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Reevaluating Antibiotic Therapy for Urinary Tract Infections in Children

Reevaluating Antibiotic Therapy for Urinary Tract Infections in Children Urinary tract infection (UTI) is a common pediatric problem, with 2% of all children experiencing one by the age of 10 years. In addition, between 2.5% and 10% of children with fever without localizing signs have a UTI.1 Thus, the pediatrician is faced with treatment decisions frequently. For many years, therapy was straightforward, but the situation has changed. Both the lay and medical literature report that bacteria are becoming increasingly resistant to commonly used antibiotics. Gram-negative enteric organisms, the most common cause of UTI, are particularly problematic. With widespread use of expanded spectrum antibiotics, a number of highly effective resistance mechanisms have evolved.2 Clinicians are often uncertain how to treat. When treating the first UTI in a child, it is generally assumed that Escherichia coli is the culprit because it is isolated in 80% to 90% of such patients. Currently, E coli isolates are resistant to ampicillin in nearly 50% of cases at our medical center, precluding ampicillin as the treatment of choice. The preferred choices for outpatient oral management are cotrimoxazole, β-lactams, and oral cephalosporins, and the parenteral choices generally are third-generation cephalosporins. Children with a previous UTI or with urological anomalies (neurogenic bladder or nephrolithiasis), particularly if they have been receiving antimicrobial prophylaxis, often have antibiotic-resistant Proteus, Klebsiella, or Pseudomonas strains. Only a decade ago, highly febrile children with UTI were routinely admitted to the hospital for parenteral therapy. This practice was confirmed by a survey of practitioners and nephrologists in France conducted in 1994; 20% of general practitioners and pediatricians and nearly 70% of pediatric nephrologists stated that they would hospitalize a hypothetical child with UTI and classic symptoms of pyelonephritis and treat parenterally.3 At that time, ampicillin and gentamicin were the most commonly used “starter” antibiotics. However, since that time, aminoglycosides have fallen into disfavor because of their potential nephrotoxicity and ototoxicity, the need to carefully monitor blood levels, and the unavailability of an oral form to transition to outpatient therapy for completing the antibiotic course. When the third-generation cephalosporins were introduced, they were a welcome addition to the pharmacological toolbox. Effective against most Gram-negative bacteria, these agents exhibited a long half-life, allowing once-a-day administration; they could be easily transitioned to oral agents; and they had a favorable safety profile. In addition, the reliance of pediatricians on cephalosporins received a boost from an important study by Hoberman et al4 demonstrating that many children with febrile UTI or pyelonephritis could be effectively treated as outpatients using cephalosporins. This led to a paradigm shift in pediatric practice: UTI and pyelonephritis in children were no longer “serious” diseases requiring prolonged hospitalization. They could be successfully treated orally or with a starter parenteral dose of third- generation cephalosporins in the clinic or emergency department followed by an oral agent. This reliance on cephalosporins led, if not to complacency, at least to a “comfort zone” for pediatricians managing childhood UTI and pyelonephritis. In this issue of the ARCHIVES, Lutter et al5 present microbiologic data from a review of 361 patients with UTI admitted to their children’s hospital. E coli were identified from 87% of the cases overall, from 58% of those receiving prophylactic antibiotics, and from 73% of those with a prior history of UTI. Antimicrobial resistance to third-generation cephalosporins was seen in 4% of the total isolates but in 27% of the isolates from children receiving prophylactic antibiotics. These data challenge our comfort zone with reliance on third-generation cephalosporins, particularly in children who have received prior therapy. Because antibiotic resistance to aminoglycosides was uncommon, the authors suggested that aminoglycosides replace cephalosporins as the first-line therapy for UTI in hospitalized children receiving prophylactic antibiotics. Are these conclusions supported by the data? Are these recommendations relevant to the management of UTI at other children’s hospitals? Before one can address these questions, the limitations of the published report should be reviewed. First, the data were obtained from children hospitalized with UTI during the years 1997 through 2001. Within many academic centers, resistance rates in Gram-negative organisms have skyrocketed over the past 4 years. Thus, the data may not be reflective of the current environment. Second, only children hospitalized with UTI with specific diagnostic codes in the medical record were included in the review, and outpatients were excluded from the review. Finally, the authors did not provide reasons why patients were receiving prophylactic antibiotics, nor was it clear whether subjects with underlying structural abnormalities, often followed up with the urologists, were included in the review. Despite these limitations, the article provides useful data to guide initial empirical therapy. First, it highlights that antibiotic resistance is an important problem and reinforces that urine culture and sensitivity should be routinely performed