respectively, but with incomplete
resolution of clinical evidence of infection.
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Effectiveness of Antityphoid Drugs currently used in Pakistan

Sex /
Age

Cipro
Group

Oflox
Group

Cefixime
Group

Chloram
Group

Co-trimox
Group

Total

Male

25

21

26

20

20

112

Female

23

24

20

24

24

115

Total

48

45

46

44

44

227

32.082

318.5

31.58.2

31.98.4

31.98.4

31.78.2

Mean Age

Table I. Demographic Characteristics of the Study Population

Relapse
Reappearance of signs and symptoms after initial disappearance for at least 48 hours (reappearance of pathogen
in blood and/or stool; as mentioned in bacteriological
relapse) within three weeks after the end of treatment.

ents in the Ciprofloxacin group, 45 in the Ofloxacin

group, 46 in the Cefixime group, 44 in the Chloramphenicol group and 44 patients in the Co-trimoxazole group.
There was no significant difference between the different groups with respect to demography.

Clinical Failure
No significant clinical response to therapy.

The clinical signs and symptoms at baseline have been

summarized in Table II, which shows that apart from
fever, abdominal pain was found in the majority (79%)
of patients in all the groups. Splenomegaly was seen in
34% of the cases, hepatomegaly in 21%, diarrhoea in
51%, dehydration in 15% and vomiting in 12% of the
cases.

Not Assessable
A clinical judgement of cure, improvement or failure
could not be made for various reason such as no followup evaluation tests performed, an underlying condition,
or premature termination of the treatment.

The bacteriology at baseline (Table III) reveals that S.

Typhi was the most common and major organism causing
the Typhoid fever. It was isolated from the cultures the
of 208 patients of all groups, out of which the organism
was found in blood culture of 184 patients and in the
stool culture of 24 patients. Similarly Salmonella Paratyphi was isolated from the culture of 18 patients of all

RESULTS
A total of 227 patients, 112 males and 115 females were
included in the study. Their mean age was 31.78.2
years. The demographic characteristics of the study
population are presented in Table I. There were 48 pati-

Table II. Clinical Signs and Symptoms of the patients

Clinical Feature
(as %)

Cipro
Group

Oflox
Group

Cefixime
Group

Chloram
Group

Co-trimox
Group

Average

Abdominal Pain

76

80

78

82

77

79

Splenomegaly

30

35

28

41

37

34

Hepatomegaly

21

19

26

18

22

21

Dehydration

19

17

10

13

15

15

Diarrhoea

58

51

50

47

49

51

Vomiting

04

20

05

09

21

12

Rose spots on skin

25

05

32

16

07

18

Temperature (C)

38.91.5

391

39.11.2

38.81.2

39.21.5

391

Pulse (beats/min)

8913

8812

8711

8812

8913

8812

Systolic BP(mmHg)

11615

11211

11413

11112

11716

11413

Diastolic BP (mmHg)

6410

659

6311

648

659

649

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Effectiveness of Antityphoid Drugs currently used in Pakistan

Group

Salmonella Typhi
Blood culture
Stool culture

Total

Salmonella Paratyphia
Blood culture
Stool culture

Total

Ciprofloxacin

40

44

Ofloxacin

33

39

--

Cefixime

38

42

Chloramphenicol

37

41

Co-trimoxazole

36

42

--

184

24

208

15

18

Total

Table III. Bacteriological findings in the different groups

with bronchial asthma and one with sickle cell anaemia.
groups, out of which the organism was found in the
blood culture of 15 patients and in stool culture of three
The Bacteriological and Clinical cure among Typhoid
patients.
fever patients has been summarized in Table VI. The
mean duration of fever or fever clearance time was 31
The results of Widal test and Typhi-Dot test are depicted
in Table IV, which shows that a total of 159 patients
days with ciprofloxacin, 2.51 days with ofloxacin,
out of 227 were positive for the DOT EIA (Typhi Dot)
3.51.5 with cefixime, 62 days with chloramphenicol
test and 87 were positive for the Widal test.
and 6.52 days with co-trimaxazole.
A search for the presence of concomitant disease
amongst typhoid fever cases (Table V) showed that
there were 41 cases in all the groups, including 16 patients with diabetes mellitus, 15 with hypertension, nine

The clinical cure rate at term was 100% for ciprofloxacin

group, 100% for ofloxacin group, 100% for the cefixime
group, 80% for the chloramphenicol group and 70%
for the co-trimoxazole group (Table VI). Thus, 20%
Table IV. Results of the Widal and Typhi-Dot test in different groups

Group

No. of Patients with +ve

Dot EIA (Typhi Dot)

No. of Patients with

+ve Widal test

Total

Ciprofloxacin Group

35

17

52

Ofloxacin Group

30

19

49

Cefixime Group

32

17

49

Chloramphenicol Group

31

18

49

Co-trimoxazole Group

31

16

47

159 (out of 227 pts)

87 (out of 227 pts)

246 (out of 227 pts)

