SGEM #427: I Want a Treatment with a Short Course…for Pediatric Urinary Tract Infections

Reference: Zaoutis T, et al. Short-course Therapy for Urinary Tract Infections in Children: the SCOUT randomized clinical trial. JAMA Pediatr. Aug 2023 Date: October 30, 2023 Dr. Ellie Hill Guest Skeptic: Dr. Ellie Hill is a pediatric emergency medicine physician at Children’s National Hospital in Washington, DC and Assistant Professor of Pediatrics and Emergency Medicine at George Washington University School of Medicine and Health Sciences. Her research interests include improving the diagnosis of urinary tract infections in children. Case: A 4-year-old girl comes to the emergency department complaining of pain with urination. She has not had any fevers or flank pain. The last time she had these symptoms a year ago, she was diagnosed with a urinary tract infection (UTI) and started on antibiotics. You obtain a urinalysis that demonstrates 43 white blood cells, positive leukocyte esterase, and positive nitrites. You tell the family the results of the urinalysis and let them know that she likely has another UTI, and you plan to prescribe some antibiotics. Her parents reply, “Last time she had to take over a week of antibiotics for her UTI, and she had bad diarrhea. Is it possible that we do a shorter treatment if she needs antibiotics?” Background: Does it seem like antibiotic courses are getting shorter these days? We covered short-course treatment for pediatric pneumonia in the SAFER trial with Dr. Andrew Tagg back on SGEM #338 and the SCOUT-CAP trial on SGEM #359. UTIs are one of the most common bacterial infections in childhood that we see in the emergency department [1]. The American Academy of Pediatrics (AAP) released guidelines for the management of febrile infants and children 2 to 24 months back in 2011 [2]. In those guidelines, they included the statement “The clinician should choose 7 to 14 days as duration of antimicrobial therapy.” However, the optimal antibiotic duration for the treatment of UTI is still uncertain [3]. Clinical Question: What is the efficacy of short-course (5-day) vs standard-course (10-day) antibiotic therapy for children with urinary tract infections? Reference:  Zaoutis T, et al. Short-course Therapy for Urinary Tract Infections in Children: the SCOUT randomized clinical trial. JAMA Pediatr. Aug 2023 Population: Children 2 months to 10 years with and without febrile UTI exhibiting clinical improvement after 5 days of antimicrobials Excluded: Second uropathogen (>104 CFU by catheterization or suprapubic aspiration, or >5x104 CFU by clean catch), hospitalization for bacteremia, admission to ICU, urine culture with pathogen resistant to initially prescribed antimicrobial, catheter-associated UTI, history of UTI within 30 days, phenylketonuria, congenital or anatomy abnormality of the GU tract other than grade I to II vesicoureteral reflux, duplicated collecting systems, or hydronephrosis, previous GU surgery, unable to tolerate PO medications, immunocompromise, Type I hypersensitivity or anaphylaxis to study products, gestation <36 weeks for children younger than 2, inability to attend follow up Intervention: Additional 5 days of antimicrobial therapy (10 days total, standard course) Comparison: Additional 5 days of placebo (5 days total, short-course) Outcome: Primary Outcome: Treatment failure is defined as symptomatic UTI at or before the first follow-up visit (day 11 to 14) Secondary Outcomes: UTI after first follow-up visit, asymptomatic bacteriuria, positive urine culture, gastrointestinal colonization with resistant organisms Trial: Multicenter, randomized, double-masked, placebo-controlled noninferiority clinical trial Authors’ Conclusions: “In this randomized clinical trial, children assigned to standard-course therapy had lower rates of treatment failure than children assigned to short-course therapy. However, the low failure rate of short-course therapy suggests that it could be considered as a reasonable option for children exhibiting clinical improvement after 5 days of antimicrobial treatment.” Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. No The patients were adequately randomized. Yes The randomization process was concealed. Yes The patients were analyzed in the groups to which they were randomized. Yes The study patients were recruited consecutively (i.e. no selection bias). Unsure The patients in both groups were similar with respect to prognostic factors. Yes All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes All groups were treated equally except for the intervention. Yes Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. Yes The treatment effect was large enough and precise enough to be clinically significant. Unsure Financial conflicts of interest. A few doctors had grants from pharmaceutical companies but reported that they were not related to this particular study. Results: They identified 1,679 eligible children and randomized 693 with 664 included in the final analysis. 