in pediatric patients with UTI. Depending on the antibiotic susceptibility, therapy can be tailored to the agent with the narrowest spectrum, least cost, and fewest adverse effects. Second, it calls into question whether β-lactam agents are the best initial antimicrobials to treat subjects with febrile UTI or pyelonephritis. A recent report showed that only 58% of women with UTIs between the ages of 18 of 45 years receiving amoxicillin-clavulanate were clinically cured, but 77% receiving ciprofloxacin were cured.6 Finally, it suggests that patients who are highly febrile, clinically unstable, or needing hospitalization should be initially treated with aminoglycosides pending definitive sensitivity testing. Decisions about antibiotic prophylaxis in patients with anatomic lesions or recurrent infections are even more difficult. With increasing antibiotic resistance, the pediatrician is often faced with the dilemma whether to use a “reasonable” starter antibiotic with a risk of failure or a broad spectrum antibiotic that would, in the long term, contribute to “antibiotic pressure” and increasing antibiotic resistance. Because urine culture and antibiotic susceptibility data are usually available within 24 hours of receipt in the laboratory, is it too long to wait for definitive results? Again, this is difficult to answer because treatment delay can result in renal scarring, even though the time frame and risk factors for the development of scars are not clearly established, and radiological definition of renal scars in children remains elusive. As Lutter and colleagues allude to in their article, the genesis of resistance is, in part, the use of prophylactic antibiotics. Prophylaxis is universal in children with urological anomalies, including ureterovesical reflux, and is also common practice (for a period of 6 months or so) in children with an episode of pyelonephritis or recurrent episodes of cystitis, even in the absence of underlying anomalies. However, many of the patients in the study by Lutter et al were experiencing their first UTI, and thus the indications for prophylactic antibiotics were not clear. It is increasingly recognized that children with asymptomatic bacteriuria do not need treatment and that treatment only selects antibiotic resistance.7 Although this is not the focus of the article, it reminds us to carefully scrutinize the indications when prescribing long-term antibiotic use. It also reminds us that we need to better understand the pathogenesis of UTIs and possible nonpharmacological ways to prevent (and treat) them. A study with elderly women, for example, found that topical application of estrogen to the perineum was extremely effective in decreasing the rate of UTIs.8 Hydration, hygiene, behavioral management of dysfunctional voiding, and the treatment of constipation are also important (and perfectly safe) interventions. Lastly, nonpharmacological approaches to the prevention and treatment of UTIs are largely unexplored, including a clear understanding of the microbial etiology of the bowel and periurethral flora, the host-parasite interactions within the urinary tract, and potential development of vaccine candidates. What is the message for the clinician? All children suspected of UTI, including children with nonfocal fever, should have a reliable urine culture obtained before starting antibiotics. Clinicians should obtain a thorough history of recent infections, both UTI and non-UTI, with resultant antibiotic use. Previous antibiotic use should alert the physician to the possibility of an antibiotic-resistant pathogen. Therapy should be modified, once cultures and sensitivity data are available, to use the agent with the narrowest spectrum, lowest cost, and best safety profile. Finally, pediatricians should thoughtfully reexamine their practice of prescribing prophylactic antibiotics; this practice further contributes to antibiotic pressure and resistance. Correspondence: Dr Edwards, CCC-5323 Medical Center North, Pediatric Clinical Research Office, Vanderbilt University, Nashville, TN 37232 (kathryn.edwards@vanderbilt.edu). References 1. American Academy of Pediatrics, Committee on Quality Improvement, Subcommittee on Urinary Tract Infection, Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics 1999;103843- 852PubMedGoogle Scholar 2. Hooper DC Efflux pumps and nosocomial antibiotic resistance: a primer for hospital epidemiologists. Clin Infect Dis 2005;401811- 1817PubMedGoogle ScholarCrossref 3. Cornu CCochat PCollet JPDelair SHaugh MCRolland C Survey of the attitudes to management of acute pyelonephritis in children. Pediatr Nephrol 1994;8275- 277PubMedGoogle ScholarCrossref 4. Hoberman AWald ERHickey RW et al. Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Pediatrics 1999;10479- 86PubMedGoogle ScholarCrossref 5. Lutter SACurrie MLMitz LBGreenbaum LA Antibiotic resistance patterns in children hospitalized for urinary tract infections. Arch Pediatr Adolesc Med 2005;159924- 928Google ScholarCrossref 6. Hooton TMScholes DGupta KStapleton AERoberts PLStamm WE Amoxicillin-clavulanate vs ciprofloxacin for the treatment of uncomplicated cystitis in women: a randomized trial. JAMA 2005;293949- 955PubMedGoogle ScholarCrossref 7. Hansson SJodal UNorén LBjure J Untreated bacteriuria in asymptomatic girls with renal scarring. Pediatrics 1989;84964- 968PubMedGoogle Scholar 8. Raz RStamm WE A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 1993;329753- 756PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Pediatrics & Adolescent Medicine American Medical Association

