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Antimicrobial Reports

Antibiotic Utilization and Efficacy Associated With Treating Pediatric Urinary Tract Infections in Texas Medicaid Patients in the First Year of Life

Coleman, Alana PharmD*,†; Vohra, Yogesh PharmD, MS*; Rascati, Karen PhD*; Kubes, Sarah PharmD, BCPS*,†,‡; Moffett, Brady PharmD, MPH, MBA§,¶

Author Information
The Pediatric Infectious Disease Journal: November 2021 - Volume 40 - Issue 11 - p 993-996
doi: 10.1097/INF.0000000000003272
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Abstract

Urinary tract infections (UTIs) are one of the most common sources of bacterial infections in childhood and cost the US healthcare system approximately $520 million annually.1 While most UTIs in pediatric patients are uncomplicated, 2%–3% of pediatric patients develop pyelonephritis and require hospitalization for treatment, which is associated with an increased risk of long-term complications, such as hypertension and chronic kidney disease.2,3 Accurate and timely diagnosis and treatment of UTIs are vital in improving pediatric health outcomes and potentially reducing total costs to the health system.

Unlike older children and adults that present with urinary-specific symptoms, infants under 12 months present with nonspecific symptoms like fever, vomiting, or abdominal pain (in most cases, their only symptom will be a high-grade fever).4,5 The diagnosis of a UTI for children 2–24 months of age includes a urinalysis with the markers suggesting infection and a positive urine culture (5 × 104 CFU/mL of a single uropathogen). While urinalysis results are rapidly available, they are not very sensitive or specific for a UTI. Thus, urinalysis should be followed with a urine culture to confirm a UTI diagnosis, which may take up to 72 hours to report.5,6

Because of the increased risk of complications associated with delayed antibiotic treatment, pediatric UTI guidelines recommend that empiric antibiotic therapy be initiated if there is a high probability of a UTI identified by a positive urinalysis and clinical symptoms.4,5 Once antimicrobial susceptibility testing is available targeted antibiotic treatment should be employed.

While management of pediatric UTIs has been well studied, treatment strategies are controversial, especially with emerging resistance to commonly used antibiotics. Escherichia coli is responsible for approximately 80% of pediatric UTIs without urinary tract abnormalities.7 Historically, amoxicillin has been the first-line agent for pediatric UTIs because of its established safety in infants and E. coli susceptibility.8

However, over the past 20 years, there has been an increasing rate of E. coli resistance to narrow-spectrum antibiotics like amoxicillin.8 Because of this recent development of increasing resistance, pediatric guidelines vary in first-line treatment recommendations and antibiotic prescribing practices have shifted.9 In particular, the utilization of the third-generation cephalosporin, cefdinir, has increased in the past few years. Cefdinir has become a primary agent for treating UTIs, as it has excellent in vitro activity against common UTI pathogens and low rates of resistance. Additionally, cefdinir is relatively inexpensive, and it is familiar to pediatric health care practitioners as it is commonly used for other pediatric infections (eg, otitis media).10–12 However, cefdinir’s safety and efficacy have not been tested in patients under 6 months of age. Furthermore, cefdinir does not have an approved indication for treating UTIs, and research assessing its clinical efficacy in treating pediatric UTIs is scant.12

The aim of this research was 2-fold: (1) to describe the utilization patterns of antibiotic prescribing for Texas Medicaid patients under 1 year of age, among place of service (healthcare practitioner’s office and emergency department) and gender (male, female) for UTI treatment and (2) to assess the treatment effectiveness of amoxicillin compared with cefdinir.

MATERIALS AND METHODS

A retrospective cohort design was employed using Texas Medicaid prescription and medical claims data from September 1, 2012, to August 31, 2016. Pediatric patients with a UTI diagnosis were included if they remained enrolled in Texas Medicaid program for at least 12-months postindex date (initial UTI diagnosis) and met the study criteria. All claims data were in deidentified form and the study protocol was exempt from approval by The University of Texas at Austin Institutional Review Board because of its retrospective nature.

