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Case

Studies

Levofloxacin: Todays Choice for the


Treatment of Typhoid Fever?
An Illustrative Case Report from Indonesia
R. H. H. Nelwan, MD, DTMH

Professor, Department of Internal Medicine, Consultant for Tropical and Infectious Diseases,
Faculty of Medicine University of Indonesia/National Top Referral Hospital Dr. Cipto Mangunkusumo,
Ministry of Health, Jakarta

Introduction
Typhoid fever is still endemic in many
parts of the developing world and can be
transferred to the developed world by re
turning visitors to these endemic regions
(1, 2). It is a potential life-threatening
disease and may produce severe complications if not treated in its early stages.
Ciprofloxacin is accepted as a drug of
choice for typhoid fever and has been
used for almost two decades (3).
In recent years, the emergence of a
decline in sensitivity of Salmonella typhi
to ciprofloxacin has been reported by
Threlfall et al (4). Also several individual
cases of the failure of ciprofloxacin to
treat typhoid fever have been reported
(5, 6). More important is the fact that lab
oratory reports of increased resistance to
ciprofloxacin are on the increase, espe
cially in the South Asian subcontinent
(79).
At the present time, serious thought
is being given about the wisdom of treat
ing future typhoid fever cases with ciprofloxacin (10). The latest Indonesian experience clearly highlights some clinical
aspects of this issue where patients on
ciprofloxacin needed, on average, a longer
time to become free from fever compared
with earlier studies in this region using
the same antibiotic regimen (11).
A case will now be described where
gastrointestinal intolerance to oral cipro
floxacin was observed with possible hepatic adverse reactions and subsequent
clinical failure of typhoid fever treatment.
Levofloxacin was substituted as it has
already been shown to be better tolerated
when treating this kind of gastrointestinal
Address for correspondence
R. H. H. Nelwan, MD, DTMH
Department of Internal Medicine, Faculty of Medicine University
of Indonesia
Jl. Salemba Raya No.6, Jakarta, Indonesia

infection. In this case, levofloxacin suc


cessfully cured the patients typhoid infection without causing any adverse gastrointestinal reactions.
Case presentation
An Indonesian male, aged 40 years, was
admitted complaining of fever for 5 days.
The fever was monitored daily and it was
more pronounced in the early evening.
He also initially suffered from loose motions for one day before becoming constipated. He also had headache and muscular pain. However, he had no nausea,
vomiting or epigastric discomfort.
His physical examination showed
that he was fully alert, with a body tem
perature of 37.9C, blood pressure of
110/70 mmHg, pulse 88/min and a respiration rate of 16/min. His height was
165 cm and his body weight was 77.5 kg.
No abnormal findings were noted following examination of his chest and abdomen. His extremities were also normal
while his laboratory findings were as
follows: Hb 15.2 g, leucocyte count
5,400/ml, thrombocyte count 199.000/ml,
and BSR 34 mm/hr. Urine and stool
examinations were normal. As far as liver
enzymes were concerned his SGOT was
112 U/l and his SGPT was 144 U/l
while his CRP was 16.658 mg/L. Widal
agglutination titers were 1/80 for S. typhi
O and 1/1,280 for S. typhi H. His Tubex
S. typhi IgM test was positive. A chest
X-ray revealed old fibrotic scar tissue at
the apex of the left lung. His ECG was
normal.
The patient was initially treated with
ciprofloxacin 25400 mg IV for 4 days
and then an IV-oral sequential switch
was made after the patient had been afebrile for 24 hours. The oral ciprofloxacin 25500 mg was continued and the
patient was allowed to leave the hospital
on the sixth day after hospitalization. All
abnormal laboratory values had im-

proved except for the SGPT which was


slightly raised when the patient was discharged.
The patient was readmitted to hospital sometime during the afternoon of
the next day with sudden epigastric distress after taking oral ciprofloxacin early
in the morning. He also experienced cold
sweats and his most significant complaint
was that he felt as if his stomach was being compressed from all sides. He was
slightly icteric but had no abnormal vital
signs and, on physical examination, there
was pain on palpation of the epigastric
region and some distention of the abdomen. This episode was diagnosed as most
probably an adverse gastrointestinal reaction to oral ciprofloxacin. To ease his
abdominal discomfort, he was prescribed
dimethicone, lansoprazole and ketorolac
tromethamine. A test for anti Helicobacter
pylori IgM and IgG were both negative.
On readmission, his CRP was near normal and antimicrobial treatment was discontinued as ciprofloxacin had already
been administered for a total of one
week.

Unfortunately, the next day his temperature had increased slightly and his
CRP had risen markedly to 28.841 mg/L
signaling a probable relapse as far as his
typhoid fever was concerned. The S. typhi
IgM was positive and the SGPT had
increased to 413 U/L, while the SGOT
was 130 U/L and there was also an increase in total bilirubin to 5.47 mg/dl.
Levofloxacin was initially administered
IV, 500 mg daily for 2 days, and then
continued orally as 500 mg daily. His
PCR for S. typhi became negative. All
markers of acute viral hepatitis infection
(A, B and C) were negative. The patients
also had blood in his stools on his second
admission that cleared after levofloxacin
was administered. His CRP returned to
normal within a few days and no adverse
gastrointestinal reactions were noted. His

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Case Studies 2

Widal agglutination test was reactive only


to S. typhi H with a titre of 1/160 on

discharge. A follow-up stool culture one


month later failed to grow any Salmo-

nella microorganisms.

