EFFECTIVENESS OF ANTIMICROBIAL PROPHYLAXIS IN RECURRENT URINARY TRACT INFECTION (UTI) IN CHILDREN

ALSAYED S. ABDELAZEZ*, MAHMOUD M. ALI**, ABDELAZEZ A EMAI**  AND ABDELRAZAK MANSOUR M ALI***
* Department of urology, Al-Azhar University, Damietta, Egypt.
**Department of urology, Al-Azhar University, Cairo, Egypt.
***Department of Pediatrics, Al-Azhar University, Cairo, Egypt.

 

Objective: To evaluate the effectiveness of trimethoprim–sulfamethoxazole (TMP-SMX) as antimicrobial prophylaxis for recurrent UTI in children.

Materials and Methods: From June 1st 2010 to June 1st 2011, 360 children <12 years with proven UTI were treated and divided into two groups: Study group (n=180) who received daily low doses of TMP-SMX suspension (2 mg of trimethoprim + 10 mg of sulfamethoxazole /kg) as a prophylaxis and Control group (n=180) who received placebo and followed-up for 12 months.

Results: The median age at entry was 44± 7.23 months. UTI developed in 8.1% in study group (n=14/172) and 9.8% in placebo group (n=14/172) and the difference was statistically insignificant (P >0.05). The most serious adverse effect was the development of antibiotic resistance organism to TMP-SMX in antibiotic group in comparison to placebo group [71.4% (n=10/14) Vs 17.7% (n=3/17) respectively] (P <0.05).

Conclusion: Low-dose TMP-SMX was not associated with decreased recurrent UTI in predisposed risk children, whereas the risk for antimicrobial resistance was significantly increased.

Keywords: Children, recurrent UTI, antibiotic prophylaxis.

 

BACKGROUND

Urinary tract infection is a very common illness in children, affecting 2% of boys and 8% of girls by the age of 7 years.1 Urinary tract infection is associated with long-term morbidity, with renal damage reported in about 5% of affected children.2 The observation that urinary tract infection and vesicoureteral reflux are associated with renal damage led administration of daily low-dose antibiotics for many years to prevent further urinary tract infections and renal damage in these children.3

It has been recognized that other children without reflux are also at risk for recurrent urinary tract infection and complications, and the use of long-term antibiotics has also been recommended for such children.4 However, since adequately powered and well-designed, placebo-controlled trials of long-term antibiotics for the prevention of urinary tract infection in children are lacking, current clinical practice has been widely questioned.5

 

OBJECTIVE

To evaluate the effectiveness of trimethoprim–sulfamethoxazole (TMP-SMX) as antimicrobial prophylaxis in recurrent UTI in children.

 

PATIENTS AND METHODS

Patients: The present study included 360 children < 12 years who had had at least one symptomatic UTI, selected from Zahra Hospital and King Khalid Hospital in Saudi Arabia at the period from June 1st 2010 to June 1st 2011. They were divided into two groups according to the protocol of treatment: First group (study group) included 180 cases who received daily low doses of TMP-SMX suspension (2 mg of trimethoprim + 10 mg of sulfamethoxazole /kg) as a prophylaxis and Second group (control group) included 180 cases who received placebo and both groups were followed-up for 12 months.

Symptomatic UTI was defined as symptoms consistent with such an infection with a positive urine culture, which was defined as any growth of a pathogenic organism from a suprapubic bladder tap or a colony-forming-unit count of 104 or more of a single organism /ml from a catheter sample or of 105 or more of a single organism /ml from a midstream voided urine sample.

The UTI occurring in the presence of catheterization, functional or anatomical abnormalities of the urinary tract, host with altered defenses, chronic renal failure, mixed pathogen growth, children with contraindication to TMP-SMX were excluded.