Reevaluating Antibiotic Therapy for Urinary Tract Infections in Children

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References (8)

Publisher
American Medical Association
Copyright
Copyright © 2005 American Medical Association. All Rights Reserved.
ISSN
1072-4710
eISSN
1538-3628
DOI
10.1001/archpedi.159.10.992
Publisher site
See Article on Publisher Site

Abstract

Urinary tract infection (UTI) is a common pediatric problem, with 2% of all children experiencing one by the age of 10 years. In addition, between 2.5% and 10% of children with fever without localizing signs have a UTI.1 Thus, the pediatrician is faced with treatment decisions frequently. For many years, therapy was straightforward, but the situation has changed. Both the lay and medical literature report that bacteria are becoming increasingly resistant to commonly used antibiotics. Gram-negative enteric organisms, the most common cause of UTI, are particularly problematic. With widespread use of expanded spectrum antibiotics, a number of highly effective resistance mechanisms have evolved.2 Clinicians are often uncertain how to treat. When treating the first UTI in a child, it is generally assumed that Escherichia coli is the culprit because it is isolated in 80% to 90% of such patients. Currently, E coli isolates are resistant to ampicillin in nearly 50% of cases at our medical center, precluding ampicillin as the treatment of choice. The preferred choices for outpatient oral management are cotrimoxazole, β-lactams, and oral cephalosporins, and the parenteral choices generally are third-generation cephalosporins. Children with a previous UTI or with urological anomalies (neurogenic bladder or nephrolithiasis), particularly if they have been receiving antimicrobial prophylaxis, often have antibiotic-resistant Proteus, Klebsiella, or Pseudomonas strains. Only a decade ago, highly febrile children with UTI were routinely admitted to the hospital for parenteral therapy. This practice was confirmed by a survey of practitioners and nephrologists in France conducted in 1994; 20% of general practitioners and pediatricians and nearly 70% of pediatric nephrologists stated that they would hospitalize a hypothetical child with UTI and classic symptoms of pyelonephritis and treat parenterally.3 At that time, ampicillin and gentamicin were the most commonly used “starter” antibiotics. However, since that time, aminoglycosides have fallen into disfavor because of their potential nephrotoxicity and ototoxicity, the need to carefully monitor blood levels, and the unavailability of an oral form to transition to outpatient therapy for completing the antibiotic course. When the third-generation cephalosporins were introduced, they were a welcome addition to the pharmacological toolbox. Effective against most Gram-negative bacteria, these agents exhibited a long half-life, allowing once-a-day administration; they could be easily transitioned to oral agents; and they had a favorable safety profile. In addition, the reliance of pediatricians on cephalosporins received a boost from an important study by Hoberman et al4 demonstrating that many children with febrile UTI or pyelonephritis could be effectively treated as outpatients using cephalosporins. This led to a paradigm shift in pediatric practice: UTI and pyelonephritis in children were no longer “serious” diseases requiring prolonged hospitalization. They could be successfully treated orally or with a starter parenteral dose of third- generation cephalosporins in the clinic or emergency department followed by an oral agent. This reliance on cephalosporins led, if not to complacency, at least to a “comfort zone” for pediatricians managing childhood UTI and pyelonephritis. In this issue of the ARCHIVES, Lutter et al5 present microbiologic data from a review of 