Commentary
As far as this case is concerned, several
aspects of typhoid fever treatment with
ciprofloxacin require comment. The first
point is the treatment failure causing an
early relapse. After finishing one week of
treatment this patient, who was initially
only readmitted to the hospital for upper
gastrointestinal pain after switching from
IV to oral ciprofloxacin, began experiencing chills at night and had a slightly
increased body temperature. Although,
on readmission, his CRP was near normal and no antimicrobial was administered due to the adverse gastrointestinal
reaction, the next day his CRP was
markedly elevated indicating a possible
clinical relapse of typhoid fever. The S.
typhi IgM test was positive and the antimicrobial treatment was switched from
ciprofloxacin to levofloxacin. Intravenous
levofloxacin was administered since from
previous experience IV ciprofloxacin did
not cause any adverse gastrointestinal
effects. His blood biochemistry results
also showed increased transaminases and
an increased total bilirubin. A comment
will be made on this finding after discussing the clinical failure of treating typhoid
fever with ciprofloxacin. Two points need
to be taken into consideration. Firstly,
the relapse occurred because of the interrupted administration of ciprofloxacin due to the severe gastrointestinal
problems that the patient experienced
and, secondly, this relapse occurred early
and probably was due to reduced sensitivity of S. typhi to ciprofloxacin. Following many years of ciprofloxacin use, it is
well known that the sensitivity of S. typhi to ciprofloxacin gradually declined.
Also, in our randomized multicenter
study comparing the clinical efficacy of
levofloxacin with ciprofloxacin (11), it
was found that in the cases that were finally diagnosed as typhoid fever, in the
ciprofloxacin group it took on average
five days until normalization of body
temperature while in the levofloxacin
group, it took only 3 days (Table 1). After initial administration of IV levofloxacin, 500 mg, and following resolution of
his gastrointestinal complaints by the
third day, a switch was made to oral administration. Following this treatment,
the patient made an excellent recovery.
There were no aggravating gastrointesti-

nal complaints during his course of


treatment with oral levofloxacin. The S.
typhi IgM that became negative was reconfirmed by a PCR test for S. typhi
which showed that his typhoid infection
had been completely cured. Levofloxacin
is also very effective against the whole
spectrum of Gram-negative microorganisms and it also exhibits excellent
pharmacokinetic and pharmacodynamic
properties (12, 13).
The second aspect for discussion is
the adverse reaction the patient experienced during ciprofloxacin treatment
which was the main cause of his readmission to hospital. The patient described his
epigastric distress as a feeling of compression from all sides of his stomach preventing him eating properly because he
readily vomited any food he managed to
swallow. The possibility of a H. pylori infection was ruled out because of negative
results for both H. pylori IgG and IgM.
Previously, he had never had any stomach problems. The ciprofloxacin was discontinued on his readmission and, as his
CRP was nearly normal, no other antimicrobials were given. This gastrointesti-

nal type of adverse reaction to ciprofloxacin has been recorded ever since its first
clinical use and has occasionally prompted its discontinuation. The results of a
randomized single-blind multicenter
study (11) comparing safety and efficacy
in patients with uncomplicated typhoid
fever in Indonesia showed that there was
a significantly lower number of gastrointestinal reactions in the levofloxacintreated patients compared to those receiving ciprofloxacin. There were also cases
where ciprofloxacin treatment needed to
be stopped suddenly compared with no
cases in the levofloxacin group where
treatment for this kind of condition was
surprisingly well tolerated. As typhoid
fever is a gastrointestinal infection, drugs
causing adverse reactions in the gastrointestinal tract may result in the interruption of treatment because of aggravation
of intestinal complaints. This is actually
what happened to cases in this large study
comparing ciprofloxacin with levofloxacin for uncomplicated typhoid fever
(Table 2). From the findings already
described regarding the treatment of
typhoid fever, levofloxacin may be a bet-

Table 1. A randomized single-blind multicenter study comparing the clinical efficacy of levofloxacin with ciprofloxacin for the treatment of typhoid fever
Clinical efficacy
Average defervescence (days)
Fever-free at day 7 (%)
Clinical relapse
Others (relapse)

No. of patients
Levofloxacin (n=53)

Ciprofloxacin (n=54)

3
100
1
0

5
77.8
1
1

Presented at the 55th Annual Meeting of the ASTMH, Atlanta, USA, November 2006.
Adapted from reference (11).

Table 2. Comparison of adverse reactions in a randomized multicenter study comparing levofloxacin with ciprofloxacin for the treatment of typhoid fever
Adverse reaction

No. of patients
Levofloxacin (n=54)

Ciprofloxacin (n=56)

Nausea
Vomiting
Nausea + vomiting
Epigastric pain
Insomnia

5
1
0
0
4

4
2
4
2
2

Cephalgia

Presented at the 55th Annual Meeting the ASTMH, Atlanta, USA, November 2006.
Adapted from reference (11).