 

Study design: Children who had completed short-term treatment, had undergone urinary tract imaging if indicated, and had been clinically asymptomatic before recruitment and randomly assigned to receive either TMP-SMX (antibiotic group) or placebo (matched for color, taste, and texture) during 12 months of follow-up. The administration of the study drug ceased when a symptomatic UTI occurred. Investigators, patients, pharmacy staff and assessors were unaware of study-group assignments. Randomization was performed after parents of all patients provided written informed consent.

 

Urinary tract imaging: Renal tract ultrasonography, radiologic voiding cystourethrography, and renal scintigraphy for recurrent cases of UTI were performed. VUR was graded according to the International Reflux Study.

 

Study medication: After randomization, and at every 3-month visit, the study drug was dispensed, with the single daily dose calculated by volume according to body weight (2 mg of trimethoprim plus 10 mg of sulfamethoxazole /kg of body weight). TMP-SMX was chosen as the study drug because it is consistently recommended as the first-line agent for the prevention of UTI worldwide.

 

Follow-up: Observation of children was seen at 3-month intervals during the 12-month follow-up. At each visit, weight, height, and blood pressure were measured, and outcomes ascertained with the use of patient diaries and medical records.

 

Outcomes: The outcome was symptomatic UTI within 12 months and sensitivity of pathogen to TMP-SMX. The affected patients who complaining from recurrent UTI at any time during the study were discontinued study drug, and routine clinical care was provided.

 

Statistical analysis: We aimed to recruit 360 children (180 in each group) on the basis of a clinically important reduction in the absolute risk of recurrent symptomatic UTI between the two groups during 12 months of follow-up. Subgroup analyses were also conducted with the use of other stratifying variables, including whether the index infection was sensitive or resistant to trimethoprim–sulfamethoxazole. All reported P values are two-sided and not been adjusted for multiple testing.

 

RESULTS

From June 1st 2010 to June 1st 2011, we reviewed the results of urine testing for 940 patients. Of these patients, only 360 were deemed to be eligible to participate in the study and agreed to be involved in our study. A total of 14 children (8 in antibiotic group and 6 in placebo group) were lost to follow-up and complete follow-up data were obtained only for 346 children (96%).

 

Baseline Characteristics:

Equal numbers of children (180) were randomly assigned to each study group. The median age was 44±7.23 months; 63.3% were girls, 34% had vesicoureteral reflux, 89.1% of infections were caused by E coli, and 9.2% of infecting bacteria were resistant to TMP-SMX (Table 1).

 

Outcome follow-up:

During follow-up in the study period, 14 of 360 patients (3.7%) at 12 months were lost follow-up for variants reasons other than the diagnosis of symptomatic urinary tract infection. UTI developed in 8.1% in study group and 9.8% in placebo group and the difference was statistically insignificant (P >0.05) (Table 2).

 

Characteristics of affected patients during follow-up period:

Overall, rates of recurrent symptomatic UTI during follow-up period were reported in 31 of 346 patients (8.95%) without significantly difference between antibiotic and control groups (8.1% vs. 9.8%) and no significant differences were identified in subgroup according to patient’s age, sex, VUR and history of UTI (Table 3).

The effect of TMP-SMX on the prevention of symptomatic UTI did not vary significantly according to any stratifying variable: age, sex, reflux status, history of more than one UTI, or susceptibility of the causative organism for the index infection to TMP-SMX.
 

Causative pathogenic organism and sensitivity

The spectrum of infecting bacteria was significantly different in the two groups, and E coli were identified as the more causative bacterium in both groups (8 of 14 patients (57.1%) in the antibiotic group and in 14 of 17 patients (82.3%) in the placebo group). The development of antibiotic resistant organism to TMP-SMX was significantly increased in the study group compared with placebo group (71.4% Vs17.7% respectively) (P <0.05) (Table 4). Fewer adverse drug reactions occurred in the antibiotic group than in the placebo group, but the differences were not significant.