361 patients with UTI admitted to their children’s hospital. E coli were identified from 87% of the cases overall, from 58% of those receiving prophylactic antibiotics, and from 73% of those with a prior history of UTI. Antimicrobial resistance to third-generation cephalosporins was seen in 4% of the total isolates but in 27% of the isolates from children receiving prophylactic antibiotics. These data challenge our comfort zone with reliance on third-generation cephalosporins, particularly in children who have received prior therapy. Because antibiotic resistance to aminoglycosides was uncommon, the authors suggested that aminoglycosides replace cephalosporins as the first-line therapy for UTI in hospitalized children receiving prophylactic antibiotics. Are these conclusions supported by the data? Are these recommendations relevant to the management of UTI at other children’s hospitals? Before one can address these questions, the limitations of the published report should be reviewed. First, the data were obtained from children hospitalized with UTI during the years 1997 through 2001. Within many academic centers, resistance rates in Gram-negative organisms have skyrocketed over the past 4 years. Thus, the data may not be reflective of the current environment. Second, only children hospitalized with UTI with specific diagnostic codes in the medical record were included in the review, and outpatients were excluded from the review. Finally, the authors did not provide reasons why patients were receiving prophylactic antibiotics, nor was it clear whether subjects with underlying structural abnormalities, often followed up with the urologists, were included in the review. Despite these limitations, the article provides useful data to guide initial empirical therapy. First, it highlights that antibiotic resistance is an important problem and reinforces that urine culture and sensitivity should be routinely performed in pediatric patients with UTI. Depending on the antibiotic susceptibility, therapy can be tailored to the agent with the narrowest spectrum, least cost, and fewest adverse effects. Second, it calls into question whether β-lactam agents are the best initial antimicrobials to treat subjects with febrile UTI or pyelonephritis. A recent report showed that only 58% of women with UTIs between the ages of 18 of 45 years receiving amoxicillin-clavulanate were clinically cured, but 77% receiving ciprofloxacin were cured.6 Finally, it suggests that patients who are highly febrile, clinically unstable, or needing hospitalization should be initially treated with aminoglycosides pending definitive sensitivity testing. Decisions about antibiotic prophylaxis in patients with anatomic lesions or recurrent infections are even more difficult. With increasing antibiotic resistance, the pediatrician is often faced with the dilemma whether to use a “reasonable” starter antibiotic with a risk of failure or a broad spectrum antibiotic that would, in the long term, contribute to “antibiotic pressure” and increasing antibiotic resistance. Because urine culture and antibiotic susceptibility data are usually available within 24 hours of receipt in the laboratory, is it too long to wait for definitive results? Again, this is difficult to answer because treatment delay can result in renal scarring, even though the time frame and risk factors for the development of scars are not clearly established, and radiological definition of renal scars in children remains elusive. As Lutter and colleagues allude to in their article, the genesis of resistance is, in part, the use of prophylactic antibiotics. Prophylaxis is universal in children with urological anomalies, including ureterovesical reflux, and is also common practice (for a period of 6 months or so) in children with an episode of