Le Infezioni in Medicina, n.

2, 155-160, 2015

Articolo originale / Original article

155

Effectiveness and tolerability of short

course co-trimoxazole, norfloxacin
and levofloxacin in bacteriological
cure of uncomplicated urinary tract
infection in outpatient setting.
An open label, parallel group,
randomized controlled trial
Studio randomizzato, controllato, in aperto e a gruppi paralleli,
sullefficacia e la tollerabilit di un ciclo breve di cotrimossazolo,
norfloxacina e levofloxacina nella guarigione microbiologica
delle infezioni comunitarie, non complicate, delle vie urinarie
Arpit Vallabhbhai Vachhani1, Manish Barvaliya1, Viren Naik1, Pramod Jha2,
Chandrabhanu Tripathi1
1
2

Department of Pharmacology, Government Medical College, Gujarat, India;

Department of Medicine, Government Medical College, Gujarat, India

n INTRODUction

rinary tract infection (UTI) is characterized

by the presence of >105 microorganisms per
milliliter of urine with pus cells and red blood
cells [1]. It is commonly caused by Gram negative
organisms like Escherichia coli, Klebsiella, Proteus,
Pseudomonas, Enterobacter and also less commonly
by gram positive organisms like Staphylococcus
saprophyticus and Streptococci [2]. Empirical antimicrobial therapy for 7-10 days is the main stay
treatment [3]. Co-trimoxazole, -lactams, aminoglycosides, and fluroquinolones are the groups of
antimicrobials commonly prescribed for treatment
of UTI [4]. Most of the time, broad spectrum antimicrobials are prescribed before the availability of
Corresponding author
Chandrabhanu Tripathi
E-mail: cbrtripathi@yahoo.co.in

bacterial culture and sensitivity test reports. Some

studies have shown that three days treatment with
antimicrobials is as effective as seven days therapy
in clinical and bacteriological cure of urinary tract
infection [5]. Short duration treatment leads to
better patient compliance, less adverse effects and
cost reduction. In the present study, we evaluated
effectiveness of short course treatment with three
commonly prescribed antimicrobials (co-trimoxazole, norfloxacin and levofloxacin) for treatment
of uncomplicated urinary tract infection in a tertiary care hospital of Gujarat, India.
n PATIENTS AND METHODS
The study protocol was approved by the Institutional Review Board (IRB), Government Medical
College, Bhavnagar (IRB No. 360/2013, dated 3rd
September, 2013). This open label, randomized
clinical trial was registered in Clinical Trial Reg-

156 A.V. Vachhani, et al.

istry of India (CTRI) [Reg. No. 2014/03/006671].

The study was conducted at the outpatient Department of Medicine at Sir Takhatsinhji General
Hospital, Bhavnagar, Gujarat, India. International
Conference on Harmonization and Good Clinical Practice (ICH-GCP) guidelines were followed.
Written informed consent was obtained from each
study participant.
Patients aged 18-65 years with symptoms of dysuria or frequency/urgency of micturation, burning micturation, fever and urine culture showing >105 colony forming unit (CFU) per milliliter
(CFU/ml) were included in the study. Patients
with urine culture showing less than 105 CFU/
mL, symptoms of upper urinary tract infection,
benign prostatic hypertrophy, prostatitis, recurrent UTI or per urethral discharge were excluded
from the study. Patients having diabetes, ECG
abnormality, abnormal liver and renal laboratory parameters, haemoglobin <8 g/dL, pregnant
women were also excluded from the study. At the
time of screening, blood samples were collected
for total blood count, liver and renal function test;
urine samples were collected for routine and microscopic examination.
All the screened patients were randomized. Randomization was done with random software to
recruit patients in 1:1:1 ratio into three different
study groups (Group A, B and C). Randomization
was done by a person not involved in the study
and randomized codes were kept in sealed envelopes and opened at the time of patient recruitment. Group A patients received co-trimoxazole
960 mg twice a day; Group B patients received
norfloxacin 400 mg twice a day, and Group C patients received levofloxacin 250 mg once a day for
3 days. Patients were called for follow-up on day
4; urine was collected for culture report. Laboratory persons from National Accreditation Board
for Testing and Calibration Laboratories (NABL)
of the institution were blinded for assigned treatment.
Outcome measures: Effectiveness of each treatment
group was evaluated by bacteriological cure rate.
Bacteriological cure rate was defined as conversion of pre-treatment positive bacterial urine culture into negative urinary culture on day 4. The
treatment failure was defined as positive culture
at the end of treatment period. Adverse drug reactions were recorded at follow up visit and compared between the treatment groups.