64% were White, non-Hispanic. Median age was 4 years old. The most common isolated pathogen was E. coli (90%). Key Result: Children assigned to standard-course therapy had lower rates of treatment failure compared to children assigned to short-course therapy for UTI. Primary Outcome: 2 children (0.6%) in the standard-course therapy group compared to 14 children (4.2%) in the short-course therapy group had treatment failure. That’s a difference of 3.6%. This effect was smaller in the per-protocol analysis. This was a difference of 2.2%. Secondary Outcomes: Children undergoing short-course therapy had asymptomatic bacteriuria (5.3%, 95% CI 1.7-8.9%) and positive urine culture (10.4%, 95% CI 6.6-14.2%) at or before day 11 to 14 visit. There were no other statistically significant differences and the NNT of 28 for treatment failure. UTI Definition: The last guidelines from the American Academy of Pediatrics in 2011 define a UTI as 50,000 cfu. The authors used a bit of a different standard for diagnosing UTI in this study as 50,000 cfu in a suprapubic aspiration or catheterized specimen and 100,000 cfu from a clean voided specimen. Defining UTI is difficult because its definition is based on patient symptoms, which may be vague in the very young. The diagnosis also requires evidence of inflammation and a positive culture.  When looking at culture data, there is research out there to suggest that a cut off of 10,000 cfu may also be appropriate in the very young population [4]. However, in those children greater than age 2, we must remember there can be the presence of sterile pyuria and asymptomatic bacteriuria which should not be diagnosed as UTI under current guidelines. It is understood that there is not a great “gold standard” for UTI, but with new biomarkers, improved culture methods, and RNA/DNA techniques there is hope for a more specific diagnostic strategy. There is uncertainty in determining whether a child has a symptomatic UTI. This is especially challenging in the less than 2-year population as some of those symptoms are nonspecific including poor feeding, vomiting, and fever. Even some of the other symptoms like suprapubic, abdominal, or flank pain are a bit challenging in this preverbal population. Antibiotic Duration: This was a study looking at the duration of antimicrobial therapy, but there is one very important question that is unclear: did the patients take their antimicrobial therapy as prescribed in the first 5 days before enrolling in the study? We don’t know the answer to this. As an extreme example, if a patient did not take any antibiotic during the initial 5 days prior to enrollment, then was enrolled into the standard-course therapy group and adhered to that, then they would only have received 5 days of antibiotics. The dosing of cefixime, trimethoprim/sulfamethoxazole, and cephalexin also differ from one another, usually 1, 2, and 3 times a day dosing respectively. This also may have contributed to medication adherence. Inclusion Criteria: This study included children under the age of 2 and those with fever. This may muddy the waters a bit. Typically, younger children (less than 2 years old) with febrile UTI are treated with longer courses of antibiotics. This group, who typically has limited language expressive abilities, can’t really tell you whether they are experiencing just dysuria or if there’s associated flank pain. So we can’t really tell whether this febrile UTI is truly just a UTI or possible pyelonephritis. Most younger kids are diagnosed with UTI when they present with fever. And there’s concern for possible renal scarring.  This study was not powered to differentiate between outcomes of patients with younger ages or patients with UTI and fever. Antibiotic Stewardship: One of the concerns of antibiotic overuse is the development of antimicrobial resistance. The authors looked at resistance patterns for E. coli or Klebsiella in the stool of children treated with long and short-course antibiotics as a proxy for this. They found no significant difference. This is a lab-oriented outcome (LOO). We’re not sure of the clinical significance of these findings. Do the resistance patterns in stool correlate with the same resistance patterns in urine? When there are resistant bacteria, how long does that resistance last? How does this impact the patient? Does this mean that they are at risk of having harder to treat UTIs in the future? Patient Oriented Outcomes: There are a few reasons for treating UTIs in children. Most obvious is because they’re having dysuria, and it is uncomfortable for them so we can make them feel better. Other bad things include the risk of urosepsis or renal scarring.