 

Table (1): Characteristics of the patients at baseline

Characteristics of the patients

Antibiotic (n=180)

Placebo (n=180)

Total (n=360)

N0

%

N0

%

N0

%

Age

Median — mo

46 mo

 

42 mo

 

44 mo

 

Group

1 to <4 yr

72

40

88

48.8

160

44.4

4 to <8 yr

50

27.7

44

24.4

94

26.1

8 to <12 yr

58

32.2

48

26.6

106

29.5

Sex

Female (girl)

112

62.2

116

64.5

228

63.3

Male (boy)

68

37.7

64

35.5

132

36.7

Circumcised

Yes (number of boy)

66

97

111

95.7

177

88.7

No (number of boy)

2

3

5

4.3

7

5.3

History of UTI

Index infection only

68

37.7

72

40

140

77.7

2 infection

84

46.6

82

45.5

166

92.2

≥3 infections

28

15.5

26

14.4

54

30

Symptoms & sign of UTI

Fever

42

23.3

49

27.2

91

25.3

Urinary symptoms

98

54.4

82

45.5

180

50

Non urinary symptoms

76

42.2

96

53.3

172

47.8

Infecting organism

Escherichia coli

162

90

159

88.3

321

89.1

Proteus

9

5

11

6.1

20

5.6

Klebsiella

6

3.33

4

2.2

10

2.8

Other

3

1.67

6

3.3

9

2.5

Sensitivity to TMP-SMX

Sensitive

168

93.3

159

88.3

327

90.8

Resistant

12

6.6

21

11.6

33

9.2

Grade of VUR

None

90

50

96

53.3

186

51.6

I or II

42

23.3

40

22.2

82

22.8

III to V

20

11.1

24

13.3

44

12.2

Unknown

28

15.5

30

16.6

58

16.1

 

Table (2): Outcome follow-up of the patient during the study period

Follow-up

Antibiotic group (n=14)

Placebo group (n=17)

Total

Case

No

%

Lost

Total

Case

no

%

Lost

P Value between number of case

Both group (n=31)

Total

Case

No

%

Lost

3 Month

173

6

3.5

1

172

7

4

1

NS

345

13

3.7

2

6 Month

168

3

1.6

2

165

5

3

2

NS

333

8

2.4

4

9 Month

162

3

1.8

3

160

3

1.8

2

NS

322

6

1.8

5

12 Month

160

2

1.2

2

159

2

1.2

1

NS

319

4

1.2

3

Complete

172

14

8.1

8

174

17

9.7

6

NS

346

31

8.95

14

NS: no significant P value (>0.05).

 

Table (3): Comparative between characteristics of affected patients during follow-up period in antibiotic and placebo group

Affected cases

Antibiotic (n=14)

Placebo (n=17)

N0

%

N0

%

P Value

Total (n=31)

N0

%

Age

1 to <4 yr (n = 160 )

7

4.4

9

5.6

NS

16

10

4 to <8 yr (n = 94 )

4

4.25

4

4.25

NS

8

8.5

4 to <12 yr (n = 106 )

3

2.8

4

3.8

NS

7

6.6

Sex

Female (girl) (n=228 )

11

4.6

12

5.6

NS

23

10

Male (boy) (n=132 )

3

2.3

5

3.8

NS

8

6

Circumcised

Yes (n=177 )

3

1.7

4

2.25

NS

7

3.9

No (n=7 )

0

 

1

14.2

NS

1

14.2

Symptoms & sign of UTI

Fever

3

21.4

6

35.3

NS

91

25.3

Urinary

11

78.6

10

58.8

NS

21

50

Non urinary

3

21.4

6

35.3

NS

10

47.8

Grade of VUR

None (n= 143 )

3

2

4

2.8

NS

7

4.8

I or II (n= 100 )

3

3

3

3

NS

6

6

III to V (n= 59 )

5

8.5

8

13.5

NS

13

22

Unknown (n= 58 )

3

5

2

3.4

NS

5

8.4

NS: no significant P value (>0.05).