Statistical analysis: Data were expressed in proportions. Chi square test was applied for comparison
of bacteriological cure rate between the study
groups. P value <0.05 was considered as statistically significant. All the statistical calculations
were performed using SPSS (version 21) software
(International Business Machine, IBM - America).
Sample Size calculation: Overall, 150 participants
were needed to achieve 80% power with level
of 0.05 (two tailed), if minimal expected difference
in bacteriological cure rate is 20%.
n RESULTS
One hundred seventy-five out of 203 screened
symptomatic patients with uncomplicated UTI
were randomized and received the assigned treatment for 3 days. Flow of study participants has
been shown in Figure 1. Demographic details
and baseline characteristics of patients have been
shown in Table 1. Overall, Escherichia coli (74.29%)
was the most common organism isolated followed
by Klebsiella spp (11.43%), Streptococcus spp (6.29%),
Staphylococcus saprophyticus (5.14%), and Pseudomonas spp (2.86%). At the end of 3 days treatment,
bacteriological cure rates were 86.2%, 87.7% and
83.3% for patients receiving co-trimoxazole, norfloxacin and levofloxacin for 3 days, respectively.
As per comparisons for bacteriological cure rates
for an individual organism between study groups
have been shown in Figure 2, there was no any
significant difference noted between the three
treatment groups for bacteriological cure rate of
an individual organism (p>0.05). 13.6% (6/44),
11.1% (1/9) and 100% (1/1) patients did not respond to the co-trimoxazole in whom Escherichia
coli, Klebsiella and Pseudomonas were isolated, respectively. 12.2% (6/49) and 100% (1/1) patients
did not respond to norfloxacin against isolated
Escherichia coli and Pseudomonas, respectively.
16.2% (6/37), 28.6% (2/7) and 28.6% (2/7) patients did not respond to levofloxacin in whom
Escherichia coli, Klebsiella spp and Streptococcus spp
were isolated, respectively.
In all treatment groups, proportions of treatment
related adverse drug reactions were found to be
similar (Table 2). There were mild adverse reactions reported by the patients. No any serious adverse drug reactions were reported during the trial. Nausea (7.43%) was the most common adverse

Effectiveness and tolerability of short course co-trimoxazole, norfloxacin and levofloxacin 157

drug reaction in all three treatment groups followed by vomiting (5.14%) and headache (1.14%).
n DISCUSSION
The present study compared the effectiveness and
tolerability of co-trimoxazole 960 mg twice a day,

norfloxacin 400 mg twice a day and levofloxacin

250 mg once a day for 3 days in patients with uncomplicated urinary tract infection. In the present
study, Escherichia coli (74.29%) followed by Klebsiella spp (11.43%), Streptococcus spp (6.29%), Staphylococcus saprophyticus (5.14%), and Pseudomonas
spp (2.86%) were responsible for causing UTI.
Gram negative bacteria were predominant com-

Figure 1 - Flow of patients in present study [CONSORT statement].

Table 1 - Baseline characteristics of study participants.

Baseline
characteristics
Age (years)
Gender

Male
Female

Organism isolated
Escherichia coli
Klebsiella spp
Pseudomonas spp
Staphylococcus saprophyticus
Streptococcus spp

Group A
co-trimoxazole
N=58
47.6816.09
25 (43.10)
33 (56.89)

Group B
norfloxacin
N=57
47.7515.66
16 (28.07)
41 (71.93)

Group C
levofloxacin
N=60
47.3813.09
24 (40)
36 (60)

47.9315.66
65 (37.14)
110 (62.86)

44 (75.86)
9 (15.52)
1 (1.72)
2 (3.45)
2 (3.45)

49 (85.96)
4 (7.018)
1 (1.75)
1 (1.75)
2 (3.51)

37 (61.67)
7 (11.67)
3 (5.00)
6 (10.00)
7 (11.67)

130 (74.29)
20 (11.43)
5 (2.86)
9 (5.14)
11 (6.29)

Data are expressed as mean SD and absolute numbers. Values in parenthesis are in percentage.

Total
N=175

158 A.V. Vachhani, et al.

pared to Gram positive in causing the UTI [6-9].

Antimicrobial spectrum of co-trimoxazole includes Gram negative bacilli like Escherichia coli,
Shigella, Salmonella, Proteus mirabilis as well as
Gram positive cocci like Staphylococcus aureus
and Streptococcus pneumoniae. Norfloxacin and
levofloxacin are a first and a second generation fluoroquinolone, respectively. While their
antimicrobial activity against Gram negative is
equal, levofloxacin has an extended spectrum
against Gram positive and atypical pathogens. In
acute and uncomplicated cases, co-trimoxazole
960 mg twice a day, norfloxacin 400 mg twice a

day and levofloxacin 250 mg once a day for 5-10

days are equally effective [4]. Various clinical trials showed similar effectiveness of short course
antimicrobial therapy (3 days) as compared to
standard duration of therapy (5-7 days) [10, 11].
In the present study, co-trimoxazole, norfloxacin
and levofloxacin for 3 days resulted in 86.2%,
87.7% and 83.3% bacteriological cure rate, respectively. Other studies have reported 55-91%
bacteriological cure rate with co-trimoxazole
and 87-91% with norfloxacin short course therapy [12-15]. High level of resistance has been reported to co-trimoxazole, norfloxacin and levo-

Figure 2 - Response of individual drug against all uropathogens, in each cotrimoxazole and norfloxacin groups,
one pseudomonas was isolated but remained untreated.
Table 2 - Adverse drug reactions noted in study participants.
Nature of ADR

Nausea
Vomiting
Headache
Total

Group A
co-trimoxazole
N=58
7 (12.07)
3 (5.17)
2 (3.45)
12 (18.96)

Group B
norfloxacin
N=57
4 (7.02)
3 (5.26)
0 (0.00)
7 (12.28)

Group C
levofloxacin
N=60
2 (3.33)
3 (5.00)
0 (0.00)
5 (8.33)

Data are expressed in absolute numbers, parenthesis shows value in proportion. P value is for Chi-square test.

