Comparison of Nitrofurantoin and Trimethoprim-Sulphamethoxazole for Long-Term Prophylaxis in Children with Recurrent Urinary Tract Infections

MATERIALS AND METHODS

In this prospective randomized study, 132 patients were consecutively selected from outpatient clinic of pediatric nephrology of Valiasr Hospital in Zanjan, between oct 2004 to oct 2006. All these patients fulfilled the following inclusion criteria: a) previous history of UTI, b) no previous antimicrobial prophylaxis, c) age of patients between 3 months to 12 years, d) normal renal function and e) the patients have one of the following indication for long-term antibacterial prophylaxis include: rUTIs (>3 per year), vesicoureteral reflux (grade I-IV), obsteructive lesion or other anatomical abnormalities, infants less than 1 year of age.

Exclusion criteria were: a) impaired renal function, b) contraindication for taking nitrofurantoin or trimethoprim-sulphamethoxazole such as G6PD deficiency, previous drug reaction and c) any side effects of drugs (gastrointestinal symptoms, rash,…). The patients were randomized to receive either 2 mg kg^-1 day^-1 of trimethoprim as trimethoprim-sulphamethoxazole (n = 66) or 1-2 mg kg^-1 day^-1 of nitrofurantoin (n = 66) as single night dose for 6 months. Age, gender and underlying renal problem were matched in two groups.

After initiation of prophylactic agents, the patients were followed up at monthly interval. The clinical approach during follow up visits consisted of full physical examination, including evaluation of growth. Urine cultures were obtained monthly and during any febrile episode.

Recurrent UTI was defined as growth of at least 100,000 Colony Forming Units (CFU) per mL in urine obtained by bag or a midstream sample with fever (38.0°C or more) or urinary symptom. After eradication of this new infection, they were started on the same prophylactic regimen (if the isolated bacteria sensitive to prophylactic agent), or another regimen (if the isolated bacteria resistance to prophylactic agent).

We removed or taken into consideration, all of excludable predisposing factor for recurrent UTI, such as constipation, fecal incontinence, incomplete bladder emptying, poor perineal hygiene, pin worm, circumsion and etc.

The following data were recorded for each patient: age, sex, indication for prophylaxis, occurrence of UTI, culture and sensitivity results.

Patients were categorized into three different age groups: 3-12 months, 1-5 years, 6-12 years.

The analysis were performed using SPSS (version 11.5). Chi-square test or Fisher's exact test were used for comparison of variables between two groups Differences with a p-value of less than 0.05 were accepted as statistically significant.

RESULTS

A total of 132 patients (96 girls, 36 boys) aged 3 months to 12 years (mean age: 3.8 years) were included in the analysis. Sixty-six children aged 4 months to 11 years (mean age: 4.4 years) were on nitrofurantoin and 66 aged 3 months to 12 years (3.8 years) were on trimethoprim-sulphamethoxazole (TMP-SMX). The two groups were similar, with no statistically significant differences in age, sex, underlying renal problem. The patients characteristics in two groups are summarized in Table 1.

During prophylaxis, the rate of recurrence was 36.2% (n = 17) in nitrofurantoin group compared with 63.8% (n = 30) in the TMP-SMX group (p = 0.029). Nitrofurantoin was more effective than TMP-SMX in preventing recurrent UTI over a six month period (RR = 2.4, 95% CI 1.15 to 5).

According to the age groups, there was no statistical difference in the infection rates in children less than 1 year and in children 6 to 12 years in two groups. However, in children between 1 to 5 years, the number of UTIs is significantly higher in the TMP-SMX group (16 in 39 children vs 7 in 39 children p = 0.046) (Table 2). Nitrofurantoin was more effective than TMP-SMX in preventing recurrent UTI in children 1-5 years (RR = 3.18, 95% CI 1.28 to 8.97).

Gender, underlying renal problem (presence of VUR or other renal abnormalities) did not make any statistically differences on recurrence rates in two groups (Table 2).

Table 1:	Demographic characteristics of two groups
n = Number, VUR = Vesicoureteral reflux, rUTI = recurrent UTI

Table 2:	Recurrence rate according to age, sex and underlying renal problem in two groups
n = Number, VUR = Vesicoureteral reflux

In children taking nitrofurantoin, 37.5% of the infecting organisms causing the UTIs were resistant to the prophylactic agent. In children taking TMP-SMX, 56% of the organisms were resistant to the prophylactic agent. The most common causative agent in recurrent UTI while receiving prophylaxis was E. coli (75%). Sensitivity and resistance of E. coli to TMP-SMX was 47.1 and 52.9%, respectively and to nitrofurantoin was 50 and 50%, respectively.

