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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,
sull’efficacia e la tollerabilità 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

U

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, β-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-

ECG abnormality. Patients with urine culture showing less than 105 CFU/ mL. As per comparisons for bacteriological cure rates for an individual organism between study groups have been shown in Figure 2. India. proportions of treatment related adverse drug reactions were found to be similar (Table 2). IBM . abnormal liver and renal laboratory parameters.86%). prostatitis. 16. Flow of study participants has been shown in Figure 1. liver and renal function test. Patients were called for follow-up on day 4.V.05 (two tailed).7% and 83. At the end of 3 days treatment. The study was conducted at the outpatient Department of Medicine at Sir Takhatsinhji General Hospital. No any serious adverse drug reactions were reported during the trial. Demographic details and baseline characteristics of patients have been shown in Table 1. P value <0. symptoms of upper urinary tract infection. istry of India (CTRI) [Reg. if minimal expected difference in bacteriological cure rate is 20%. Gujarat.05 was considered as statistically significant. and Group C patients received levofloxacin 250 mg once a day for 3 days. respectively. urine was collected for culture report.1% (1/9) and 100% (1/1) patients did not respond to the co-trimoxazole in whom Escherichia coli. 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. Bhavnagar. 28. Adverse drug reactions were recorded at follow up visit and compared between the treatment groups. Patients having diabetes. urine samples were collected for routine and microscopic examination. Overall. benign prostatic hypertrophy. Klebsiella spp and Streptococcus spp were isolated.2% (6/49) and 100% (1/1) patients did not respond to norfloxacin against isolated Escherichia coli and Pseudomonas. 13. 11. respectively. Group B patients received norfloxacin 400 mg twice a day. Nausea (7. respectively. blood samples were collected for total blood count.6% (2/7) and 28.43%).14%). Streptococcus spp (6. No.156 A. International Conference on Harmonization and Good Clinical Practice (ICH-GCP) guidelines were followed. et al. Outcome measures: Effectiveness of each treatment group was evaluated by bacteriological cure rate.29%). burning micturation. bacteriological cure rates were 86. Randomization was done with random software to recruit patients in 1:1:1 ratio into three different study groups (Group A. Bacteriological cure rate was defined as conversion of pre-treatment positive bacterial urine culture into negative urinary culture on day 4. 150 participants were needed to achieve 80% power with α level of 0. Chi square test was applied for comparison of bacteriological cure rate between the study groups. Staphylococcus saprophyticus (5. Patients aged 18-65 years with symptoms of dysuria or frequency/urgency of micturation.2%. In all treatment groups. There were mild adverse reactions reported by the patients.05).6% (6/44).29%) was the most common organism isolated followed by Klebsiella spp (11. respectively. Group A patients received co-trimoxazole 960 mg twice a day. there was no any significant difference noted between the three treatment groups for bacteriological cure rate of an individual organism (p>0. recurrent UTI or per urethral discharge were excluded from the study.6% (2/7) patients did not respond to levofloxacin in whom Escherichia coli. and Pseudomonas spp (2. B and C). Escherichia coli (74. 2014/03/006671]. The treatment failure was defined as positive culture at the end of treatment period. Vachhani. Written informed consent was obtained from each study participant.2% (6/37). At the time of screening. pregnant women were also excluded from the study.3% for patients receiving co-trimoxazole. 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. 87. Klebsiella and Pseudomonas were isolated. 12.America). norfloxacin and levofloxacin for 3 days. Sample Size calculation: Overall. Laboratory persons from National Accreditation Board for Testing and Calibration Laboratories (NABL) of the institution were blinded for assigned treatment. All the screened patients were randomized. fever and urine culture showing >105 colony forming unit (CFU) per milliliter (CFU/ml) were included in the study.43%) was the most common adverse . Statistical analysis: Data were expressed in proportions. All the statistical calculations were performed using SPSS (version 21) software (International Business Machine. haemoglobin <8 g/dL.

51) 37 (61.93±15.07) 41 (71.67) 3 (5.86) 9 (15.14%) and headache (1. Values in parenthesis are in percentage.00) 6 (10.10) 33 (56. Table 1 . and Pseudomonas spp (2. norfloxacin 400 mg twice a day and levofloxacin 250 mg once a day for 3 days in patients with uncomplicated urinary tract infection.29%) followed by Klebsiella spp (11.86) 44 (75.43) 5 (2.Flow of patients in present study [CONSORT statement].93) Group C levofloxacin N=60 47.14) 11 (6.67) 130 (74.14%).75±15. Streptococcus spp (6.14%).00) 7 (11.14) 110 (62.Baseline characteristics of study participants. n DISCUSSION The present study compared the effectiveness and tolerability of co-trimoxazole 960 mg twice a day. 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 47.89) Group B norfloxacin N=57 47.86%) were responsible for causing UTI. Escherichia coli (74.72) 2 (3.45) 49 (85. Gram negative bacteria were predominant com- Figure 1 .86) 9 (5. Total N=175 .29%). Staphylococcus saprophyticus (5.66 65 (37.29) Data are expressed as mean ± SD and absolute numbers.45) 2 (3.66 16 (28.29) 20 (11.018) 1 (1. norfloxacin and levofloxacin 157 drug reaction in all three treatment groups followed by vomiting (5.43%). In the present study.Effectiveness and tolerability of short course co-trimoxazole.09 24 (40) 36 (60) 47.75) 1 (1.68±16.38±13.75) 2 (3.09 25 (43.67) 7 (11.52) 1 (1.96) 4 (7.

