Oral Cephalosporins for Urinary Tract Infections: Why Not Cefdinir for All?

Column Author: Alaina Burns, PharmD, BCPPS | Adjunct Clinical Assistant Professor of Pharmacy, University of Missouri-Kansas City School of Pharmacy

Column Editor: Rana El Feghaly, MD, MSCI | Director, Clinical Services | Director, Outpatient Antibiotic Stewardship Program | Associate Professor of Pediatrics, UMKC School of Medicine

Cephalosporins are considered first-line antibiotics for treating pediatric urinary tract infections (UTIs).¹ Based on local susceptibility patterns of uropathogens, empiric UTI therapy can vary from first-generation cephalosporins (e.g., cefazolin, cephalexin) for uncomplicated UTIs to third-generation cephalosporins (e.g., ceftriaxone, cefixime, cefpodoxime, cefdinir). The broader gram-negative bacterial coverage and overall good tolerability of third-generation cephalosporins make them an appealing option for many prescribers. However, not all cephalosporins are created equal, and strategic marketing of non-inferiority trials and observational studies has resulted in use without consideration of their pharmacokinetic and pharmacodynamic limitations.²

Why are oral third-generation cephalosporins not always the answer for pediatric UTI treatment?

A common misconception by prescribers is that oral and intravenous (IV) cephalosporins with the same generation are interchangeable. However, this is an inaccurate assumption about oral third-generation cephalosporins for the following reasons:

• Most have poor bioavailability, high protein binding and rapid elimination.²
  • To put this observation in perspective, for cephalexin, >90% of the dose is absorbed and 10%-15% bound to protein compared to cefdinir where only 16%-25% of the dose absorbed and 60%-70% bound to protein. This difference indicates difficulty achieving and sustaining necessary concentrations above the minimal inhibitory concentration with oral third-generation cephalosporins.
• Achieving and sustaining effective concentrations at the site of infection can be challenging.²
• Renal elimination may differ in pediatrics compared to adults for some agents (e.g., cefdinir).³
• Using IV third-generation susceptibility to predict if an oral third-generation cephalosporin is active against an enteric gram-negative bacteria, such as Escherichia coli and Klebsiella pneumoniae, will result in overcalling the oral third-generation cephalosporin susceptibility. Essentially, there are cases where a ceftriaxone-susceptible E. coli will be resistant to oral third-generation cephalosporins.⁴
• Cefazolin or cephalexin will cover ≥ 95% of E. coli, Proteus mirabilis and K. pneumoniae (the most common causes of UTI) based on our local antibiogram of urine isolates.

How can I interpret susceptibilities on a urine culture to select the best oral cephalosporin for a patient’s UTI?

The following are important to consider when interpreting urine culture susceptibility for E. coli, Klebsiella pneumoniae and Proteus mirabilis:

• Cefazolin is a surrogate marker of susceptibility of oral third-generation cephalosporins (e.g., cefpodoxime, cefixime, cefdinir). However, if cefazolin susceptible, then use cephalexin!
• Oral third-generation cephalosporin susceptibility (e.g., cefpodoxime) can be used as a surrogate for susceptibility to other oral third-generation cephalosporins.⁴
• If the organism is cefazolin resistant and no oral third-generation cephalosporin susceptibility is available, close follow-up may be indicated or an alternative agent (e.g., trimethoprim-sulfamethoxazole, ciprofloxacin) can be considered.

Why do some experts recommend avoiding cefdinir for pediatric UTIs?

While sources supporting cefdinir for pediatric UTIs can be found, some experts still recommend avoiding cefdinir for pediatric UTIs based on the following pharmacokinetic characteristics and limited available outcome data.

• Using adult data to support cefdinir as an effective treatment for pediatric UTI is inappropriate because:
  • Cefdinir renal elimination is lower in pediatrics (2.7%-12.7%) compared to adults (12.7%-23%)³;
  • Extrapolating adult outcome data for UTI treatment may not be appropriate as children may have lower urinary cefdinir concentrations.
• Newer observational pediatric studies supporting cefdinir as an option for uncomplicated pediatric UTIs are limited because^5,6:
  • The noted high rates of cefazolin-susceptible E. coli⁶ mean that cefdinir may work for cefazolin-susceptible isolates but may not be appropriate for cefazolin-resistant isolates without confirmed oral third-generation cephalosporin susceptibility;
  • The studies included mostly uncomplicated UTIs, with limited extrapolation to complicated UTIs.

For the reasons above, we still prefer alternative third-generation cephalosporins, such as cefixime or cefpodoxime, over cefdinir for pediatric UTIs.

In conclusion, cefazolin or cephalexin continues to be the drug of choice empirically for most children based on local susceptibility patterns as well as for definitive therapy of cefazolin-susceptible gram-negative bacteria. In the setting of cefazolin-resistant gram-negative bacteria, caution should be used extrapolating ceftriaxone susceptibility to oral third-generation cephalosporins. Instead, providers should use specific oral cephalosporin susceptibility (e.g., cefpodoxime) to guide therapy. Finally, based on pharmacokinetic difference and limitations of available data, cefdinir is not recommended for complicated UTIs or uncomplicated UTIs caused by cefazolin-resistant gram-negative organisms without confirmed susceptibility to an oral third-generation cephalosporin.

References:

1. Mattoo TK, Shaikh N, Nelson CP. Contemporary management of urinary tract infections in children. Pediatrics. 2021;147(2):e2020012138.
2. Parker S, Mitchell, M, Child J. Cephem antibiotics: wise use today preserves cure for tomorrow. J Pediatr Rev. 2013;34(11):510-524.
3. Guay DRP. Pharmacodynamics and pharmacokinetics of cefdinir, an oral extended spectrum cephalosporin. Pediatr Infect Dis J. 2000;19:S141-S146.
4. Watson JR, Burch C, Leber AL. Surrogate testing of oral third-generation cephalosporin susceptibility to common uropathogens. Diagn Microbiol Infect Dis. 2021;99:115299.
5. Coleman A, Vohra Y, Rascati K, Kubes S, Moffett B. Antibiotic utilization and efficacy associated with treating pediatric urinary tract infections in Texas Medicaid patients in the first year of life. Pediatr Infect Dis J. 2021;40:993-996.
6. Cardinale B, Zembles TN, Ray K, et al. Retrospective comparison of cefdinir, cephalexin, and sulfamethoxazole-trimethoprim in the treatment of outpatient pediatric urinary tract infections. Clin Pediatr (Phila). 2023;62(1):47-54.