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What is the role of tacrolimus and pimecrolimus in atopic dermatitis?
When the standard therapies—mild topical corticosteroids and moisturizers—fail in the treatment of atopic dermatitis, patients are left with few proven remedies. The recently introduced topical immunosuppressive treatments—pimecrolimus and tacrolimus—offer an alternative to topical corticosteroids.
Tacrolimus 0.1% (Protopic) appears to be both safe and effective in treating eczema in adults and children (strength of recommendation [SOR]: A). In multiple studies, it has been as effective as potent topical corticosteroids and more effective than mild topical corticosteroids (SOR: A).
Pimecrolimus (Elidel) is more effective than placebo but less effective than potent topical corticosteroids (SOR: A). At this time, no data compare pimecrolimus with mild corticosteroids.
It is important to note that while the studies with the topical immunosuppressive agents included patients with mild to severe atopic dermatitis, none assessed the use of these agents on patients with steroid-refractory atopic dermatitis. The US Food and Drug Administration (FDA) has recommended limited use of these agents in atopic dermatitis because of potential cancer risk (SOR: C).
Benefits of topical immunosuppressants don’t overcome cost and risks
Allen Daugird, MD
University of North Carolina, Chapel Hill
This Clinical Inquiry is an excellent example of how evidence has to be used in a broader context when making clinical decisions, and how evidence is critical in evaluating both benefits and risks of treatments. There seems to be strong evidence that topical immunosuppressants are at least as good as topical steroids, but not better. They apparently do not have a lower risk of infection. We are then left with the only potential benefits being that of not causing HPA axis suppression and possibly not causing skin thinning.
However, this seems to be a small benefit for the enormous cost of these products (more than $60 for a 30-g tube) as well as increased burning on application. In the end, this is all trumped by the recent FDA Advisory warning of a potential cancer risk and advising use only as second-line agents and for short intermittent periods. The practical answer to this question, therefore, is to use the decades-old treatment of higher potency topical steroids with prudence.
Evidence summary
A recent meta-analysis included 25 randomized controlled trials involving tacrolimus and pimecrolimus.1 This review included trials of tacrolimus and pimecrolimus in comparison with placebo, topical corticosteroids of varying strengths, and each other. They reported on both safety and efficacy. Fifteen vehicle-controlled trials of pimecrolimus and tacrolimus were reviewed. Both medications proved to be significantly more effective than the vehicle alone. A total of 3 trials (732 patients) compared tacrolimus 0.1% with potent topical corticosteroids (hydrocortisone butyrate 0.1%, beta-methasone valerate 0.1%) and found it to be as effective as the topical steroids after 3 weeks of application (number needed to treat [NNT]=6).2,3
At both the 0.03% and 0.1% strengths, tacrolimus was found to be more effective than mild topical corticosteroids (hydrocortisone acetate 1%) in 2 studies enrolling a total of 1183 children with moderate to severe atopic dermatitis4,5 (NNT=5 for the tacrolimus 0.03%, and NNT= 3 for tacrolimus 0.1%).6 A randomized, double-blinded, multicenter trial compared the use of pimecrolimus 1% cream with 0.1% triamcinolone acetonide cream and 1% hydrocortisone acetate cream for 658 adults with moderate-to-severe atopic dermatitis.7 The majority of patients used either form of treatment for 1 year.
Although long-term safety and tolerability were similar, topical corticosteroids were more efficacious (NNT=13). Another study compared pimecrolimus 1% with betamethasone valerate 0.1% (a potent corticosteroid) in a study of 87 patients.8 At the end of 3 weeks, the pimecrolimus 1% cream was significantly less effective than betamethasone valerate 0.1% (NNT=4).
In a meta-analysis of 3 randomized studies of head-to-head comparison of pimecrolimus 1% and tacrolimus 0.03% or 0.1% among children and adults, tacrolimus ointment was more effective than pimecrolimus cream at the end of the study for adults (P<.0001), for children with moderate-to-severe disease (P=.04), in the combined analysis (P<.0001), and at week 1 for children with mild disease (P=.04). No significant difference was seen in the incidence of adverse effects, although more pimecrolimus-treated patients withdrew from the studies because of a lack of efficacy (P≤.03) or adverse events (P=.002; pediatric mild).9
The authors of the first meta-analysis concluded that pimecrolimus 1% was more effective compared with placebo, less effective than potent topical corticosteroids, and had yet to be studied in comparison with low-potency topical corticosteroids. Tacrolimus 0.1% was more effective than placebo, more effective than mild corticosteroids, and as effective as potent topical corticosteroids. It was noted that both these agents caused more burning of the skin than topical corticosteroids—pimecrolimus 1% compared with betamethasone valerate 0.1% (number needed to harm [NNH]=50); tacrolimus 0.1% compared with betamethasone valerate 0.1% and hydrocortisone butyrate 0.1% (NNH=3); and tacrolimus 0.03% compared with the mild corticosteroid hydrocortisone acetate 1% (NNH=10). However, there was no significant difference in the rate of skin infections.
Recommendations from others
In 2003, a work group of dermatologists appointed by the president of the American Academy of Dermatology published a technical report on the guidelines of care for atopic dermatitis.10 This group evaluated the effectiveness of several topical treatments for the treatment of atopic dermatitis. They noted that coal tar and its derivatives may reduce the severity of atopic dermatitis symptoms, but there are significant barriers to compliance. The severity of pruritus associated with atopic dermatitis may be reduced with shortterm use of topical doxepin.
Evidence supports the use of emollients in combination with other topical corticosteroid treatments to reduce the severity of atopic dermatitis. However, emollients need frequent application, which may be associated with poor compliance. The work group also concluded that both tacrolimus and pimecrolimus are effective and safe in reducing the severity of atopic dermatitis symptoms for both children and adults up to 1 year of treatment.
