Effectiveness and Tolerability of Short Course Co-Trimoxazole, Norfloxacin

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 1Department of Pharmacology, Government Medical College, Gujarat, India; 2Department of Medicine, Government Medical College, Gujarat, India

n INTRODUction bacterial culture and sensitivity test reports. Some studies have shown that three days treatment with rinary tract infection (UTI) is characterized antimicrobials is as effective as seven days therapy Uby the presence of >105 microorganisms per in clinical and bacteriological cure of urinary tract milliliter of urine with pus cells and red blood infection [5]. Short duration treatment leads to cells [1]. It is commonly caused by Gram negative better patient compliance, less adverse effects and organisms like Escherichia coli, Klebsiella, Proteus, cost reduction. In the present study, we evaluated Pseudomonas, Enterobacter and also less commonly effectiveness of short course treatment with three by gram positive organisms like Staphylococcus commonly prescribed antimicrobials (co-trimoxa- saprophyticus and Streptococci [2]. Empirical anti- zole, norfloxacin and levofloxacin) for treatment microbial therapy for 7-10 days is the main stay of uncomplicated urinary tract infection in a ter- treatment [3]. Co-trimoxazole, β-lactams, amino- tiary care hospital of Gujarat, India. glycosides, and fluroquinolones are the groups of antimicrobials commonly prescribed for treatment of UTI [4]. Most of the time, broad spectrum anti- n PATIENTS AND METHODS microbials are prescribed before the availability of The study protocol was approved by the Institu- tional Review Board (IRB), Government Medical Corresponding author College, Bhavnagar (IRB No. 360/2013, dated 3rd Chandrabhanu Tripathi September, 2013). This open label, randomized E-mail: [email protected] clinical trial was registered in Clinical Trial Reg- 156 A.V. Vachhani, et al.

istry of India (CTRI) [Reg. No. 2014/03/006671]. Statistical analysis: Data were expressed in propor- The study was conducted at the outpatient De- tions. Chi square test was applied for comparison partment of Medicine at Sir Takhatsinhji General of bacteriological cure rate between the study Hospital, Bhavnagar, Gujarat, India. International groups. P value <0.05 was considered as statis- Conference on Harmonization and Good Clini- tically significant. All the statistical calculations cal Practice (ICH-GCP) guidelines were followed. were performed using SPSS (version 21) software Written informed consent was obtained from each (International Business Machine, IBM - America). study participant. Sample Size calculation: Overall, 150 participants Patients aged 18-65 years with symptoms of dys- were needed to achieve 80% power with α level uria or frequency/urgency of micturation, burn- of 0.05 (two tailed), if minimal expected difference ing micturation, fever and urine culture show- in bacteriological cure rate is 20%. ing >105 colony forming unit (CFU) per milliliter (CFU/ml) were included in the study. Patients with urine culture showing less than 105 CFU/ n RESULTS mL, symptoms of upper urinary tract infection, benign prostatic hypertrophy, prostatitis, recur- One hundred seventy-five out of 203 screened rent UTI or per urethral discharge were excluded symptomatic patients with uncomplicated UTI from the study. Patients having diabetes, ECG were randomized and received the assigned treat- abnormality, abnormal liver and renal labora- ment for 3 days. Flow of study participants has tory parameters, haemoglobin <8 g/dL, pregnant been shown in Figure 1. Demographic details women were also excluded from the study. At the and baseline characteristics of patients have been time of screening, blood samples were collected shown in Table 1. Overall, Escherichia coli (74.29%) for total blood count, liver and renal function test; was the most common organism isolated followed urine samples were collected for routine and mi- by Klebsiella spp (11.43%), Streptococcus spp (6.29%), croscopic examination. Staphylococcus saprophyticus (5.14%), and Pseudomo- All the screened patients were randomized. Ran- nas spp (2.86%). At the end of 3 days treatment, domization was done with random software to bacteriological cure rates were 86.2%, 87.7% and recruit patients in 1:1:1 ratio into three different 83.3% for patients receiving co-trimoxazole, nor- study groups (Group A, B and C). Randomization floxacin and levofloxacin for 3 days, respectively. was done by a person not involved in the study As per comparisons for bacteriological cure rates and randomized codes were kept in sealed enve- for an individual organism between study groups lopes and opened at the time of patient recruit- have been shown in Figure 2, there was no any ment. Group A patients received co-trimoxazole significant difference noted between the three 960 mg twice a day; Group B patients received treatment groups for bacteriological cure rate of norfloxacin 400 mg twice a day, and Group C pa- an individual organism (p>0.05). 13.6% (6/44), tients received levofloxacin 250 mg once a day for 11.1% (1/9) and 100% (1/1) patients did not re- 3 days. Patients were called for follow-up on day spond to the co-trimoxazole in whom Escherichia 4; urine was collected for culture report. Labora- coli, Klebsiella and Pseudomonas were isolated, re- tory persons from National Accreditation Board spectively. 12.2% (6/49) and 100% (1/1) patients for Testing and Calibration Laboratories (NABL) did not respond to norfloxacin against isolated of the institution were blinded for assigned treat- Escherichia coli and Pseudomonas, respectively. ment. 16.2% (6/37), 28.6% (2/7) and 28.6% (2/7) pa- Outcome measures: Effectiveness of each treatment tients did not respond to levofloxacin in whom group was evaluated by bacteriological cure rate. Escherichia coli, Klebsiella spp and Streptococcus spp Bacteriological cure rate was defined as conver- were isolated, respectively. sion of pre-treatment positive bacterial urine cul- In all treatment groups, proportions of treatment ture into negative urinary culture on day 4. The related adverse drug reactions were found to be treatment failure was defined as positive culture similar (Table 2). There were mild adverse reac- at the end of treatment period. Adverse drug re- tions reported by the patients. No any serious ad- actions were recorded at follow up visit and com- verse drug reactions were reported during the tri- pared between the treatment groups. al. 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 fol- norfloxacin 400 mg twice a day and levofloxacin lowed by vomiting (5.14%) and headache (1.14%). 250 mg once a day for 3 days in patients with un- complicated urinary tract infection. In the present study, Escherichia coli (74.29%) followed by Klebsi- n DISCUSSION ella spp (11.43%), Streptococcus spp (6.29%), Staph- ylococcus saprophyticus (5.14%), and Pseudomonas The present study compared the effectiveness and spp (2.86%) were responsible for causing UTI. tolerability of co-trimoxazole 960 mg twice a day, Gram negative bacteria were predominant com-