P value

0.208
0.994
0.13

Effectiveness and tolerability of short course co-trimoxazole, norfloxacin and levofloxacin 159

floxacin for Gram negative organisms in patients

of various regions of India [16-18]. In contrast to
an overall resistance of 13.8%, 12.3% and 16.7%
reported in the present study, Somashekara et
al. reported 75.2%, 62.4% and 51.4% overall resistance to co-trimoxazole, norfloxacin and levofloxacin, respectively [17].
In the present study, co-trimoxazole resistance
was found in 13.6% Escherichia coli, 11.1% Klebsiella and 100% Pseudomonas whereas Somashekara et al. reported values of 68.8% in Escherichia
coli, 52.2% in Klebsiella spp and 100% in Pseudomonas spp [17]. With regard to norfloxacin, resistance was found in Escherichia coli [12.2% vs.
78.6%] and Pseudomonas [100% vs. 92%] in contrast to the report of Somashekara SC et al. [17].
Somashekara SC et al reported 76.5% Escherichia
coli, 31% Klebsiella, 82.6% Pseudomonas spp and
53.5% Streptococcus spp whereas the present study
found 16.2% Escherichia coli, 28.6% Klebsiella spp
and 28.6% Streptococcus resistant to levofloxacin. All the three patients in whom Pseudomonas was isolated got bacteriological eradication
with levofloxacin in the present study (Figure 2).
All these findings suggest that the 3 days therapy with co-trimoxazole, norfloxacin and levofloxacin are equally effective for bacteriological
cure of uncomplicated UTI and that levofloxacin
is highly effective, compared to cotrimoxazole
and norfloxacin, for treatment of UTI caused by
pseudomonas.

All the three treatments were well tolerated by the

study participants, without occurrence of any serious adverse events. According to the Infectious
Disease Society of America (IDSA) guidelines,
cotrimoxazole is the current standard therapy for
uncomplicated community acquired urinary tract
infection (CAUTI) in women [19]. Fluoroquinolones should be reserved as a second line drug for
CAUTI [19]. Findings of the present study recommend the use of co-trimoxazole 960 mg twice a
day as first line drug for the cases of uncomplicated UTI. There is no added advantage of using
norfloxacin and levofloxacin as first line; they can
be used as reserved drug. However, we could not
measure the effectiveness of short course therapy
in preventing UTI relapse.
n CONCLUSION
In conclusion, co-trimoxazole, norfloxacin and levofloxacin can be recommended for a three days
period to reduce bacterial overload in UTI. Cotrimoxazole should be given as a first line drug.
There is no added advantage of using norfloxacin
and levofloxacin as first line; they can be used as
reserved drug.
Keywords: urinary tract infection (UTI), co-trimoxazole, norfloxacin, levofloxacin, short-course
treatment.

SummaRY
To compare the bacteriological cure rate of shortcourse (3-day) treatment of uncomplicated urinary
tract infection (UTI) using co-trimoxazole, norfloxacin
and levofloxacin, patients with uncomplicated UTI
were randomized to receive either co-trimoxazole (960
mg) twice a day or norfloxacin (400 mg) twice a day
or levofloxacin (250 mg) once a day for three days.
Urine culture was done at the end of treatment and
evaluated for bacteriological cure rate in each group.
Among a total of 175 patients, Escherichia coli (74.29%)

was the most common organism isolated followed by

Klebsiella (11.43%), Streptococcus (6.29%), Staphylococcus
saphrophyticus (5.14%), and Pseudomonas (2.86%). At
the end of three days treatment, bacteriological cure
rates were 86.2%, 87.7% and 83.3% for co-trimoxazole,
norfloxacin and levofloxacin, respectively (p>0.05).
Therefore short-course treatment with co-trimoxazole
960 mg twice a day, norfloxacin 400 mg twice a day
and levofloxacin 250 mg once a day are almost equally
effective for treatment of uncomplicated UTI.

160 A.V. Vachhani, et al.

RIASSUNTO
Al fine di confrontare il tasso di eradicazione batteriologica
conseguente a un ciclo breve (3 giorni) di trattamento per
le infezioni delle vie urinarie (IVU) non complicate con cotrimossazolo, norfloxacina e levofloxacina, pazienti affetti
da IVU sono stati randomizzati a ricevere uno dei seguenti
trattamenti: cotrimossazolo (960 mg) bid, norfloxacina (400
mg) bid o levofloxacina (250 mg) qd per tre giorni. Lurinocoltura stata effettuata al termine del trattamento e il tasso di eradicazione batteriologica stato valutato in ciascun
gruppo di pazienti. Nellambito dei 175 pazienti, Escherichia coli (74,29%) ha rappresentato il microrganismo iso-

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