Study Selection Criteria

Patients were included in the study if they were (1) less than 1 year of age and (2) had a medical claim associated with an initial (first) UTI diagnosis and a corresponding outpatient prescription for UTI treatment. Date of birth was not included in the claims database, only a year of age. If a patient’s age was coded as 0 years in the prescription claim, this indicated the child was less than 1 year old.

For medical claims before October 1, 2015, a UTI diagnosis would be determined by International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes: 771.82, 599.0. After October 1, 2015, International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes: N39.0 or P39.3 were utilized. Exclusion criteria included patients who had genitourinary tract abnormalities (ICD-9-CM codes: 59730, N1370 and ICD-10-CM codes: N1370, R394), a permanent catheter in place, or required inpatient treatment (hospitalization).

Study Variables

Medical and prescription claims were extracted from the Texas Medicaid database. Extracted medical claims data variables included: deidentified patient ID, date of service, place of service, medical diagnosis, medical procedures performed, charge and reimbursement costs. Prescription data variables included deidentified patient ID (matching the medical claims), gender (male, female), drug dispensed, American Hospital Formulary Service Pharmacologic Therapeutic Classification, General Code Number, quantity and day supply of drug dispensed, charge and reimbursement amount.

Study Outcomes

Individual patient claims were analyzed to assess antibiotic utilization and treatment efficacy. To assess whether treatment practices differ between the place of service, Texas Medicaid & Healthcare Partnership codes were utilized to assign place of service. The date of the first antibiotic prescription dispensed was considered the patient’s medication index date. Treatment failure was defined as another (different) antibiotic prescription dispensed within 7 days the patient’s medication index date. Seven days were selected based on expert clinical advice to differentiate between patients needing retreatment for their initial UTI infection and subsequent UTIs infections. Treatment efficacy was assigned to the place of service where the initial UTI encounter occurred and did not include where the follow-up visit took place.

Statistical Analysis

Statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC) and using an a priori significance level of P < 0.05. Antibiotic prescribing differences among place of service and gender were analyzed using Pearson’s χ2 tests.

Logistic regression was conducted to estimate the odds of treatment failure for the first antibiotic. The model controlled for place of service (office as reference category) and gender (male as reference category).

RESULTS

After applying the inclusion study selection criteria, a sample size of 12,795 patients was obtained (Table 1). Cefdinir was the most utilized drug for initial UTI management (49.2%), followed by amoxicillin (24.1%), cephalexin (13.0%), and amoxicillin-clavulanate (11.9%). The remaining patients (1.83%) were prescribed other antibiotics for their initial UTI treatment. For simplicity, only the top 4 prescribed antibiotics were incorporated in further statistical analysis (N = 12,561).

TABLE 1. - Patient Attrition Among Texas Medicaid Patients
Inclusion Criteria Included Patients
N (% of Total)
Excluded Patients
N (% of Total)
Patients less than 1 with a UTI diagnosis between September 1, 2012, to August 31, 2016* 41,439
(100.0)
Patients treated in the healthcare practitioners’ office or emergency department 14,588
(35.2)
26,851
(64.8)
Patients treated with an outpatient prescription 12,795
(30.9)
1793
(4.3)
Final sample 12,795
*Enrolled in Texas Medicaid at least 12 mo postindex date.
UTI indicates urinary tract infection.

The subgroup of patients that were prescribed one of the top 4 medications (N = 12,561) were 69.7% (N = 8760) female and 30.3% (N = 3801) male, and were primarily seen at a health care practitioner’s office (86.4%; N = 10,853) compared with the emergency department (13.6%; N = 1708). Utilization patterns of the top 4 prescribed antibiotics, stratified by gender and place of service, are displayed in Table 2.