Total

Table V. Presence of other diseases amongst the Typhoid patients

Disease

Cipro
Group

Oflox
Group

Cefixime
Group

Chloram
Group

Co-trimox
Group

Total

Diabetes Mellitus

--

--

16

Hypertension

--

15

Bronchial Asthma

--

--

Sickle cell anaemia

--

--

--

--

20

11

41

Total

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Effectiveness of Antityphoid Drugs currently used in Pakistan

Cure Type

Clinical Cure
Patients (%)
Defervescence (Days)

Bacteriological Cure: Blood/Stool

Patients No. Organism -ve(Days)

Ciprofloxacin Group

100%

31

48

Ofloxacin Group

100%

2.5 1

45

Cefixime Group

100%

3.5 1.5

46

Chloramphenicol Group

80%

62

35

14

Co-trimoxazole Group

70%

6.5 2

31

14

Table VI. Bacteriology and Clinical Cure

patients in chloramphenicol group and 30% patients in
the co-trimoxazole group were found resistant against
their respective drug, but they were kept on that drug
to observe any difference of in-vivo response of the
drug. But the resistant cases failed to respond the drug,
indicating that in-vivo response matched with in-vitro
sensitivity. These patients were then treated with ciprofloxacin and got cured.

effects noted included abdominal pain in 14 patients,

diarrhea in seven, heartburn in nine, headache/dizziness
in nine, anorexia in eight, cough in one, palpitation in
five and anemia in two patients; the last being in the
Chloramphenicol group only.
DISCUSSION
There was no significant difference in the study population with respect to gender, age, weight and height.
Most of the patients belonged to the lower socioeconomic
stratum and were living in unhygienic conditions. It is
important to note that significant concomitant conditions
such as asthma and sickle cell anaemia did not preclude
treatment, as the efficacy and tolerability were judged
good. In this study, there was no incidence of bacteriological or clinical relapse at follow-up. The leucocyte
counts also normalized after the treatment in the cured
patients of all the groups.

The patients compliance was excellent in all test groups.

Upon follow-up, not even a single case of relapse was
found among clinically and bacteriologically cured patients in all test groups.
The side effects of all the drugs were found mild and
clinically insignificant. However the main side effects/
adverse events were nausea and vomiting, occuring in
10 patients of the Ciprofloxacin group, six patients of
the Ofloxacin group, three patients of Cefixime group,
four patients of Chloramphenicol group and one patient
of the Co-trimazole group (Table VII). The other side

The emergence of multidrug resistant S. typhi led to the

Table VII. Adverse Events/Side Effects

Adverse events/
Side effects

Cipro
Group

Oflox
Group

Cefixime
Group

Chloram
Group

Co-trimox
Group

Average

Nausea/Vomiting

10

24

Abdominal pain

--

14

Diarrhoea

--

--

Heartburn

--

--

Headache/Dizziness

--

--

Anorexia

--

--

--

Cough

--

--

--

--

Palpitation

--

Anaemia

--

--

--

--

mild

mild

mild

mild

mild

mild

Mild/Moderate/Severe

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Effectiveness of Antityphoid Drugs currently used in Pakistan

in children, when given in a short eight day course22.
In our study we prescribed 200mg of cefixime orally
twice daily for seven days, with excellent (100%) efficacy and compliance, and negligible side effects. Not
a single case of relapse was encountered.

use of ciprofloxacin as the first-line drug in the treatment

of patients with typhoid fever5-8. The ciprofloxacin regimen recommended by the manufacturers for typhoid
fever is 500mg twice daily for 14 days, although studies
justifying short-course therapy for ciprofloxacin have
also been conducted in recent times9. Another study
concludes that 500mg twice a day of the ciprofloxacin
given for 10 days is as effective as 14 days at the same
dosage10. It was also concluded that ciprofloxacin treatment even upto ten days in enteric fever is not necessary11. In the present study we prescribed 500 mg of
ciprofloxacin twice a day orally and found excellent
results (100% efficacy and compliance). Not a single
case of relapse was encountered. Few adverse events
were recorded, which were mild in nature and left no
permanent sequelae. This drug also shortened the duration of illness.

Chloramphenicol 3-4 grams per day in four divided

doses for adult is usually prescribed3. It has been suggested that as a result of the widespread dissemination of
multidrug resistant strains, chloramphenicol can no
longer be regarded as the first-line drug for typhoid
fever23. Resistance to chloramphenicol, both in vitro
and in-vivo, has been found at variable percentages
during different clinical trials; the in-vivo response
matched with the in-vitro sensitivity most of the time.
For instance, in Rajastan (India) strains of S. typhi showed 56.6% in-vitro resistance to chloramphenicol. In
these cases chloramphenicol was initially started but
there was no response to this drug even after 7-10 days
therapy, indicating that in-vivo response matched with
in-vitro sensitivity5. Another study conducted in Iran
indicated that 41.9% of isolated S. typhi strains were
resistant to cloramphenicol24. Additionally, a certain
percentage of S. paratyphi A strains was also found
resistant to chloamphenicol6. A delay in defervescence
even in chloramphenicol sensitive S. typhi patients was
also found with chloramphenicol therapy25. Several
authors have quoted considerable resistance to chloramphenicol by S. Typhi strains15,26.