In March 2005, the FDA posted a Public Health Advisory and Alerts for Healthcare Professionals regarding the potential cancer risk from the use tacrolimus and pimecrolimus products when applied to the skin to treat atopic dermatitis. These creams will carry a “black box” warning regarding this potential risk. They recommended use only as a second-line therapy, at minimal amounts necessary, and for short periods of time, not continuously. They also recommended against their use for children aged <2 years and for people with diminished immune systems.
1. Ashcroft D, Dimmock P, Garside R, Steinand K, Williams H. Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis of randomized controlled trials. BMJ 2005;330:516. Epub-2005 Feb 24.
2. Reitamo S, Rustin M, Ruzicka T, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone butyrate ointment in adult patients with a topic dermatitis. J Allergy Clin Immunology 2002;109:547-555.
3. FK506 Ointment Study Group. Phase III comparative study of FK506 ointment vs betamethasone valerate ointment in atopic dermatitis (trunk/extremities) [in Japanese]. Nishinihon J Dermatol 1997;59:870-879.
4. Reitamo S, Van Leent EJM, Ho V, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone acetate ointment in children with atopic dermatitis. J Allergy Clin Immunology 2002;109:539-546.
5. Reitamo S, Harper J, Bos JD, et al. 0.03% tacrolimus ointment applied once or twice daily is more efficacious than 1% hydrocortisone acetate in children with moderate to severe atopic dermatitis: results of a randomized double-blind controlled trial. Br J Dermatol 2004;150:554-562.
6. Flaherty RJ. A simple method for evaluating the clinical literature. Fam Pract Manag 2004;47-52.
7. Luger T, Lahta M, Folster-Holst R, et al. Long term safety and tolerability of pimecrolimus cream 1% and topical corticosteroids in adults with moderate to severe atopic dermatitis. J Dermatol Treatment 2004;15:169-178.
8. Luger T, Van Leent EJM, Graeber M, et al. SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis. Br J Dermatol 2001;144:788-794.
9. Paller AS, Lebwohl M, Fleischer AB, Jr, et al. Tacrolimus ointment is more effective than pimecrolimus cream with a similar safety profile in the treatment of atopic dermatitis: results from 3 randomized, comparative studies. J Am Acad Dermatol 2005;52:810-822.
10. American Academy of Dermatology. Guidelines of Care for Atopic Dermatitis. Technical report. 2003. Available at: www.aad.org/public/DermatologyA-Z/atoz_e.htm. Accessed on July 6, 2005.
When the standard therapies—mild topical corticosteroids and moisturizers—fail in the treatment of atopic dermatitis, patients are left with few proven remedies. The recently introduced topical immunosuppressive treatments—pimecrolimus and tacrolimus—offer an alternative to topical corticosteroids.
Tacrolimus 0.1% (Protopic) appears to be both safe and effective in treating eczema in adults and children (strength of recommendation [SOR]: A). In multiple studies, it has been as effective as potent topical corticosteroids and more effective than mild topical corticosteroids (SOR: A).
Pimecrolimus (Elidel) is more effective than placebo but less effective than potent topical corticosteroids (SOR: A). At this time, no data compare pimecrolimus with mild corticosteroids.
It is important to note that while the studies with the topical immunosuppressive agents included patients with mild to severe atopic dermatitis, none assessed the use of these agents on patients with steroid-refractory atopic dermatitis. The US Food and Drug Administration (FDA) has recommended limited use of these agents in atopic dermatitis because of potential cancer risk (SOR: C).
Benefits of topical immunosuppressants don’t overcome cost and risks
Allen Daugird, MD
University of North Carolina, Chapel Hill
This Clinical Inquiry is an excellent example of how evidence has to be used in a broader context when making clinical decisions, and how evidence is critical in evaluating both benefits and risks of treatments. There seems to be strong evidence that topical immunosuppressants are at least as good as topical steroids, but not better. They apparently do not have a lower risk of infection. We are then left with the only potential benefits being that of not causing HPA axis suppression and possibly not causing skin thinning.
However, this seems to be a small benefit for the enormous cost of these products (more than $60 for a 30-g tube) as well as increased burning on application. In the end, this is all trumped by the recent FDA Advisory warning of a potential cancer risk and advising use only as second-line agents and for short intermittent periods. The practical answer to this question, therefore, is to use the decades-old treatment of higher potency topical steroids with prudence.
Evidence summary
A recent meta-analysis included 25 randomized controlled trials involving tacrolimus and pimecrolimus.1 This review included trials of tacrolimus and pimecrolimus in comparison with placebo, topical corticosteroids of varying strengths, and each other. They reported on both safety and efficacy. Fifteen vehicle-controlled trials of pimecrolimus and tacrolimus were reviewed. Both medications proved to be significantly more effective than the vehicle alone. A total of 3 trials (732 patients) compared tacrolimus 0.1% with potent topical corticosteroids (hydrocortisone butyrate 0.1%, beta-methasone valerate 0.1%) and found it to be as effective as the topical steroids after 3 weeks of application (number needed to treat [NNT]=6).2,3
At both the 0.03% and 0.1% strengths, tacrolimus was found to be more effective than mild topical corticosteroids (hydrocortisone acetate 1%) in 2 studies enrolling a total of 1183 children with moderate to severe atopic dermatitis4,5 (NNT=5 for the tacrolimus 0.03%, and NNT= 3 for tacrolimus 0.1%).6 A randomized, double-blinded, multicenter trial compared the use of pimecrolimus 1% cream with 0.1% triamcinolone acetonide cream and 1% hydrocortisone acetate cream for 658 adults with moderate-to-severe atopic dermatitis.7 The majority of patients used either form of treatment for 1 year.
Although long-term safety and tolerability were similar, topical corticosteroids were more efficacious (NNT=13). Another study compared pimecrolimus 1% with betamethasone valerate 0.1% (a potent corticosteroid) in a study of 87 patients.8 At the end of 3 weeks, the pimecrolimus 1% cream was significantly less effective than betamethasone valerate 0.1% (NNT=4).