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

Table 1 - Baseline characteristics of study participants. Baseline Group A Group B Group C Total characteristics co-trimoxazole norfloxacin levofloxacin N=175 N=58 N=57 N=60 Age (years) 47.68±16.09 47.75±15.66 47.38±13.09 47.93±15.66 Gender Male 25 (43.10) 16 (28.07) 24 (40) 65 (37.14) Female 33 (56.89) 41 (71.93) 36 (60) 110 (62.86) Organism isolated Escherichia coli 44 (75.86) 49 (85.96) 37 (61.67) 130 (74.29) Klebsiella spp 9 (15.52) 4 (7.018) 7 (11.67) 20 (11.43) Pseudomonas spp 1 (1.72) 1 (1.75) 3 (5.00) 5 (2.86) Staphylococcus saprophyticus 2 (3.45) 1 (1.75) 6 (10.00) 9 (5.14) Streptococcus spp 2 (3.45) 2 (3.51) 7 (11.67) 11 (6.29) Data are expressed as mean ± SD and absolute numbers. Values in parenthesis are in percentage. 158 A.V. Vachhani, et al.

pared to Gram positive in causing the UTI [6-9]. day and levofloxacin 250 mg once a day for 5-10 Antimicrobial spectrum of co-trimoxazole in- days are equally effective [4]. Various clinical tri- cludes Gram negative bacilli like Escherichia coli, als showed similar effectiveness of short course Shigella, Salmonella, Proteus mirabilis as well as antimicrobial therapy (3 days) as compared to Gram positive cocci like Staphylococcus aureus standard duration of therapy (5-7 days) [10, 11]. and Streptococcus pneumoniae. Norfloxacin and In the present study, co-trimoxazole, norfloxacin levofloxacin are a first and a second genera- and levofloxacin for 3 days resulted in 86.2%, tion fluoroquinolone, respectively. While their 87.7% and 83.3% bacteriological cure rate, re- antimicrobial activity against Gram negative is spectively. Other studies have reported 55-91% equal, levofloxacin has an extended spectrum bacteriological cure rate with co-trimoxazole against Gram positive and atypical pathogens. In and 87-91% with norfloxacin short course ther- acute and uncomplicated cases, co-trimoxazole apy [12-15]. High level of resistance has been re- 960 mg twice a day, norfloxacin 400 mg twice a ported 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 Group A Group B Group C P value co-trimoxazole norfloxacin levofloxacin N=58 N=57 N=60 Nausea 7 (12.07) 4 (7.02) 2 (3.33) 0.208 Vomiting 3 (5.17) 3 (5.26) 3 (5.00) 0.994 Headache 2 (3.45) 0 (0.00) 0 (0.00) 0.13 Total 12 (18.96) 7 (12.28) 5 (8.33) Data are expressed in absolute numbers, parenthesis shows value in proportion. P value is for Chi-square test. Effectiveness and tolerability of short course co-trimoxazole, norfloxacin and levofloxacin 159

