ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1993, p. 1197-1199 Vol. 37, No.

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0066-4804/93/051197-03$02.00/0

Ciprofloxacin for Treatment of Severe Typhoid

Fever in Children
P. DUTI'A,l* R. RASAILY,' M. R. SAHA,' U. MITRA,' S. K. BHATTACHARYA,l
M. K. BHATTACHARYA,l AND M. LAHIRI2
National Institute of Cholera and Enteric Diseases, P-33, C.L T. Road, Scheme-XM,
Calcutta 700 010,1 and Dr. B. C. Roy Memorial Hospital for Children,
-

Calcutta-700 054,2 India

Received 30 October 1992/Accepted 24 February 1993

Eighteen children with bacteriologically confirmed severe typhoid fever were initially treated intravenously
with ciprofloxacin (10 mg/kg of body weight per day). Clinical cure with eradication of multiresistant
SalmoneUla typhi infection was observed in 17 patients (94.4%; 95% confidence interval [CI], 84 to 100%).
Children regained normal consciousness within an average of 2 days (95% CI, 1.8 to 2.2 days). The
temperatures of the children returned to normal within 3.3 days (95% CI, 3.1 to 3.5 days). Complications were
not observed during the hospital stay or a 3-month follow-up period. Relapse and carrier state were also not
encountered during the follow-up period.

Typhoid fever continues to be a major health problem,
especially in developing countries (9). It has been estimated
that the case fatality rate from typhoid fever has reduced
dramatically to less than 2% because of the introduction of
chloramphenicol (21). However, the case fatality rate is still
high among patients suffering from severe typhoid fever (8,
14). Intravenous administration of chloramphenicol with
supportive measures is considered ideal for the prevention
death in severely ill patients with typhoid fever (10). Several
workers have also recommended the use of corticosteroid
along with chloramphenicol infusion to reduce the mortality
from severe typhoid fever (12, 18). The prevalence of severe
typhoid fever caused by multi-drug-resistant strains of Sal-
monella typhi has recently increased in Calcutta (2). These
circulating strains of S. typhi are highly susceptible to
ciprofloxacin (19), a new synthetic fluoroquinolone with a
broad spectrum of bactericidal activity and effective tissue
penetration (7). Ciprofloxacin has also been used success-
fully in the treatment of typhoid fever in children (20),
despite controversy over its use in individuals in this age
group (1). We report here our experience of treating life-
threatening typhoid fever in children with intravenous cip-
rofloxacin.
Five hundred ninety-two febrile patients with clinically
suggestive typhoid fever who were admitted to the Dr. B. C.
Roy Memorial Hospital for Children in Calcutta between
February 1990 and January 1992 were screened for S. typhi.
Typhoid fever was suspected in patients who had a sustained
fever (>39°C) for 10 days or more but who did not have signs
and symptoms suggesting other infections. Among the 592
patients, 33 had an abnormal state of consciousness or shock
and were considered to have severe typhoid fever. Of these
33 patients with clinically suggestive severe typhoid fever,
only 18 were positive for S. typhi by blood culture, and these
18 patients met the entry criteria for inclusion into the study.
An abnormal state of consciousness in patients with severe
typhoid fever was defined as a condition in which the patient
had one or more of the signs like delirium, obtundation,
stupor, coma, or shock (12). Delirium was defined by mark-
*
Corresponding author.
1197
edly confused thinking or speech. An obtunded patient was
one who appeared unconscious but when stimulated re-
sponded appropriately to questions and commands. Stupor-
ous patients were those who did not respond verbally to any
stimuli but who responded only to painful stimuli. Comatose
patients were those who did not respond to any noxious
cutaneous stimuli. Shock was considered to be present if the
patient had a systolic blood pressure of <80 mm Hg and cold
clammy skin with altered consciousness.
A blood sample (5 ml) was collected aseptically from each
patient and was inoculated into tryptic soy broth at the
bedside of the patient for isolation of S. typhi by standard
techniques (22). Two milliliters of blood was also collected in
a test tube for the Widal test, and sera were tested by the
conventional agglutination method (6) with commercially
available antigen (Entero test; Stangen Immunodiagnostic,
Hydrabad, India). Antimicrobial susceptibility testing of the
isolated strains of S. typhi was done by the Kirby Bauer disk
diffusion method (3). The MICs for the isolated strains of S.
typhi were tested by the agar plate dilution method (13).
Blood samples were also collected from these patients for
other laboratory tests, including routine blood counts and
blood biochemistry (e.g., sugar, urea, creatinine, serum
sodium, potassium, chloride, and total bicarbonate). In-
creased intracranial pressure was estimated by lumbar punc-
ture and manometry. Funduscopic examination was also
done to look for papilloedema. Cerebrospinal fluid was also
tested for routine investigation.
Patients who were clinically suspected of having severe
typhoid fever (having an abnormal state of consciousness)
were included in the study. All these patients had received
two or more conventional drugs, either singly or in combi-
nation, for treatment of their typhoid fever before inclusion
into the study. Informed verbal consent and a complete
history were obtained from the patients' parents. Patients
were weighed to the nearest 100 g. A thorough physical
examination was performed, and treatment was initiated.
Patients were followed up three times daily for the assess-
ment of general condition, state of consciousness, and
remission of their fever to 37.5°C (axillary). Patients were
also carefully observed for possible complications like gas-
trointestinal bleeding, anemia requiring blood transfusion,
1198 NOTES ANTIMICROB. AGENTS CHEMOTHER.