In a meta-analysis of 3 randomized studies of head-to-head comparison of pimecrolimus 1% and tacrolimus 0.03% or 0.1% among children and adults, tacrolimus ointment was more effective than pimecrolimus cream at the end of the study for adults (P<.0001), for children with moderate-to-severe disease (P=.04), in the combined analysis (P<.0001), and at week 1 for children with mild disease (P=.04). No significant difference was seen in the incidence of adverse effects, although more pimecrolimus-treated patients withdrew from the studies because of a lack of efficacy (P≤.03) or adverse events (P=.002; pediatric mild).9
The authors of the first meta-analysis concluded that pimecrolimus 1% was more effective compared with placebo, less effective than potent topical corticosteroids, and had yet to be studied in comparison with low-potency topical corticosteroids. Tacrolimus 0.1% was more effective than placebo, more effective than mild corticosteroids, and as effective as potent topical corticosteroids. It was noted that both these agents caused more burning of the skin than topical corticosteroids—pimecrolimus 1% compared with betamethasone valerate 0.1% (number needed to harm [NNH]=50); tacrolimus 0.1% compared with betamethasone valerate 0.1% and hydrocortisone butyrate 0.1% (NNH=3); and tacrolimus 0.03% compared with the mild corticosteroid hydrocortisone acetate 1% (NNH=10). However, there was no significant difference in the rate of skin infections.
Recommendations from others
In 2003, a work group of dermatologists appointed by the president of the American Academy of Dermatology published a technical report on the guidelines of care for atopic dermatitis.10 This group evaluated the effectiveness of several topical treatments for the treatment of atopic dermatitis. They noted that coal tar and its derivatives may reduce the severity of atopic dermatitis symptoms, but there are significant barriers to compliance. The severity of pruritus associated with atopic dermatitis may be reduced with shortterm use of topical doxepin.
Evidence supports the use of emollients in combination with other topical corticosteroid treatments to reduce the severity of atopic dermatitis. However, emollients need frequent application, which may be associated with poor compliance. The work group also concluded that both tacrolimus and pimecrolimus are effective and safe in reducing the severity of atopic dermatitis symptoms for both children and adults up to 1 year of treatment.
In March 2005, the FDA posted a Public Health Advisory and Alerts for Healthcare Professionals regarding the potential cancer risk from the use tacrolimus and pimecrolimus products when applied to the skin to treat atopic dermatitis. These creams will carry a “black box” warning regarding this potential risk. They recommended use only as a second-line therapy, at minimal amounts necessary, and for short periods of time, not continuously. They also recommended against their use for children aged <2 years and for people with diminished immune systems.
When the standard therapies—mild topical corticosteroids and moisturizers—fail in the treatment of atopic dermatitis, patients are left with few proven remedies. The recently introduced topical immunosuppressive treatments—pimecrolimus and tacrolimus—offer an alternative to topical corticosteroids.
Tacrolimus 0.1% (Protopic) appears to be both safe and effective in treating eczema in adults and children (strength of recommendation [SOR]: A). In multiple studies, it has been as effective as potent topical corticosteroids and more effective than mild topical corticosteroids (SOR: A).
Pimecrolimus (Elidel) is more effective than placebo but less effective than potent topical corticosteroids (SOR: A). At this time, no data compare pimecrolimus with mild corticosteroids.
It is important to note that while the studies with the topical immunosuppressive agents included patients with mild to severe atopic dermatitis, none assessed the use of these agents on patients with steroid-refractory atopic dermatitis. The US Food and Drug Administration (FDA) has recommended limited use of these agents in atopic dermatitis because of potential cancer risk (SOR: C).
Benefits of topical immunosuppressants don’t overcome cost and risks
Allen Daugird, MD
University of North Carolina, Chapel Hill
This Clinical Inquiry is an excellent example of how evidence has to be used in a broader context when making clinical decisions, and how evidence is critical in evaluating both benefits and risks of treatments. There seems to be strong evidence that topical immunosuppressants are at least as good as topical steroids, but not better. They apparently do not have a lower risk of infection. We are then left with the only potential benefits being that of not causing HPA axis suppression and possibly not causing skin thinning.
However, this seems to be a small benefit for the enormous cost of these products (more than $60 for a 30-g tube) as well as increased burning on application. In the end, this is all trumped by the recent FDA Advisory warning of a potential cancer risk and advising use only as second-line agents and for short intermittent periods. The practical answer to this question, therefore, is to use the decades-old treatment of higher potency topical steroids with prudence.
Evidence summary
A recent meta-analysis included 25 randomized controlled trials involving tacrolimus and pimecrolimus.1 This review included trials of tacrolimus and pimecrolimus in comparison with placebo, topical corticosteroids of varying strengths, and each other. They reported on both safety and efficacy. Fifteen vehicle-controlled trials of pimecrolimus and tacrolimus were reviewed. Both medications proved to be significantly more effective than the vehicle alone. A total of 3 trials (732 patients) compared tacrolimus 0.1% with potent topical corticosteroids (hydrocortisone butyrate 0.1%, beta-methasone valerate 0.1%) and found it to be as effective as the topical steroids after 3 weeks of application (number needed to treat [NNT]=6).2,3
At both the 0.03% and 0.1% strengths, tacrolimus was found to be more effective than mild topical corticosteroids (hydrocortisone acetate 1%) in 2 studies enrolling a total of 1183 children with moderate to severe atopic dermatitis4,5 (NNT=5 for the tacrolimus 0.03%, and NNT= 3 for tacrolimus 0.1%).6 A randomized, double-blinded, multicenter trial compared the use of pimecrolimus 1% cream with 0.1% triamcinolone acetonide cream and 1% hydrocortisone acetate cream for 658 adults with moderate-to-severe atopic dermatitis.7 The majority of patients used either form of treatment for 1 year.
Although long-term safety and tolerability were similar, topical corticosteroids were more efficacious (NNT=13). Another study compared pimecrolimus 1% with betamethasone valerate 0.1% (a potent corticosteroid) in a study of 87 patients.8 At the end of 3 weeks, the pimecrolimus 1% cream was significantly less effective than betamethasone valerate 0.1% (NNT=4).