norfloxacin and levo- Figure 2 .Response of individual drug against all uropathogens.208 0.02) 3 (5. While their antimicrobial activity against Gram negative is equal. P value 0.994 0.V.45) 12 (18.28) Group C levofloxacin N=60 2 (3.7% and 83. norfloxacin 400 mg twice a day and levofloxacin 250 mg once a day for 5-10 days are equally effective [4].17) 2 (3.33) Data are expressed in absolute numbers. P value is for Chi-square test. High level of resistance has been reported to co-trimoxazole. in each cotrimoxazole and norfloxacin groups.3% bacteriological cure rate. et al.158 A. respectively. pared to Gram positive in causing the UTI [6-9].00) 5 (8. Proteus mirabilis as well as Gram positive cocci like Staphylococcus aureus and Streptococcus pneumoniae. Table 2 .Adverse drug reactions noted in study participants.00) 0 (0. co-trimoxazole. 11]. Salmonella. Shigella.07) 3 (5. Various clinical trials showed similar effectiveness of short course antimicrobial therapy (3 days) as compared to standard duration of therapy (5-7 days) [10. Vachhani. respectively. Nature of ADR Nausea Vomiting Headache Total Group A co-trimoxazole N=58 7 (12. one pseudomonas was isolated but remained untreated.96) Group B norfloxacin N=57 4 (7. In the present study. 87. Other studies have reported 55-91% bacteriological cure rate with co-trimoxazole and 87-91% with norfloxacin short course therapy [12-15]. co-trimoxazole 960 mg twice a day. Antimicrobial spectrum of co-trimoxazole includes Gram negative bacilli like Escherichia coli. Norfloxacin and levofloxacin are a first and a second generation fluoroquinolone.2%. norfloxacin and levofloxacin for 3 days resulted in 86. levofloxacin has an extended spectrum against Gram positive and atypical pathogens. parenthesis shows value in proportion.33) 3 (5.00) 7 (12. In acute and uncomplicated cases.26) 0 (0.13 .

Somashekara SC et al reported 76.6%] and Pseudomonas [100% vs. Escherichia coli (74. All these findings suggest that the 3 days therapy with co-trimoxazole. co-trimoxazole resistance was found in 13. norfloxacin and levofloxacin. There is no added advantage of using norfloxacin and levofloxacin as first line. norfloxacin and levofloxacin are equally effective for bacteriological cure of uncomplicated UTI and that levofloxacin is highly effective.8% in Escherichia coli. 62.2% vs. for treatment of UTI caused by pseudomonas. without occurrence of any serious adverse events. norfloxacin and levofloxacin 159 floxacin for Gram negative organisms in patients of various regions of India [16-18].29%) was the most common organism isolated followed by Klebsiella (11.86%). compared to cotrimoxazole and norfloxacin. resistance was found in Escherichia coli [12. respectively (p>0. In the present study.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). 11. 12. In contrast to an overall resistance of 13. With regard to norfloxacin. 92%] in contrast to the report of Somashekara SC et al. norfloxacin and levofloxacin can be recommended for a three days period to reduce bacterial overload in UTI. reported 75. respectively [17].5% Streptococcus spp whereas the present study found 16. short-course treatment.6% Escherichia coli.2%.2% Escherichia coli.14%). There is no added advantage of using norfloxacin and levofloxacin as first line. SummaRY To compare the bacteriological cure rate of shortcourse (3-day) treatment of uncomplicated urinary tract infection (UTI) using co-trimoxazole. norfloxacin and levofloxacin. co-trimoxazole. levofloxacin. co-trimoxazole.3% for co-trimoxazole. Streptococcus (6. All the three treatments were well tolerated by the study participants.29%).Effectiveness and tolerability of short course co-trimoxazole. Fluoroquinolones should be reserved as a second line drug for CAUTI [19]. 28. bacteriological cure rates were 86. 78. we could not measure the effectiveness of short course therapy in preventing UTI relapse.2%. 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. Therefore short-course treatment with co-trimoxazole 960 mg twice a day. 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. Urine culture was done at the end of treatment and evaluated for bacteriological cure rate in each group.3% and 16. Cotrimoxazole should be given as a first line drug. At the end of three days’ treatment.6% Pseudomonas spp and 53. and Pseudomonas (2.7% reported in the present study.2% in Klebsiella spp and 100% in Pseudomonas spp [17]. Staphylococcus saphrophyticus (5. cotrimoxazole is the current standard therapy for uncomplicated community acquired urinary tract infection (CAUTI) in women [19]. 82. However. 31% Klebsiella. Keywords: urinary tract infection (UTI). Among a total of 175 patients. reported values of 68. 52. they can be used as reserved drug.1% Klebsiella and 100% Pseudomonas whereas Somashekara et al.05). . Somashekara et al. According to the Infectious Disease Society of America (IDSA) guidelines.4% overall resistance to co-trimoxazole.4% and 51.7% and 83.5% Escherichia coli. they can be used as reserved drug. norfloxacin and levofloxacin. norfloxacin. n CONCLUSION In conclusion.8%. [17].43%). 87. norfloxacin 400 mg twice a day and levofloxacin 250 mg once a day are almost equally effective for treatment of uncomplicated UTI.

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