DISCUSSION

The aims of this study was to compare efficacy of nitrofurantoin and trimethoprim-sulphamethoxazole (TMP-SMX) in preventing recurrent UTI (rUTI) in children. The study showed nitrofurantoin was more effective than TMP-SMX in preventing rUTI in a six month period and this protective effect was more significant in children between 1 to 5 years age compared to other age groups.

In one study the efficacy of nitrofurantoin and trimethoprim-sulphamethoxazole prophylaxis in prevention rUTI was compared. In a six month trial nitrofurantoin was more effective than TMP-SMX in preventing rUTI, but was more likely to be discontinued because of side effects, which were mainly gastrointestinal (Brendstrup et al., 1990). In another study for comparison of nitrofurantoin vs trimethoprim-sulphamethoxazole (TMP-SMX), there were no significant difference between the two groups concerning the recurrence rate. They concluded that nitrofurantoin and TMP-SMX are equally suitable for prophylaxis in rUTI (Vahlensieck and Westenfelder, 1992).

We found important differences related to patient age. In our population, nitrofurantoin was a more suitable antibiotic for prophylaxis of rUTI in children aged 1 to 5 years. In Iran, TMP-SMX is the favorite antimicrobial agent for the empirical treatment of many infections such as urinary tract, respiratory tract and gastrointestinal tract infections. These infections are more common in children aged 1-5 years. Because TMP-SMX is a popular antibiotic in this age group, probably the emergence of TMP-SMX resistant bacteria result in, TMP-SMX be less effective than nitrofurantoin in prevention of rUTI in this age group.

In one study, nitrofurantoin proved to be the most efficient prophylactic drug in patients with abnormal urography and or reflux (Brendstrup et al., 1990). We found no statistically difference between two drugs in preventing rUTI in patients with reflux or the other urinary tract abnormalities.

One of our goals was to define the prevalence of resistance to nitrofurantoin and TMP-SMX among isolated bacteria from patients with rUTI while receiving prophylaxis. there was 37.5% resistance to nitrofurantoin and 56% to TMP-SMX.

In one study patients receiving TMP-SMX prophylaxis had 76% TMP-SMX resistance bacteria during prophylaxis (Brendstrup et al., 1990). In Turkey evaluation of antibiotic resistance of urinary tract pathogens revealed resistance to TMP-SMX in all uropathogens was significant (61.1%) and nitrofurantoin had the lowest resistance rate (5.8%) (Yukser et al., 2006). Children with underlying renal disease, rUTIs, or under antibiotic prophylaxis will have more resistant bacteria causing UTI (Ladhani and Gransden, 2003).

Bacterial resistance to TMP-SMX has in recent year been shown to increase rapidly in many regions of the world (Beets, 2006). The results of our study which are in agreement with those obtained elsewhere emphasize on high TMP-SMX resistance rate. However, in our region the nitrofurantoin resistance rate was also high.

In this study E. coli was the most common causative agent in rUTI While taking prophylaxis. It was reported E. coli was significantly less common in children receiving prophylactic antibiotics (Lutter et al., 2005).

Sensitivity and resistance of E. coli to nitrofurantoin and TMP-SMX in our study was also different from other studies. In was reported, in children sensitivity of E. coli to TMP-SMX 16.4% and to nitrofurantoin 15.9% (Mohanna and Raja'a, 2005). In another study resistance rate of E. coli to TMP-SMX was greater than 20% and to nitrofurantoin was less than 1% (Gaspari et al., 2005) and one research reported overall resistance rate of E. coli to TMP-SMX 21.3% and to nitrofurantoin 1.1% (Zhanel et al., 2006). The reasons for these differences are, children who receive antibiotic for long-term periods are more likely to have resistant E. coli than children have not received prolonged antibiotic treatment. Moreover children with abnormalities of urinary tract are approximately more have resistant E. coli than children without abnormalities of urinary tract (Shakil et al., 2004).

Altogether, there are considerable geographic variation in bacterial patterns and resistance properties depending on local antibacterial prescription practice. There is much evidence suggesting a relationship between prescribing habits and antibiotic resistance. Limitation: The major limitation of this study was, we do not check patient's compliance. recurrent UTI can be results from non-compliance and also from development of bacterial resistance. non-compliance is an important cause for failure of prophylaxis.

CONCLUSION

On the basis of this data, nitrofurantoin has a lower rate of recurrence and causes less emergence of resistance bacteria than TMP-SMX and therefore is more suitable for prevention of recurrent UTI in children.