In a meta-analysis of 3 randomized studies of head-to-head comparison of pimecrolimus 1% and tacrolimus 0.03% or 0.1% among children and adults, tacrolimus ointment was more effective than pimecrolimus cream at the end of the study for adults (P<.0001), for children with moderate-to-severe disease (P=.04), in the combined analysis (P<.0001), and at week 1 for children with mild disease (P=.04). No significant difference was seen in the incidence of adverse effects, although more pimecrolimus-treated patients withdrew from the studies because of a lack of efficacy (P≤.03) or adverse events (P=.002; pediatric mild).9
The authors of the first meta-analysis concluded that pimecrolimus 1% was more effective compared with placebo, less effective than potent topical corticosteroids, and had yet to be studied in comparison with low-potency topical corticosteroids. Tacrolimus 0.1% was more effective than placebo, more effective than mild corticosteroids, and as effective as potent topical corticosteroids. It was noted that both these agents caused more burning of the skin than topical corticosteroids—pimecrolimus 1% compared with betamethasone valerate 0.1% (number needed to harm [NNH]=50); tacrolimus 0.1% compared with betamethasone valerate 0.1% and hydrocortisone butyrate 0.1% (NNH=3); and tacrolimus 0.03% compared with the mild corticosteroid hydrocortisone acetate 1% (NNH=10). However, there was no significant difference in the rate of skin infections.
Recommendations from others
In 2003, a work group of dermatologists appointed by the president of the American Academy of Dermatology published a technical report on the guidelines of care for atopic dermatitis.10 This group evaluated the effectiveness of several topical treatments for the treatment of atopic dermatitis. They noted that coal tar and its derivatives may reduce the severity of atopic dermatitis symptoms, but there are significant barriers to compliance. The severity of pruritus associated with atopic dermatitis may be reduced with shortterm use of topical doxepin.
Evidence supports the use of emollients in combination with other topical corticosteroid treatments to reduce the severity of atopic dermatitis. However, emollients need frequent application, which may be associated with poor compliance. The work group also concluded that both tacrolimus and pimecrolimus are effective and safe in reducing the severity of atopic dermatitis symptoms for both children and adults up to 1 year of treatment.
In March 2005, the FDA posted a Public Health Advisory and Alerts for Healthcare Professionals regarding the potential cancer risk from the use tacrolimus and pimecrolimus products when applied to the skin to treat atopic dermatitis. These creams will carry a “black box” warning regarding this potential risk. They recommended use only as a second-line therapy, at minimal amounts necessary, and for short periods of time, not continuously. They also recommended against their use for children aged <2 years and for people with diminished immune systems.
1. Ashcroft D, Dimmock P, Garside R, Steinand K, Williams H. Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis of randomized controlled trials. BMJ 2005;330:516. Epub-2005 Feb 24.
2. Reitamo S, Rustin M, Ruzicka T, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone butyrate ointment in adult patients with a topic dermatitis. J Allergy Clin Immunology 2002;109:547-555.
3. FK506 Ointment Study Group. Phase III comparative study of FK506 ointment vs betamethasone valerate ointment in atopic dermatitis (trunk/extremities) [in Japanese]. Nishinihon J Dermatol 1997;59:870-879.
4. Reitamo S, Van Leent EJM, Ho V, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone acetate ointment in children with atopic dermatitis. J Allergy Clin Immunology 2002;109:539-546.
5. Reitamo S, Harper J, Bos JD, et al. 0.03% tacrolimus ointment applied once or twice daily is more efficacious than 1% hydrocortisone acetate in children with moderate to severe atopic dermatitis: results of a randomized double-blind controlled trial. Br J Dermatol 2004;150:554-562.
6. Flaherty RJ. A simple method for evaluating the clinical literature. Fam Pract Manag 2004;47-52.
7. Luger T, Lahta M, Folster-Holst R, et al. Long term safety and tolerability of pimecrolimus cream 1% and topical corticosteroids in adults with moderate to severe atopic dermatitis. J Dermatol Treatment 2004;15:169-178.
8. Luger T, Van Leent EJM, Graeber M, et al. SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis. Br J Dermatol 2001;144:788-794.
9. Paller AS, Lebwohl M, Fleischer AB, Jr, et al. Tacrolimus ointment is more effective than pimecrolimus cream with a similar safety profile in the treatment of atopic dermatitis: results from 3 randomized, comparative studies. J Am Acad Dermatol 2005;52:810-822.
10. American Academy of Dermatology. Guidelines of Care for Atopic Dermatitis. Technical report. 2003. Available at: www.aad.org/public/DermatologyA-Z/atoz_e.htm. Accessed on July 6, 2005.
1. Ashcroft D, Dimmock P, Garside R, Steinand K, Williams H. Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis of randomized controlled trials. BMJ 2005;330:516. Epub-2005 Feb 24.
2. Reitamo S, Rustin M, Ruzicka T, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone butyrate ointment in adult patients with a topic dermatitis. J Allergy Clin Immunology 2002;109:547-555.
3. FK506 Ointment Study Group. Phase III comparative study of FK506 ointment vs betamethasone valerate ointment in atopic dermatitis (trunk/extremities) [in Japanese]. Nishinihon J Dermatol 1997;59:870-879.
4. Reitamo S, Van Leent EJM, Ho V, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone acetate ointment in children with atopic dermatitis. J Allergy Clin Immunology 2002;109:539-546.
5. Reitamo S, Harper J, Bos JD, et al. 0.03% tacrolimus ointment applied once or twice daily is more efficacious than 1% hydrocortisone acetate in children with moderate to severe atopic dermatitis: results of a randomized double-blind controlled trial. Br J Dermatol 2004;150:554-562.
6. Flaherty RJ. A simple method for evaluating the clinical literature. Fam Pract Manag 2004;47-52.
7. Luger T, Lahta M, Folster-Holst R, et al. Long term safety and tolerability of pimecrolimus cream 1% and topical corticosteroids in adults with moderate to severe atopic dermatitis. J Dermatol Treatment 2004;15:169-178.