floxacin for Gram negative organisms in patients All the three treatments were well tolerated by the of various regions of India [16-18]. In contrast to study participants, without occurrence of any se- an overall resistance of 13.8%, 12.3% and 16.7% rious adverse events. According to the Infectious reported in the present study, Somashekara et Disease Society of America (IDSA) guidelines, al. reported 75.2%, 62.4% and 51.4% overall re- cotrimoxazole is the current standard therapy for sistance to co-trimoxazole, norfloxacin and levo- uncomplicated community acquired urinary tract floxacin, respectively [17]. infection (CAUTI) in women [19]. Fluoroquino- In the present study, co-trimoxazole resistance lones should be reserved as a second line drug for was found in 13.6% Escherichia coli, 11.1% Klebsi- CAUTI [19]. Findings of the present study recom- ella and 100% Pseudomonas whereas Somashek- mend the use of co-trimoxazole 960 mg twice a ara et al. reported values of 68.8% in Escherichia day as first line drug for the cases of uncompli- coli, 52.2% in Klebsiella spp and 100% in Pseudo- cated UTI. There is no added advantage of using monas spp [17]. With regard to norfloxacin, re- norfloxacin and levofloxacin as first line; they can sistance was found in Escherichia coli [12.2% vs. be used as reserved drug. However, we could not 78.6%] and Pseudomonas [100% vs. 92%] in con- measure the effectiveness of short course therapy trast to the report of Somashekara SC et al. [17]. in preventing UTI relapse. Somashekara SC et al reported 76.5% Escherichia coli, 31% Klebsiella, 82.6% Pseudomonas spp and 53.5% Streptococcus spp whereas the present study n CONCLUSION found 16.2% Escherichia coli, 28.6% Klebsiella spp and 28.6% Streptococcus resistant to levofloxa- In conclusion, co-trimoxazole, norfloxacin and le- cin. All the three patients in whom Pseudomo- vofloxacin can be recommended for a three days nas was isolated got bacteriological eradication period to reduce bacterial overload in UTI. Co- with levofloxacin in the present study (Figure 2). trimoxazole should be given as a first line drug. All these findings suggest that the 3 days ther- There is no added advantage of using norfloxacin apy with co-trimoxazole, norfloxacin and levo- and levofloxacin as first line; they can be used as floxacin are equally effective for bacteriological reserved drug. cure of uncomplicated UTI and that levofloxacin is highly effective, compared to cotrimoxazole Keywords: urinary tract infection (UTI), co-tri- and norfloxacin, for treatment of UTI caused by moxazole, norfloxacin, levofloxacin, short-course pseudomonas. treatment.

SummaRY To compare the bacteriological cure rate of short- was the most common organism isolated followed by course (3-day) treatment of uncomplicated urinary Klebsiella (11.43%), Streptococcus (6.29%), Staphylococcus tract infection (UTI) using co-trimoxazole, norfloxacin saphrophyticus (5.14%), and Pseudomonas (2.86%). At and levofloxacin, patients with uncomplicated UTI the end of three days’ treatment, bacteriological cure were randomized to receive either co-trimoxazole (960 rates were 86.2%, 87.7% and 83.3% for co-trimoxazole, mg) twice a day or norfloxacin (400 mg) twice a day norfloxacin and levofloxacin, respectively (p>0.05). or levofloxacin (250 mg) once a day for three days. Therefore short-course treatment with co-trimoxazole Urine culture was done at the end of treatment and 960 mg twice a day, norfloxacin 400 mg twice a day evaluated for bacteriological cure rate in each group. and levofloxacin 250 mg once a day are almost equally Among a total of 175 patients, Escherichia coli (74.29%) effective for treatment of uncomplicated UTI. 160 A.V. Vachhani, et al.

RIASSUNTO Al fine di confrontare il tasso di eradicazione batteriologica lato con maggiore frequenza cui hanno fatto seguito Kleb- conseguente a un ciclo breve (3 giorni) di trattamento per siella (11,43%), Streptococcus (6,29%), Staphylococcus le infezioni delle vie urinarie (IVU) non complicate con co- saphrophyticus (5,14%), e Pseudomonas (2,86%). Al trimossazolo, norfloxacina e levofloxacina, pazienti affetti termine dei tre giorni di trattamento, i tassi di eradicazione da IVU sono stati randomizzati a ricevere uno dei seguenti batteriologica sono stati pari a 86,2%, 87,7% e 83,3% per trattamenti: cotrimossazolo (960 mg) bid, norfloxacina (400 i pazienti trattati con cotrimossazolo, norfloxacina e levo- mg) bid o levofloxacina (250 mg) qd per tre giorni. L’urino- floxacina, rispettivamente (p>0,05). Quindi, cicli di tratta- coltura è stata effettuata al termine del trattamento e il tas- mento breve con cotrimossazolo 960 mg bid, norfloxacina so di eradicazione batteriologica è stato valutato in ciascun 400 mg bid e levofloxacina 250 mg qd presentano una effi- gruppo di pazienti. Nell’ambito dei 175 pazienti, Escheri- cacia all’incirca sovrapponibile per il trattamento delle IVU chia coli (74,29%) ha rappresentato il microrganismo iso- non complicate.

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