TABLE 2. - Antibiotic Utilization Patterns by Gender and Place of Service
Antibiotic Prescribed Female
N = 8760
OF = 7667
ED = 1093
Male
N = 3801
OF = 3186
ED = 615
Cefdinir OF: 3889 (50.7% OF visits)
ED: 623 (57.0% ED visits)
OF: 1464 (45.9% OF visits)
ED: 316 (51.4% ED visits)
Amoxicillin-Clavulanate OF: 942 (12.3% OF visits)
ED: 89 (8.1 % ED visits)
OF: 432 (13.6% OF visits)
ED: 60 (9.8% ED visits)
Amoxicillin OF: 1744 (22.7% OF visits)
ED: 221 (20.2% ED visits)
OF: 961 (30.2% OF visits)
ED: 152 (24.7% ED visits)
Cephalexin OF: 1092 (14.2% OF visits)
ED: 160 (14.6% ED visits)
OF: 329 (10.3% OF visits)
ED: 87 (14.1% ED visits)
ED indicates emergency department; OF, Healthcare Practitioner’s Office.

Controlling for gender, there was a significant relationship between place of service and top 4 antibiotics utilized (X2 = 36.10, P < 0.001). While cefdinir was the preferred antibiotic in both emergency department (55.0%) and the health care practitioner’s office (49.3%), it was more heavily favored in the emergency department. Additionally, cephalexin was utilized more than amoxicillin-clavulanate in the emergency department (14.5% and 8.7%, respectively) compared with the healthcare practitioner’s office (13.1% and 12.7%, respectively).

Conversely, when assessing combined data across all places of service for gender, there was a significant relationship between gender and antibiotic utilization (X2 = 87.73, P < 0.001). Cefdinir was the favored antibiotic for both males and females; however, the utilization patterns between the 2 genders differed. For females, cefdinir was utilized more than twice as often as amoxicillin (51.5% and 22.4%, respectively). In contrast, cefdinir utilization was approximately 50% higher than amoxicillin (46.8% and 29.3%, respectively) in males. Additionally, amoxicillin and amoxicillin-clavulanate utilization was higher in males (29.3% and 12.9%, respectively) compared with females (22.4% and 11.8%, respectively).

Overall treatment failure, as defined as a different antibiotic received within 7 days of the index antibiotic, occurred for approximately 1.6% (N = 199/12,561) of all patients. The failure rate of amoxicillin was 2.7% (N = 82/3078), compared with 1.9% for cephalexin (N = 31/1668), 1.2% for amoxicillin-clavulanate (19/1523), and 1.1% for cefdinir (N = 67/6292). When controlling for a place of service and gender, the odds of treatment failure were greater with initial treatment with amoxicillin (OR = 2.54; 95% confidence intervals: 1.84–3.54; P < 0.001) versus cefdinir (Table 3). Similarly, the odds of treatment failure were greater with the initial treatment with cephalexin (OR = 1.76; 95% confidence intervals: 1.13–2.68; P < 0.001) versus cefdinir. Patients initially prescribed amoxicillin and cephalexin were most commonly switched to cefdinir (Table 4).

TABLE 3. - Odds Ratio of Treatment Failure (Different Antibiotics Prescribed Within 7 Days)
Predictor Odds Ratio 95% CI of Odds Ratio P
Place of service 1.00
 Office*
 Emergency 1.30 0.87 1.87 0.17
Gender
 Male* 1.00
 Female 0.93 0.69 1.26 0.63
First antibiotic
 Cefdinir* 1.00
 Amoxicillin-Clavulanate 1.18 0.69 1.94 0.51
 Amoxicillin 2.54 1.84 3.54 <0.001
 Cephalexin 1.76 1.13 2.68 <0.001
*Reference group.
Statistically significant (<0.05).
CI indicates confidence intervals.

TABLE 4. - Switch From First-line Antibiotic (Column) to Second-line Antibiotic (Row) After Treatment Failure
Amoxicillin-Clavulanate Amoxicillin Cefaclor Cefdinir Ceftriaxone Cefuroxime Cephalexin
Cefdinir 27 35 0 0 1 0 4
Amoxicillin-Clavulanate 0 4 0 8 1 1 5
Amoxicillin 20 0 0 46 0 1 15
Cephalexin 8 10 1 12 0 0 0

DISCUSSION

Overall, in this Texas Medicaid population, cefdinir was the most commonly utilized antibiotic as a first-line treatment for uncomplicated UTIs in patients 1-year-old and younger.