8. Luger T, Van Leent EJM, Graeber M, et al. SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis. Br J Dermatol 2001;144:788-794.
9. Paller AS, Lebwohl M, Fleischer AB, Jr, et al. Tacrolimus ointment is more effective than pimecrolimus cream with a similar safety profile in the treatment of atopic dermatitis: results from 3 randomized, comparative studies. J Am Acad Dermatol 2005;52:810-822.
10. American Academy of Dermatology. Guidelines of Care for Atopic Dermatitis. Technical report. 2003. Available at: www.aad.org/public/DermatologyA-Z/atoz_e.htm. Accessed on July 6, 2005.
Evidence-based answers from the Family Physicians Inquiries Network
Do antibiotics prevent recurrent UTI in children with anatomic abnormalities?
Evidence is insufficient to recommend for or against antibiotic prophylaxis to prevent recurrent urinary tract infections (UTI) in children with anatomic abnormalities. Guidelines acknowledge this lack of evidence, but still recommend using prophylactic antibiotics in children with vesiculoureteral reflux (strength of recommendation: B, based on poor-quality or inconclusive cohort and randomized controlled studies).1-3 No controlled, prospective studies have examined the effectiveness of prophylactic antibiotics to prevent UTI recurrence or renal scarring.
Evidence summary
Recommendations about antibiotic prophylaxis are based on several premises. Reflux predisposes children to acute pyelonephritis; reflux plus infection leads to reflux nephropathy and ultimately to renal scarring. In theory, if antibiotics could be initiated at the appropriate time and be maintained until reflux resolves, we could successfully prevent infection and scarring.4
A recent systematic review evaluated the use of antibiotics to prevent UTI in children.5 This review of 5 randomized controlled trials included a total of 463 children between the ages of 2 months to 16 years. Three out of 5 trials evaluated the effectiveness of antibiotic treatment for 2 to 6 months to prevent subsequent off-treatment recurrence. The 2 smaller trials (n=71) evaluated the use of low-dose long-term antibiotics to prevent UTI.
There was a clinically, but not statistically, significant trend towards reduced risk of UTI during long-term antibiotic treatment (risk reduction [RR]=0.31; 95% confidence interval [CI]=0.10–1.00); however, no sustained benefit was seen once antibiotics were stopped (RR=0.79; 95% CI, 0.61–1.02). There were many problems with the methodological quality of these trials, including significant heterogeneity. The researchers concluded that well-designed randomized controlled trails are still needed to evaluate this commonly used intervention in the pediatric population.4 Benefits for long-term prophylaxis are even less clear in children with low-grade reflux (I–II).5 Furthermore, no randomized controlled trials assess whether prophylaxis prevents the development of new renal scars in children.6
In addition, a recent systematic review of studies done in children with normal urinary tracts, as well in children with neurogenic bladders, found that the available evidence is of low quality. Only 6 out of 31 potential studies fulfilled the inclusion criteria. These were small (mean sample size was 28), and the quality scores of all 6 trials were low, indicating that the evidence may be unreliable.7
Two of 3 studies done in children with normal urinary tracts demonstrated statistically significant higher rates of UTI recurrence in control groups compared with treatment groups receiving 6 to 10 months of either nitrofurantoin or cotrimoxazole (RR=24–31). The third study showed no difference between groups.
One of 2 trials in children with neurogenic bladder demonstrated higher recurrence rates of 2.9 per 10 patient years for patients receiving antibiotics compared with 1.5 in the untreated group. The other study showed lower recurrence rates of 17.1 for patients receiving antibiotics, compared with 33 in the untreated group.7Neither of these findings were statistically significant.
A different meta-analysis of 15 controlled clinical trials in children with neurogenic bladder due to spinal cord dysfunction. This analysis showed that antibiotic prophylaxis was associated with a reduction in asymptomatic bacteruria among children with acute spinal cord injury (P<.05), but there was no significant reduction in symptomatic infections. Prophylaxis resulted in an approximately twofold increase in antimicrobial-resistant bacteria. The researchers concluded that although a clinically important effect has not been excluded, the regular use of antimicrobial prophylaxis for most patients who have neurogenic bladder caused by spinal cord dysfunction is not supported at this time.8
Poor compliance may be an issue with long-term prophylaxis and may represent patient or parent practice.9One study found that in children taking low-dose trimethoprim, 97% of the parents reported giving antibiotics on daily basis, but in 31% of subjects, trimethoprim was not detectable in the urine.6Risk of prophylaxis includes nausea, vomiting, and rash in 8% to 10% of patients; development of resistant organisms; and change in indigenous microflora.6 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 Escherichia coli isolates than children who had not received prolonged antibiotic treatment (odds ratio [OR]=13.9; 95% CI, 8.2–23.5). Children with abnormalities of the genitourinary tract were approximately 4 times more likely to have resistant isolates of E coli than children without abnormalities of the genitourinary tract (OR=3.9; 95% CI, 2.7–5.7).11
Recommendations from others
The American Academy of Pediatrics, American Urological Association, and the Swedish Medical Research Council guidelines recommend prophylaxis for children with reflux ( Table ), but they all acknowledge that the recommendations are not supported by well-designed randomized controlled trials.1-3 No guidelines are available for children with neurogenic bladder and recurrent urinary tract infections.7
TABLE
Oral antibiotics for prophylaxis of urinary tract infections in children
| Antimicrobial | Prophylaxis dosage |
|---|---|
| Trimethoprim/sulfamethoxazole (TMP/SMX) (Bactrim, Septra) | 2 mg of TMP, 10 mg of SMX per kg as single bedtime or 5 mg of TMP, 25 mg of SMX per kg twice per week |
| Nitrofurantoin (Macrodantin) | 1–2 mg/kg as single daily dose |
| Cephalexin (Keflex) | 10 mg/kg as single daily dose |
| Amoxicillin | 10 mg/kg as single daily dose |
| Sulfisoxazole (Gantrisin Pedatric) | 10–20 mg/kg divided every 12h |
| Modified with permission from AAP 1999;3Allen et al1999.10 | |
UTI prevention most successful when the child exhibits efficiency of voiding
William R Strand MD
Division of Pediatric Urology, University of Texas Southwestern Medical Center, Dallas
The relative benefit of antibiotic prophylaxis in prevention of UTI in children with anatomic abnormalities like vesicoureteral reflux could best be determined if all other risk factors for UTI were controlled. Unfortunately, these other factors are often more significant in promoting UTI than is reflux, and they are also more difficult to quantify. Voiding dysfunction and constipation can both increase bladder storage pressures and postvoid residual urine volumes, and as such greatly predispose children for UTI. Furthermore, a distended colon provides an abundant reservoir of pathogens with an array of uropathogenic virulence factors.