The Ofloxacin regimen recommended by the manufacturers for typhoid fever is 200mg twice daily for 5-10
days. However, some studies revealed that short course
treatment with oral ofloxacin (5 days) is significantly
better than with ceftriaxone (3 days i.v.) and will be of
particular benefit in areas where multiresistant strains
of S. typhi are encountered12. A three day course of ofloxacin proved to be safe and highly effective in the
treatment of uncomplicated, multidrug-resistant typhoid
fever13. Treatment with ofloxacin for 2-3 days is equally
effective in adults with uncomplicated enteric fever
caused by nalidixic acid sensitive strains of S. typhi14.
However another study recommended that short courses
of quinolones should not be used in patients infected
with NARST (Nalidixic acid resistant srains), as they
may require re-treatment15,16. In this study we prescribed
200mg of the drug twice daily for seven days per oral
in order to avoid any relapse or treatment. Here also
we found excellent (100%) efficacy and compliance.
Not even a single case of relapse was encountered. The
few adverse events seen were of mild nature and left
no permanent sequelae.

Recently the number of favorable reports for the use

chloramphenicol for typhoid fever are on the increase.
A study from India showed that a greater number of
patients were sensitive to chloramphenicol during 199697 (80%) as compared to 1991 (65%)27. During an epidemic in India from April 1990 to early 1993 strains
sensitive to chloramphenicol were continuously isolated.
The relative prevalences showed that the frequency of
chloramphenicol sensitive variety was unaffected by
the epidemic of multidrug resistant variety. This is an
unusual epidemiological pattern, which indicates that
there may have been factors which favored the epidemic
of the multidrug resistant variety but not the chloramphenicol sensitive one28,29. In this study we prescribed
750mg of the drug four times a day for 14 days. We
found that 20% strains of the organism were resistant
to the drug, giving an overall cure rate of 80%. Even
in cured patients defervescence was late.

Usual adolescent and adult dose of Cefixime is 200mg

every twelve hours or 400mg once daily17. According
to a previous study cefixime is the most cost-effective
drug on an outpatient basis18. Other studies suggest that
cefixime due to its effectiveness, oral administration
and shorter courses of treatment could be the therapy
of choice in cases of typhoid fever caused by multiple
resistant strains especially when we have a shortage of
hospital beds19,20. In a comparative study clinical cure
was observed in 90% patients treated with cefixime and
45% treated with chloramphenicol. Patients who did
not respond to chloramphenicol, were also cured by
giving cefixime21. The drug was also found to be safe
in the management of multidrug resistant typhoid fever

Co-trimoxazole is given in a dose of 960mg twice a

day for 14 days. We prescribed the same regimen. The
clinical and bacteriological cure rate was 70%; the drug
resistant rate was 30%. Like chloramphenicol group,
defervescence was much delayed. In one series, S. typhi
strains showed 70% resistance to amoxycillin, 40% to
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Effectiveness of Antityphoid Drugs currently used in Pakistan

ampicillin and 33.3% to co-trimoxazole5.

8. Alsoub H, Uwaydah AK, Mator I, Zebeib M, Elhag

KM. A clinical comparison of Typhoid fever caused
by susceptible and multidrug-resistant strains of
Salmonella typhi. Br J Clin Pract 1997 Jan-Feb; 51
(1): 8-10.

CONCLUSION
There were no significant discrepancies among the effect of the drugs in the study population with respect to
gender, age, weight, height, climate, racial factor and
dietary habits. Most of the patients belonged to the lower socioeconomic stratum and were living in unhygienic conditions, the main source of the spread of disease.

9. Limson BM. Short course quinolone therapy of Typhoid fever in developing countries. Drug 1995;
49 (Suppl.2): 13608.
10. Alam MN, Haq SA, Das KK, Baral PK, Mazid
MN, Siddique RU, Rehman KM, Hasan Z, Khan
MA, Dutta P. Efficacy of ciprofloxacin in Enteric
fever: Comparison of treatment duration in sensitive
and multidrug-resistant Salmonella. Am J Trop Med
Hyg 1995 Sep; 53(3): 306-311.

It is also concluded that Ciprofloxacin, Ofloxacin and

Cefixime has an excellent cure rate and efficacy. They
also shorten the span of disease as they cause an early
defervescence. These drugs also avoid the chances of
any rapid relapse of the disease. Chloramphenicol and
Co-trimoxazol should not be recommended as the drug
of choice for the disease, due to a high rate of resistance
against them and also due to the late defervescene and
cure.

11. Agalar C, Usubuttun E, Tutuncu E, Turkyilmaz R.

Comparison of two regimens for ciprofloxacin
treatment of Enteric infections. Eur J Clin Microbiol
Infect Dis 1997 Nov 16; 11: 803-6.

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