Despite being an off-label indication for pediatric UTIs, cefdinir is likely a more favored choice by practitioners as it is less likely to be associated with a treatment failure due to its low rates of resistance to E. coli. Furthermore, place of service and gender influenced antimicrobial selection, with cefdinir utilization higher in females and the emergency department. Differences in antibiotic utilization between the healthcare practitioner’s office and the emergency department may have occurred because of differences in prescribing practices. While prescribing practices in the emergency department may be more driven by institutional antimicrobial susceptibility patterns, prescribing patterns in the healthcare practitioner offices may be driven more by individual practitioner preference.

Our study is one of the first and largest retrospective studies assessing the efficacy of cefdinir for treating pediatric UTIs. Compared with the other top utilized antibiotics, cefdinir and amoxicillin-clavulanate had the lowest treatment failure rates 1.1% and 1.2%, respectively, making them both seemingly desirable options for treatment pediatric UTIs in the outpatient setting. Despite having similar outcomes, cefdinir was utilized at a much higher rate than amoxicillin-clavulanate for both first-line and second-line antibiotic therapy after treatment failure. Amoxicillin-clavulanate may be prescribed at a lower rate than cefdinir because of its higher incidence of diarrhea (28% and 18%, respectively) and more narrow coverage of Gram-negative uropathogens compared with cefdinir.12,13 This study demonstrates that amoxicillin-clavulanate is a potential option due to its low rate of treatment failure and may be an effective first-line option in addition to cefdinir.

One limitation in the study is the use of retrospective claims data for study inclusion. Although the initial diagnosis might be for a UTI, follow-up cultures may indicate a different infection. Another limitation in this study is the lack of information determining if the antibiotic selection was empiric or target-driven therapy as we did not collect culture data. Compared with other studies evaluating ampicillin (which has similar in vitro activity to amoxicillin) in pediatric UTIs. Our study has a lower projected incidence of treatment failure, which may indicate amoxicillin and other narrow-spectrum antibiotic utilization was target-driven.14–16 However, the high-efficacy rate among the top utilized antibiotics may be because children under one are less likely to harbor drug-resistant bacteria and usually have little to no exposure to prior antimicrobials compared with older children. While this study supports the use of cefdinir for empiric therapy, to reduce the exposure of broad-spectrum antibiotics in pediatric patients culture susceptibly results should guide therapy when available. In addition, if local or institution-specific antibiograms show low rates of resistance to amoxicillin, this may be factored into prescribing decisions.

There are inherent limitations associated with the studies analyzing retrospective claims databases as certain assumptions must be made. For example, we assume that patients switched from one antibiotic to another because treatment failure occurred. However, patients may have switched to another antibiotic because of its side effect profile, or the prescriber may have selected another antibiotic based on susceptibility results.

Looking at which antibiotics patients were prescribed as second-line therapy provides a clearer story to which factors guided antibiotic selection. Patients initially prescribed amoxicillin were most often switched to cefdinir (n = 46) and amoxicillin-clavulanate (n = 20), suggesting initial treatment failure because patients required broader-spectrum antibiotics to treat their infection. Furthermore, patients initially prescribed cefdinir were most often switched to narrow-spectrum antibiotics like amoxicillin (n = 35), suggesting culture susceptibility results guided secondary antibiotic selection. The prescribing patterns for second-line therapies are less clear when cephalexin or amoxicillin-clavulanate was initially prescribed with antibiotic switching indicating tolerance issues (eg, amoxicillin-clavulanate) or target-driven therapy.