Published reports have failed to detect significant benefit for antibiotic prophylaxis in part because the children studied possess varying risks for UTI. Prevention of UTI is most successful when the child exhibits efficiency of voiding and elimination. Clinical practice in pediatric urology advocates use of antibiotic prophylaxis in children with vesicoureteral reflux. Reflux should be suspected in children with hydroureter, multicystic renal dysplasia, ureteral duplication, and ureterocele.
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.
2. 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.
3. Practice parameter: the diagnosis treatment and evaluation of the initial urinary tract infection in febrile infants and young children. American Academy of Pediatrics. Committee on Quality Improvement. Subcommittee on Urinary Tract Infection. Pediatrics 1999;103:843-852.
4. Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, Wald ER. Imaging studies after a first febrile urinary tract infection in young children. N Engl J Med 2003;348:195-202.
5. 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.
6. Bollgren I. Antibacterial prophylaxis in children with urinary tract infection. Acta Paediatr Suppl 1999;88:48-52.
7. Le Saux N, Pham B, Moher D. Evaluating the benefits of antimicrobial prophylaxis to prevent urinary tract infections in children: a systematic review. CMAJ 2000;163:523-529.
8. Morton SC, Shekelle PG, Adams JL, et al. Antimicrobial prophylaxis for urinary tract infection in persons with spinal cord dysfunction. Arch Phys Med Rehabil 2002;83:129-138.
9. Ghiro L, Cracco AT, Sartor M, Comacchio S, Zacchello G, Dall’Amico R. 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.
10. 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.
11. Allen UD, MacDonald N, Fiute L, Chan F, Stephen D. Risk factors for resistance to “first-line” antimicrobials among urinary tract isolates of Escherichia coli in children. CMAJ 1999;160:1436-1440.
Evidence is insufficient to recommend for or against antibiotic prophylaxis to prevent recurrent urinary tract infections (UTI) in children with anatomic abnormalities. Guidelines acknowledge this lack of evidence, but still recommend using prophylactic antibiotics in children with vesiculoureteral reflux (strength of recommendation: B, based on poor-quality or inconclusive cohort and randomized controlled studies).1-3 No controlled, prospective studies have examined the effectiveness of prophylactic antibiotics to prevent UTI recurrence or renal scarring.
Evidence summary
Recommendations about antibiotic prophylaxis are based on several premises. Reflux predisposes children to acute pyelonephritis; reflux plus infection leads to reflux nephropathy and ultimately to renal scarring. In theory, if antibiotics could be initiated at the appropriate time and be maintained until reflux resolves, we could successfully prevent infection and scarring.4
A recent systematic review evaluated the use of antibiotics to prevent UTI in children.5 This review of 5 randomized controlled trials included a total of 463 children between the ages of 2 months to 16 years. Three out of 5 trials evaluated the effectiveness of antibiotic treatment for 2 to 6 months to prevent subsequent off-treatment recurrence. The 2 smaller trials (n=71) evaluated the use of low-dose long-term antibiotics to prevent UTI.
There was a clinically, but not statistically, significant trend towards reduced risk of UTI during long-term antibiotic treatment (risk reduction [RR]=0.31; 95% confidence interval [CI]=0.10–1.00); however, no sustained benefit was seen once antibiotics were stopped (RR=0.79; 95% CI, 0.61–1.02). There were many problems with the methodological quality of these trials, including significant heterogeneity. The researchers concluded that well-designed randomized controlled trails are still needed to evaluate this commonly used intervention in the pediatric population.4 Benefits for long-term prophylaxis are even less clear in children with low-grade reflux (I–II).5 Furthermore, no randomized controlled trials assess whether prophylaxis prevents the development of new renal scars in children.6
In addition, a recent systematic review of studies done in children with normal urinary tracts, as well in children with neurogenic bladders, found that the available evidence is of low quality. Only 6 out of 31 potential studies fulfilled the inclusion criteria. These were small (mean sample size was 28), and the quality scores of all 6 trials were low, indicating that the evidence may be unreliable.7
Two of 3 studies done in children with normal urinary tracts demonstrated statistically significant higher rates of UTI recurrence in control groups compared with treatment groups receiving 6 to 10 months of either nitrofurantoin or cotrimoxazole (RR=24–31). The third study showed no difference between groups.
One of 2 trials in children with neurogenic bladder demonstrated higher recurrence rates of 2.9 per 10 patient years for patients receiving antibiotics compared with 1.5 in the untreated group. The other study showed lower recurrence rates of 17.1 for patients receiving antibiotics, compared with 33 in the untreated group.7Neither of these findings were statistically significant.