pyelonephritis or recurrent episodes of cystitis, even in the absence of underlying anomalies. However, many of the patients in the study by Lutter et al were experiencing their first UTI, and thus the indications for prophylactic antibiotics were not clear. It is increasingly recognized that children with asymptomatic bacteriuria do not need treatment and that treatment only selects antibiotic resistance.7 Although this is not the focus of the article, it reminds us to carefully scrutinize the indications when prescribing long-term antibiotic use. It also reminds us that we need to better understand the pathogenesis of UTIs and possible nonpharmacological ways to prevent (and treat) them. A study with elderly women, for example, found that topical application of estrogen to the perineum was extremely effective in decreasing the rate of UTIs.8 Hydration, hygiene, behavioral management of dysfunctional voiding, and the treatment of constipation are also important (and perfectly safe) interventions. Lastly, nonpharmacological approaches to the prevention and treatment of UTIs are largely unexplored, including a clear understanding of the microbial etiology of the bowel and periurethral flora, the host-parasite interactions within the urinary tract, and potential development of vaccine candidates. What is the message for the clinician? All children suspected of UTI, including children with nonfocal fever, should have a reliable urine culture obtained before starting antibiotics. Clinicians should obtain a thorough history of recent infections, both UTI and non-UTI, with resultant antibiotic use. Previous antibiotic use should alert the physician to the possibility of an antibiotic-resistant pathogen. Therapy should be modified, once cultures and sensitivity data are available, to use the agent with the narrowest spectrum, lowest cost, and best safety profile. Finally, pediatricians should thoughtfully reexamine their practice of prescribing prophylactic antibiotics; this practice further contributes to antibiotic pressure and resistance. Correspondence: Dr Edwards, CCC-5323 Medical Center North, Pediatric Clinical Research Office, Vanderbilt University, Nashville, TN 37232 (kathryn.edwards@vanderbilt.edu). References 1. American Academy of Pediatrics, Committee on Quality Improvement, Subcommittee on Urinary Tract Infection, Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics 1999;103843- 852PubMedGoogle Scholar 2. Hooper DC Efflux pumps and nosocomial antibiotic resistance: a primer for hospital epidemiologists. Clin Infect Dis 2005;401811- 1817PubMedGoogle ScholarCrossref 3. Cornu CCochat PCollet JPDelair SHaugh MCRolland C Survey of the attitudes to management of acute pyelonephritis in children. Pediatr Nephrol 1994;8275- 277PubMedGoogle ScholarCrossref 4. Hoberman AWald ERHickey RW et al. Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Pediatrics 1999;10479- 86PubMedGoogle ScholarCrossref 5. Lutter SACurrie MLMitz LBGreenbaum LA Antibiotic resistance patterns in children hospitalized for urinary tract infections. Arch Pediatr Adolesc Med 2005;159924- 928Google ScholarCrossref 6. Hooton TMScholes DGupta KStapleton AERoberts PLStamm WE Amoxicillin-clavulanate vs ciprofloxacin for the treatment of uncomplicated cystitis in women: a randomized trial. JAMA 2005;293949- 955PubMedGoogle ScholarCrossref 7. Hansson SJodal UNorén LBjure J Untreated bacteriuria in asymptomatic girls with renal scarring. Pediatrics 1989;84964- 968PubMedGoogle Scholar 8. Raz RStamm WE A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 1993;329753- 756PubMedGoogle ScholarCrossref

Journal

Archives of Pediatrics & Adolescent MedicineAmerican Medical Association

Published: Oct 1, 2005

Keywords: urinary tract infections,child,antibiotic therapy

There are no references for this article.