Other potential issues that arise from analyzing retrospective claims include not knowing whether the antibiotic was actually consumed or the patient’s caregiver complied with physician instructions. Additionally, the database used is composed only of Texas Medicaid patient claims and therefore the findings of the study may not be generalizable to the entire US population. Finally, this study excluded patients hospitalized or at risk for recurrent and complicated urinary limiting its applicability to the management of uncomplicated UTIs in the outpatient setting.

While cefdinir and amoxicillin-clavulanate had the lowest treatment failure rates, the clinical impact of utilizing these agents over amoxicillin or cephalexin may be low as all antibiotics examined had a high perceived treatment success rate. Cefdinir and amoxicillin-clavulanate’s true impact on health outcomes should be further explored by examining other measures of treatment failure, such as hospital admissions. An additional next step would be to calculate the differences in the total cost associated with treating each UTI episode (first-line visits and medications plus any follow-up visits and medications) to determine if cefdinir or amoxicillin-clavulanate is more cost-effective than other commonly utilized antibiotics.

CONCLUSIONS

In conclusion, the widespread utilization of cefdinir for may be appropriate for the empiric treatment of uncomplicated UTIs in pediatric Texas Medicaid patients as it has a lower incidence of treatment failure compared with cephalexin and amoxicillin. Despite not knowing the influence of susceptibility testing on antimicrobial selection, this study supports the utilization of cefdinir as a first-line option for initial UTI treatment.

REFERENCES

1. Spencer JD, Schwaderer A, McHugh K, et al. Pediatric urinary tract infections: an analysis of hospitalizations, charges, and costs in the USA. Pediatr Nephrol. 2010;25:2469–2475.
2. Zorc JJ, Kiddoo DA, Shaw KN. Diagnosis and management of pediatric urinary tract infections. Clin Microbiol Rev. 2005;18:417–422.
3. Shaikh N, Mattoo TK, Keren R, et al. Early antibiotic treatment for pediatric febrile urinary tract infection and renal scarring. JAMA Pediatr. 2016;170:848–854.
4. Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management, Roberts KB Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics. 2011;128:595–610.
5. Roberts KB. Revised AAP guideline on UTI in febrile infants and young children. Am Fam Physician. 2012;86:940–946.
6. Simerville JA, Maxted WC, Pahira JJ. Urinalysis: a comprehensive review [published correction appears in Am Fam Physician. Am Fam Physician. 2005;71:1153–1162.
7. Schmidt B, Copp HL. Work-up of pediatric urinary tract infection. Urol Clin North Am. 2015;42:519–526.
8. White B. Diagnosis and treatment of urinary tract infections in children. Am Fam Physician. 2011;83:409–415.
9. Arshad M, Seed PC. Urinary tract infections in the infant. Clin Perinatol. 2015;42:17–vii.28
10. Omnicef (cefdinir) [package insert]. 2015.AbbVie, Inc;
11. Amoxicillin. Lexi-Drugs. 2015. Lexicomp, Available at: http://online.lexi.com/. Accessed July 27, 2020.
12. Sader HS, Biedenbach DJ, Streit JM, et al. Cefdinir activity against contemporary North American isolates from community-acquired urinary tract infections. Int J Antimicrob Agents. 2005;25:89–92.
13. Block SL, Schmier JK, Notario GF, et al. Efficacy, tolerability, and parent reported outcomes for cefdinir vs. high-dose amoxicillin/clavulanate oral suspension for acute otitis media in young children. Curr Med Res Opin. 2006;22:1839–1847.
14. Augmentin (amoxicillin-Clavulanate) [package insert]. 2013.Hagerstown, MD: GlaxoSmithKline;
15. Bonsu BK, Shuler L, Sawicki L, et al. Susceptibility of recent bacterial isolates to cefdinir and selected antibiotics among children with urinary tract infections. Acad Emerg Med. 2006;13:76–81.
16. Bodey GP, Nance J. Amoxicillin: in vitro and pharmacological studies. Antimicrob Agents Chemother. 1972;1:358–362.
Keywords:

pediatrics; urinary tract infection; antibiotic; utilization; treatment failure; outpatient

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