A different meta-analysis of 15 controlled clinical trials in children with neurogenic bladder due to spinal cord dysfunction. This analysis showed that antibiotic prophylaxis was associated with a reduction in asymptomatic bacteruria among children with acute spinal cord injury (P<.05), but there was no significant reduction in symptomatic infections. Prophylaxis resulted in an approximately twofold increase in antimicrobial-resistant bacteria. The researchers concluded that although a clinically important effect has not been excluded, the regular use of antimicrobial prophylaxis for most patients who have neurogenic bladder caused by spinal cord dysfunction is not supported at this time.8
Poor compliance may be an issue with long-term prophylaxis and may represent patient or parent practice.9One study found that in children taking low-dose trimethoprim, 97% of the parents reported giving antibiotics on daily basis, but in 31% of subjects, trimethoprim was not detectable in the urine.6Risk of prophylaxis includes nausea, vomiting, and rash in 8% to 10% of patients; development of resistant organisms; and change in indigenous microflora.6 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 Escherichia coli isolates than children who had not received prolonged antibiotic treatment (odds ratio [OR]=13.9; 95% CI, 8.2–23.5). Children with abnormalities of the genitourinary tract were approximately 4 times more likely to have resistant isolates of E coli than children without abnormalities of the genitourinary tract (OR=3.9; 95% CI, 2.7–5.7).11
Recommendations from others
The American Academy of Pediatrics, American Urological Association, and the Swedish Medical Research Council guidelines recommend prophylaxis for children with reflux ( Table ), but they all acknowledge that the recommendations are not supported by well-designed randomized controlled trials.1-3 No guidelines are available for children with neurogenic bladder and recurrent urinary tract infections.7
TABLE
Oral antibiotics for prophylaxis of urinary tract infections in children
| Antimicrobial | Prophylaxis dosage |
|---|---|
| Trimethoprim/sulfamethoxazole (TMP/SMX) (Bactrim, Septra) | 2 mg of TMP, 10 mg of SMX per kg as single bedtime or 5 mg of TMP, 25 mg of SMX per kg twice per week |
| Nitrofurantoin (Macrodantin) | 1–2 mg/kg as single daily dose |
| Cephalexin (Keflex) | 10 mg/kg as single daily dose |
| Amoxicillin | 10 mg/kg as single daily dose |
| Sulfisoxazole (Gantrisin Pedatric) | 10–20 mg/kg divided every 12h |
| Modified with permission from AAP 1999;3Allen et al1999.10 | |
UTI prevention most successful when the child exhibits efficiency of voiding
William R Strand MD
Division of Pediatric Urology, University of Texas Southwestern Medical Center, Dallas
The relative benefit of antibiotic prophylaxis in prevention of UTI in children with anatomic abnormalities like vesicoureteral reflux could best be determined if all other risk factors for UTI were controlled. Unfortunately, these other factors are often more significant in promoting UTI than is reflux, and they are also more difficult to quantify. Voiding dysfunction and constipation can both increase bladder storage pressures and postvoid residual urine volumes, and as such greatly predispose children for UTI. Furthermore, a distended colon provides an abundant reservoir of pathogens with an array of uropathogenic virulence factors.
Published reports have failed to detect significant benefit for antibiotic prophylaxis in part because the children studied possess varying risks for UTI. Prevention of UTI is most successful when the child exhibits efficiency of voiding and elimination. Clinical practice in pediatric urology advocates use of antibiotic prophylaxis in children with vesicoureteral reflux. Reflux should be suspected in children with hydroureter, multicystic renal dysplasia, ureteral duplication, and ureterocele.
Evidence is insufficient to recommend for or against antibiotic prophylaxis to prevent recurrent urinary tract infections (UTI) in children with anatomic abnormalities. Guidelines acknowledge this lack of evidence, but still recommend using prophylactic antibiotics in children with vesiculoureteral reflux (strength of recommendation: B, based on poor-quality or inconclusive cohort and randomized controlled studies).1-3 No controlled, prospective studies have examined the effectiveness of prophylactic antibiotics to prevent UTI recurrence or renal scarring.
Evidence summary
Recommendations about antibiotic prophylaxis are based on several premises. Reflux predisposes children to acute pyelonephritis; reflux plus infection leads to reflux nephropathy and ultimately to renal scarring. In theory, if antibiotics could be initiated at the appropriate time and be maintained until reflux resolves, we could successfully prevent infection and scarring.4
A recent systematic review evaluated the use of antibiotics to prevent UTI in children.5 This review of 5 randomized controlled trials included a total of 463 children between the ages of 2 months to 16 years. Three out of 5 trials evaluated the effectiveness of antibiotic treatment for 2 to 6 months to prevent subsequent off-treatment recurrence. The 2 smaller trials (n=71) evaluated the use of low-dose long-term antibiotics to prevent UTI.
There was a clinically, but not statistically, significant trend towards reduced risk of UTI during long-term antibiotic treatment (risk reduction [RR]=0.31; 95% confidence interval [CI]=0.10–1.00); however, no sustained benefit was seen once antibiotics were stopped (RR=0.79; 95% CI, 0.61–1.02). There were many problems with the methodological quality of these trials, including significant heterogeneity. The researchers concluded that well-designed randomized controlled trails are still needed to evaluate this commonly used intervention in the pediatric population.4 Benefits for long-term prophylaxis are even less clear in children with low-grade reflux (I–II).5 Furthermore, no randomized controlled trials assess whether prophylaxis prevents the development of new renal scars in children.6
In addition, a recent systematic review of studies done in children with normal urinary tracts, as well in children with neurogenic bladders, found that the available evidence is of low quality. Only 6 out of 31 potential studies fulfilled the inclusion criteria. These were small (mean sample size was 28), and the quality scores of all 6 trials were low, indicating that the evidence may be unreliable.7
Two of 3 studies done in children with normal urinary tracts demonstrated statistically significant higher rates of UTI recurrence in control groups compared with treatment groups receiving 6 to 10 months of either nitrofurantoin or cotrimoxazole (RR=24–31). The third study showed no difference between groups.
One of 2 trials in children with neurogenic bladder demonstrated higher recurrence rates of 2.9 per 10 patient years for patients receiving antibiotics compared with 1.5 in the untreated group. The other study showed lower recurrence rates of 17.1 for patients receiving antibiotics, compared with 33 in the untreated group.7Neither of these findings were statistically significant.