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Case Studies 2

ter choice than ciprofloxacin because of


its excellent proven clinical efficacy and
lower incidence of adverse gastrointestinal reactions in this kind of infection. An
analysis of the toxicity profile of fluoroquinolones supports this finding (14).
The third aspect of interest this case
was the fact that although the patient became afebrile the increased liver transaminase SGPT on admission did not
return to normal but increased slightly
after his temperature returned to normal. Subsequently, when the patient was
readmitted, his SGPT increased to over
10 times the upper limit of normal and
his bilirubin also increased. This event
may be a possible dual reaction that
caused hepatic insufficiency due to both
an adverse reaction to ciprofloxacin and a
possible complication involving the
hepato-biliary system due to typhoid
fever. However, as has been reported by
Aggarwal et al, the possibility of cholestasis caused by ciprofloxacin should be
connsidered (15). This third aspect of
hepatic problems is very interesting and
it would be useful to discuss it more in
depth. However, no hard evidence is currently available on the performance of
ciprofloxacin in cases where hepatic
problems are present. As reported by
Parry et al, the levels of liver enzymes in
typhoid fever are usually two to three
times the upper limit of normal (16).
This was exactly what happened in the
case of our patient when he was admitted. Although his condition improved, his
SGPT was still slightly elevated on his
discharge on day 6. In addition, a very
interesting result emerged from the study
comparing the treatment of uncomplicated typhoid fever with either ciprofloxacin or levofloxacin. In the group of
typhoid fever patients treated with ciprofloxacin there was a significantly higher
number of patients with increased liver
transaminases compared with those treat-

ed with levofloxacin (6 vs. 2, Table 3).


Typhoid fever itself may cause hepatic
complications that will be marked by an
increase in bilirubin with liver transaminases that are only slightly increased. In
10 cases of typhoid hepatitis reported by
Khosla SN, the total serum bilirubin
ranged from 2.0 to 7.2 mg while the
SGPT was between 80186 IU (17). In
the present case, a complication of typhoid
fever may have occurred after the failure
of ciprofloxacin to completely eradicate
S. typhi. However, looking at the very
high SGPT, it seems more likely that an
adverse hepatic reaction occurred. After
the infection was neutralized by levofloxacin, the bilirubin values slowly returned to normal as did the liver transaminases which prolonged the
hospitalization of the patient. Whether
this could have been avoided by initial
immediate institution of levofloxacin
treatment is a very good point for discussion. The findings of Harding and
Simpson regarding the low potential of
levofloxacin to cause adverse hepatobiliary reactions should be stressed in this
kind of situation (18). As already reported, the efficacy of levofloxacin for the
treatment of typhoid fever is excellent,
and in 2 trials involving an open study
and a comparative study with ciprofloxacin, it was found that all the patients in
the levofloxacin group were free of fever
by day 6, averaging 3 days without any

post-treatment carrier state, and the relapse rate was no different from that in
the ciprofloxacin group (11, 19). Also, no
severe adverse gastrointestinal reactions
were noted during the use of levofloxacin while, in the ciprofloxacin group,
the number of adverse gastrointestinal
reactions was significantly higher resulting in more withdrawals of treatment.
Also, in the cases of liver insufficiency,
there seems to be less chance of such
problems in the levofloxacin group
compared with the ciprofloxacin group.
We have to remember that the typhoid
fever cases may already have had liver
function impairment when admitted to
hospital. In the case presented above, all
sero markers for hepatitis A, B and C were
negative proving that the deterioration in
liver function may not have been caused
by a co-infection of hepatitis viruses but
could possibly be attributed to the drug
that was used together will possible late
hepatic complications of typhoid fever.
It looks as if there is a bright future
for the early use of levofloxacin in typhoid fever patients in general and, especially, in patients with impaired liver
function. The chance of levofloxacin exacerbating this condition is significantly
smaller compared with the use of ciprofloxacin while, at the same time, levofloxacin offers a very high level of clinical efficacy with a minimal number of
adverse gastrointestinal reactions.

Summary
A case was presented describing the
treatment failure of typhoid fever with
ciprofloxacin, along with gastrointestinal
and hepatic adverse reactions resulting in

prolonged morbidity and hospitalization.


The case was finally treated with levofloxacin producing excellent results and
rapid hospital discharge. It appears that
typhoid fever can be better treated with

levofloxacin because of its dual features


of high efficacy and lower rate of adverse
reactions compared with ciprofloxacin
especially in infections due to S. typhi.

Table 3. Laboratory reactions in a comparative study of levofloxacin vs. ciprofloxacin for the
treatment of uncomplicated typhoid fever
Laboratory reaction
Hematologic
Renal
Hepatic (> 3 fold increase in SGPT)

No. of patients
Levofloxacin (n=54)

Ciprofloxacin (n=56)

None
None
2

None
None
6

Presented at the 55th Annual Meeting the ASTMH, Atlanta, USA, November 2006.
Adapted from reference (11).

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