 

Table (4): Causative organism and its antibiotic sensitivity in recurrent UTI cases during follow-up of both groups

Character of bacteria

Antibiotic (n = 14)

Placebo (n = 17)

N0

%

N0

%

P Value

Total (n = 31)

N0

%

Infecting organism

Escherichia coli

8

57.1

14

82.3

S

22

70.9

Proteus

3

21.4

2

11.8

NS

5

16.1

Klebsiella

1

7.1

0

0

NS

1

3.2

Other

2

14.2

1

5.9

NS

3

9.7

Sensitivity to TMP-SMX

Sensitive

4

28.6

14

82.3

S

18

58

Resistant

10

71.4

3

17.7

S

13

42

S: significant P value (<0.05). NS: no significant P value (>0.05).

 

 

DISCUSSION

Data from randomized, controlled trials for treatment of children with urinary tract infection have been sparse.6 In the 1970s, four trials of the prophylactic use of antibiotics tended to favor the antibiotic group. However, the combined studies involved only 171 children and the reporting of positive urine cultures rather than clinically important, so that antibiotic prophylaxis was considered to be good clinical practice, and the use of placebo in a trial unethical.7

During the past decade, as a reflection of the growing efficacy of antibiotic prophylaxis for UTI, the results of five randomized, controlled trials of antibiotics in children with and without reflux have been published did not show a benefit for prophylactic antibiotics, with the absolute difference in the risk of symptomatic UTI in the antibiotic group.8.

The agreement of these results with our findings may confirm and strength of recent data-linkage cohort study that showed no benefit from antibiotic prophylaxis. Not only that but also, our study was adequately powered to show a reduction in the rate of symptomatic urinary tract infection. However, all the trials were underpowered, with sample sizes of between 100 and 218 patients.9,10

Other systematic review of 5 randomized controlled trials included a total of 463 children under 16 years, evaluated the use of antibiotics to prevent UTI in children was demonstrated a clinically, but not statistically significant reduced risk of UTI during long-term antibiotic treatment12 so that many researchers concluded that well-designed randomized controlled trails are still needed to evaluate this commonly used intervention in the pediatric population.13

Long-term, low-dose TMP-SMX was associated with decrease in the number of symptomatic UTI in predisposed children. The pattern of recurrence suggested that the benefit of antibiotic therapy was greatest during the first 6 months of treatment, the most likely time for recurrent infection.7

Other studies concluded that in children who have established risk factors for urinary tract infection as female sex, vesicoureteral reflux, and recurrent urinary tract infection, prophylaxis with trimethoprim–sulfamethoxa-zole may be recommended.11

Only 3% of boys in this study were uncircumcised, which reflects the common current rate of circumcision among boys under 12 years in Saudi. Accordingly, the study was not designed to address the effect of trimethoprim–sulfamethoxazole over uncircumcision.

Although trimethoprim–sulfamethoxazole prevented UTI overall, some studies suggest that prolonged administration resulted in changes in the susceptibility of pathogenic bacteria, with an increased risk of symptomatic UTI caused by bacteria that were resistant to TMP-SMX. The results indicated that children with an index infection that was resistant to TMP-SMX might not benefit from such prophylaxis.7

In our study, the rate of resistant of organism to antibiotic was significantly differ between the two study groups which make the risk of infections other than UTI were severe enough to require the use of specific antibiotics in the antibiotic group, it would be reasonable for clinicians to avoid using of TMP-SMX in children who are at high risk for infection although the rate of adverse events did not significantly differ between the two study groups.