A different meta-analysis of 15 controlled clinical trials in children with neurogenic bladder due to spinal cord dysfunction. This analysis showed that antibiotic prophylaxis was associated with a reduction in asymptomatic bacteruria among children with acute spinal cord injury (P<.05), but there was no significant reduction in symptomatic infections. Prophylaxis resulted in an approximately twofold increase in antimicrobial-resistant bacteria. The researchers concluded that although a clinically important effect has not been excluded, the regular use of antimicrobial prophylaxis for most patients who have neurogenic bladder caused by spinal cord dysfunction is not supported at this time.8
Poor compliance may be an issue with long-term prophylaxis and may represent patient or parent practice.9One study found that in children taking low-dose trimethoprim, 97% of the parents reported giving antibiotics on daily basis, but in 31% of subjects, trimethoprim was not detectable in the urine.6Risk of prophylaxis includes nausea, vomiting, and rash in 8% to 10% of patients; development of resistant organisms; and change in indigenous microflora.6 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 Escherichia coli isolates than children who had not received prolonged antibiotic treatment (odds ratio [OR]=13.9; 95% CI, 8.2–23.5). Children with abnormalities of the genitourinary tract were approximately 4 times more likely to have resistant isolates of E coli than children without abnormalities of the genitourinary tract (OR=3.9; 95% CI, 2.7–5.7).11
Recommendations from others
The American Academy of Pediatrics, American Urological Association, and the Swedish Medical Research Council guidelines recommend prophylaxis for children with reflux ( Table ), but they all acknowledge that the recommendations are not supported by well-designed randomized controlled trials.1-3 No guidelines are available for children with neurogenic bladder and recurrent urinary tract infections.7
TABLE
Oral antibiotics for prophylaxis of urinary tract infections in children
| Antimicrobial | Prophylaxis dosage |
|---|---|
| Trimethoprim/sulfamethoxazole (TMP/SMX) (Bactrim, Septra) | 2 mg of TMP, 10 mg of SMX per kg as single bedtime or 5 mg of TMP, 25 mg of SMX per kg twice per week |
| Nitrofurantoin (Macrodantin) | 1–2 mg/kg as single daily dose |
| Cephalexin (Keflex) | 10 mg/kg as single daily dose |
| Amoxicillin | 10 mg/kg as single daily dose |
| Sulfisoxazole (Gantrisin Pedatric) | 10–20 mg/kg divided every 12h |
| Modified with permission from AAP 1999;3Allen et al1999.10 | |
UTI prevention most successful when the child exhibits efficiency of voiding
William R Strand MD
Division of Pediatric Urology, University of Texas Southwestern Medical Center, Dallas
The relative benefit of antibiotic prophylaxis in prevention of UTI in children with anatomic abnormalities like vesicoureteral reflux could best be determined if all other risk factors for UTI were controlled. Unfortunately, these other factors are often more significant in promoting UTI than is reflux, and they are also more difficult to quantify. Voiding dysfunction and constipation can both increase bladder storage pressures and postvoid residual urine volumes, and as such greatly predispose children for UTI. Furthermore, a distended colon provides an abundant reservoir of pathogens with an array of uropathogenic virulence factors.
Published reports have failed to detect significant benefit for antibiotic prophylaxis in part because the children studied possess varying risks for UTI. Prevention of UTI is most successful when the child exhibits efficiency of voiding and elimination. Clinical practice in pediatric urology advocates use of antibiotic prophylaxis in children with vesicoureteral reflux. Reflux should be suspected in children with hydroureter, multicystic renal dysplasia, ureteral duplication, and ureterocele.
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.
2. 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.
3. Practice parameter: the diagnosis treatment and evaluation of the initial urinary tract infection in febrile infants and young children. American Academy of Pediatrics. Committee on Quality Improvement. Subcommittee on Urinary Tract Infection. Pediatrics 1999;103:843-852.
4. Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, Wald ER. Imaging studies after a first febrile urinary tract infection in young children. N Engl J Med 2003;348:195-202.
5. 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.
6. Bollgren I. Antibacterial prophylaxis in children with urinary tract infection. Acta Paediatr Suppl 1999;88:48-52.
7. Le Saux N, Pham B, Moher D. Evaluating the benefits of antimicrobial prophylaxis to prevent urinary tract infections in children: a systematic review. CMAJ 2000;163:523-529.
8. Morton SC, Shekelle PG, Adams JL, et al. Antimicrobial prophylaxis for urinary tract infection in persons with spinal cord dysfunction. Arch Phys Med Rehabil 2002;83:129-138.
9. Ghiro L, Cracco AT, Sartor M, Comacchio S, Zacchello G, Dall’Amico R. 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.
10. 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.
11. Allen UD, MacDonald N, Fiute L, Chan F, Stephen D. Risk factors for resistance to “first-line” antimicrobials among urinary tract isolates of Escherichia coli in children. CMAJ 1999;160:1436-1440.
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.
2. 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.
3. Practice parameter: the diagnosis treatment and evaluation of the initial urinary tract infection in febrile infants and young children. American Academy of Pediatrics. Committee on Quality Improvement. Subcommittee on Urinary Tract Infection. Pediatrics 1999;103:843-852.
4. Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, Wald ER. Imaging studies after a first febrile urinary tract infection in young children. N Engl J Med 2003;348:195-202.
5. 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.
6. Bollgren I. Antibacterial prophylaxis in children with urinary tract infection. Acta Paediatr Suppl 1999;88:48-52.
7. Le Saux N, Pham B, Moher D. Evaluating the benefits of antimicrobial prophylaxis to prevent urinary tract infections in children: a systematic review. CMAJ 2000;163:523-529.
8. Morton SC, Shekelle PG, Adams JL, et al. Antimicrobial prophylaxis for urinary tract infection in persons with spinal cord dysfunction. Arch Phys Med Rehabil 2002;83:129-138.
9. Ghiro L, Cracco AT, Sartor M, Comacchio S, Zacchello G, Dall’Amico R. 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.
10. 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.
11. Allen UD, MacDonald N, Fiute L, Chan F, Stephen D. 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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