pneumonia (on the basis of clinical examination), and intes- TABLE 1. Clinical and laboratory findings of the patients with
tinal perforation. Patients who had remission of fever and severe typhoid fever at the time of inclusion in the study
whose state of consciousness became normal within 8 days Parameter Observed value Range
of drug therapy and also who did not develop complications
were discharged from the hospital on day 15. Remission of Age (yr)a 6.4 ± 2.0 1.5-9.5
fever was considered when the maximum body temperature
(axillary) was <37.5°C for 48 h or more. Drug efficacy was Body weight (kg)a 15.3 ± 3.4 11-18.2
judged primarily by the reduction in mortality of the severely Days of illness 22.7 ± 13.1 10-62
ill patients and secondarily by the patients' clinical re- before inclusiona
sponses, with particular attention given to the number of
days of treatment required to make the patients afebrile. Axillary temp (OC)a 39.9 ± 0.5 38.9-40.2
At the time of discharge from the hospital, blood and stool
samples were collected for isolation of S. typhi. Bacterio- Clinical condition
logic cure was considered if blood and stool cultures were (no. of patients)
negative for S. typhi at the time of discharge. Parents were Delirium 5
advised to bring their children to the hospital for follow-up Delirium and 7
every 15 days for 3 consecutive months. They were also obtundation
advised to contact the investigators immediately if their Stupor 4
Shock 2
children develop fever or any complication after discharge.
At the time of the follow-up examinations, blood and stool Hematological
samples were also collected to screen for S. typhi. Routine findingsa
blood counts, blood biochemistry, and examination of cere- Total leukocyte (2.8 + 0.8) x 109 (2.0-4.2) x 109
brospinal fluid, including the estimation of increased intra- count/liter
cranial pressure, were done at the time of discharge from the Platelet count/liter (110 + 10.5) x 109 (80-180) x 109
study. Routine blood counts and blood biochemistry were Hemoglobin 1.0 ± 0.3 0.98-1.4
repeated at the time of the last follow-up examination. (mmol/liter)
Lumbar puncture and manometry were done if patients had Cerebrospinal fluid
clinical evidence of increased intracranial pressure. We findingsa
regarded relapse as the occurrence of fever and other No. of cells/liter (0.003 + 0.001) x 109 (0.002-0.006) x 109
symptoms of typhoid fever after an initial response to Protein (mg/liter) 125 ± 8.0 100-186
therapy and the isolation of S. typhi on blood culture. Sugar (mmol/liter) 2.8 ± 0.6 2.3-3.6
Patients who were found to be excreting S. typhi during the a Values are means ± standard deviations.
follow-up period, after the completion of therapy, were
labelled as carriers.
All the patients received ciprofloxacin at a dose of 10
mg/kg of body weight per day in two divided doses by were severely ill with an abnormal state of consciousness.
intravenous infusion over 10 min. When the patients were The mean age was 6.4 ± 2.0 years (standard deviation [SD]).
able to take substances orally, therapy was switched to The mean body weight was 15.3 ± 3.4 kg (SD). They
ciprofloxacin in tablet form at the same dosage regimen. suffered for a period of 22.7 ± 13.1 days (SD) before
Ciprofloxacin (intravenously and orally) was given for a administration of ciprofloxacin. Cure was achieved in 17
period of 14 or 7 days after the patient became afebrile. patients (94.4%; 95% confidence interval [CI], 84 to 100%).
Intravenous fluid was administered according to the pa- Children regained normal consciousness within an average 2
tient's body weight, temperature, hydration status, clinical days (95% CI, 1.8 to 2.2 days). Their temperatures returned
condition, and urinary output. Five percent glucose saline or to normal within 3.3 days (95% CI, 3.1 to 3.5 days). Data
Ringer's lactate were used. Sponging with tepid water and were analyzed by using the SPSS PC+ software package to
fanning were needed in children with a high temperature determine the correlation between the duration of illness
(240°C). Convulsions were controlled with intravenous di- before inclusion and the duration of fever and abnormal
azepam. Oxygen was given by nasal catheter to dyspneic mentation following the initiation of therapy. No significant
and cyanotic patients. Shock was treated only with intrave- correlation between the duration of illness and duration of
nous fluid and/or blood transfusion. fever (0.15) and abnormal mentation (-0.19) were observed.