The loss of the benefit and the possibility of serious complications from the use of TMP-SMX, such as the Stevens–Johnson syndrome, suggest that the drug should not be used as a prophylactic in children who have had a symptomatic UTI. Poor compliance may be an issue with long-term prophylaxis and may represent patient or parent practice.13,14

One study of resistance found that children who received antibiotics for more than 4 weeks in the previous 6 months were more likely to have resistant E coli than children who had not received prolonged antibiotic treatment.15,16

 

CONCLUSION

Low-dose trimethoprim–sulfamethoxazole was not associated with a decreased number of urinary tract infections in predisposed risk children for recurrent UTI, whereas the risk for antimicrobial resistance was significantly increased.

 

REFERENCES

  1. Jodal U, Lindberg U: Guidelines for management of children with urinary tract infection and vesico-ureteric reflux. Recommendations from a Swedish state-of-the-art conference. Swedish Medical Research Council. Acta. Paediatr. Suppl., 1999; 88: 87–89.

  1. Elder JS, Peters CA, Arant BS Jr, et al: Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J. Urol., 1997, 157: 1846–1851.

  1. Williams G, Lee A, Craig J: Antibiotics for the prevention of urinary tract infection in children. A systematic review of randomized controlled trials. J. Pediatr., 2001, 138: 868–874.

  1. Ghiro L, Cracco AT, Sartor M, et al.: Veneto Urinary Tract Infection Study Group. Retrospective study of children with acute pyelonephritis. Evaluation of bacterial etiology, Antimicrobial susceptibility, drug management and imaging studies. Nephron, 2002, 90: 8–15.

  1. Evidence based clinical guideline for children with first UTI: Health Policy and Clinical Effectiveness Program. Cincinnati, Ohio: Cincinnati Children’s Hospital Medical Center; 1999. Available at: www.cincinnatichildrens.org/svc/dept-div/health-policy/ev-based/uti.htm. Accessed on May 5, 2004.

  1. Caldwell PH, Murphy SB, Butow PN, Craig JC: Clinical trials involving children. Lancet, 2004, 364: 803-11.

  1. Jonathan C Craig, Judy M Simpson, Gabrielle J Williams et al.: Antibiotic prophylaxis and recurrent urinary tract infection in children. N. Engl. J. Med., 2009, 361: 1748-1759.

  1. Roussey-Kesler G, Gadjos V, Idres N et al.: Antibiotic prophylaxis for the prevention of recurrent urinary tract infection in children with low grade vesicoureteral reflux: results from a prospective randomized study. J. Urol., 2008, 179: 674-9.

  1. Williams G, Craig JC: Prevention of recurrent urinary tract infection in children. Curr. Opin. Infect Dis., 2009, 22: 72-6.

  1. Williams GJ, Lee A, Craig JC: Long-term antibiotics for preventing recurrent urinary tract infection in children. Cochrane Database Syst. Rev., 2006, 3: CD 001534.

  1. Conway PH, Cnaan A, Zaoutis T et al.: Recurrent urinary tract infections in children: risk factors and association with prophylactic antimicrobials. JAMA, 2007, 298: 179-86.

  1. Williams G, Lee A, Craig J: Antibiotics for the prevention of urinary tract infection in children. A systematic review of randomized controlled trials. J. Pediatr., 2001, 138: 868–874.

  1. Myers MW, Jick H: Hospitalization for serious blood and skin disorders following use of co-trimoxazole. Br. J. Clin. Pharmacol., 1997, 43: 446-8.

  1. Ghiro L, Cracco AT, Sartor M et al.: Veneto Urinary Tract Infection Study Group. Retrospective study of children with acute pyelonephritis. Evaluation of bacterial etiology, antimicrobial susceptibility, drug management and imaging studies. Nephron, 2002, 90: 8–15.

  1. Bollgren I: Antibacterial prophylaxis in children with urinary tract infection. Acta. Paediatr. Suppl., 1999, 88: 48–52.

  1. Allen UD, Mac Donald N, Fiute L et al.: Risk factors for resistance to “first-line” antimicrobials among urinary tract isolates of Escherichia coli in children. CMAJ, 1999, 160: 1436–1440.

 
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