Eighteen children suffering from severe typhoid fever Only one patient died after 24 h of ciprofloxacin administra-
were treated intravenously with ciprofloxacin. They were tion. This child was severely malnourished (body weight,
positive for S. typhi by blood culture and had a positive <50% of the Harvard standard weight for age) and suffered
Widal test (antibody titer against S. typhi 0 antigen, 1:320 or for a prolonged period (62 days). He was in shock at the time
greater). All S. typhi strains isolated from the patients were of ciprofloxacin administration. All 17 children who were
susceptible to nalidixic acid, norfloxacin, ciprofloxacin, gen- included in the study and survived attended the hospital for
tamicin, amikacin, and furazolidone but were resistant to reevaluation every 15 days for 3 months after discharge. S.
chloramphenicol, ampicillin, trimethoprim-sulfamethox- typhi could not be isolated from stool or blood samples from
azole, and amoxicillin. The MICs of ampicillin were 800 to these patients at the time of discharge or during follow-up.
1,600 ,ug/ml, those of chloramphenicol were 200 to 400 None had a relapse of fever or complications such as
,ug/ml, those of trimethoprim-sulfamethoxazole were > 1,600 arthropathy, metabolic acidosis, and increased intracranial
,ug/ml, and those of amoxicillin were 400 to 800 p,g/ml. Of pressure. They were not observed either clinically, by
these 18 children, 5 had delirium, 7 had delirium and biochemical tests, or by lumbar puncture and manometry.
obtundation, 4 had stupor, and 2 had shock. Detailed clinical The results of the present study indicate that intravenous
and laboratory findings for these patients at the time of use of ciprofloxacin is beneficial in patients with severe
inclusion in the study are shown in Table 1. All the patients typhoid fever. The cure rate was as high as 94% in the
VOL. 37, 1993
present study. Chloramphenicol was the first drug shown to
be effective therapy for typhoid fever and remains the drug
of choice in many parts of the world. Chloramphenicol has
also been used intravenously in patients with severe typhoid
fever; however, the cure rate could never have been as high
as that obtained in the present study (5, 11). Corticosteroids
have also been recommended by several workers for reduc-
ing mortality in severely ill patients. Case fatality rate
reductions of 10% were observed by some workers after the
use of intravenous chloramphenicol and corticosteroid (12).
However, a recent study conducted in Papua New Guinea
showed that the mortality rate from severe typhoid fever was
as high as 44% after the use of intravenous chloramphenicol
and hydrocortisone (18). Broad-spectrum cephalosporins
have also been evaluated clinically for the treatment of
severe typhoid fever; the mortality rate was 16% (17).
The emergence of chloramphenicol-resistant strains of S.
typhi has necessitated the use of other antimicrobial agents
(2, 19). Recently, ciprofloxacin has successfully been used to
treat typhoid fever in adults and children (4, 16, 20). It has
been documented that ciprofloxacin penetrates tissue well
and that therapeutic concentrations can be achieved in
cerebrospinal fluid, even when there is no inflammation of
the meninges (15). These results instigated us to use this drug
to treat patients with severe typhoid fever who were deliri-
ous, obtunded, stuporous, and in shock. These patients had
an extremely poor prognosis and were at high risk of
development of shock, coma, or death (12). Ciprofloxacin
not only reduced the case fatality rate but also shortened the
course of illness to a great extent. Patients regained their
normal consciousness within 2 days and had remission of
fever within 3 days. We did not encounter any relapse or
carrier state in our study population during the 3-month
follow-up period. Several side effects of ciprofloxacin, in-
cluding development of metabolic acidosis, occurrence of
intracranial hypertension, and development of arthralgia,
have been reported previously (1), but these were not
observed among the children in our study.
On the basis of the results of this noncomparative study,
ciprofloxacin is one of the drugs that can be used to treat
multiply resistant, severe typhoid infections in children.
We acknowledge the superintendent and visiting physicians of Dr.
B. C. Roy Memorial Hospital for Children, Calcutta, for allowing us
to study patients admitted to the hospital.
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