Wise Use of Antibiotics

Oral Cephalosporins for Respiratory Infections: Not Always Better

Author: Alaina Burns, PharmD, BCPPS | Pharmacy | 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

Oral cephalosporins have long served as common antibiotics prescribed for a variety of infections in pediatrics. Broader spectrum of activity provided by second- (e.g., cefuroxime) and third-generation (e.g., cefdinir, cefixime, cefpodoxime) cephalosporins combined with their ease of dosing and palatability has made them appealing options for many prescribers. Unfortunately, strategic marketing of the positive aspects of non-inferiority trials has resulted in increased use without consideration of their pharmacokinetic (PK) and pharmacodynamic (PD) limitations.¹ As a result, oral broad-spectrum cephalosporins, such as cefdinir, are some of the most inappropriately prescribed antibiotic classes in pediatrics.^2,3  

Why are oral cephalosporins not always better than first-line antibiotics? 

Most oral broad-spectrum cephalosporins received Food and Drug Administration approval through non-inferiority trials, which were designed only to demonstrate they were not “unacceptably worse than a standard.” Over the years, misconceptions about equivalence or superiority have resulted in practitioners believing all cephalosporins (whether oral or intravenous) are interchangeable within the respective generations. However, oral second- and third-generation cephalosporins are not well absorbed and are highly protein bound and rapidly eliminated, which can make obtaining effective concentrations at the site of infection challenging.¹ For example, amoxicillin is still considered superior to oral cephalosporins for susceptible pneumococcal infections. Table 1 highlights the PK parameters of amoxicillin, cefdinir and cefpodoxime. The PK parameters explain why effective concentrations may not be possible in respiratory tissues with cefdinir, making cefdinir inferior to oral high-dose amoxicillin. However, parenteral third generations (such as ceftriaxone) are not limited by absorption given their route of administration. Thus parenteral third-generation cephalosporins do provide broader pneumococcal coverage than amoxicillin or oral cephalosporins. The superiority of amoxicillin for susceptible pneumococcal infections has been highlighted further in a recent study of 249 pneumococcal isolates, where 93.6% were amoxicillin-susceptible while only 73.9% were susceptible to cefdinir.⁴ In contrast, cefpodoxime is considered an alternative over cefdinir in national guidelines for treatment of pneumonia in penicillin-allergic patients, given better absorption, lower protein binding and longer half-life.   

When are broad-spectrum oral cephalosporins recommended for respiratory infections in children? 

Oral second- and third-generation cephalosporins are rarely considered first-line treatment for pediatric respiratory infections. They may be appropriate as an alternative for patients with mild or moderate penicillin allergy (e.g., rashes including hives) with one of the following infections: 

• Acute otitis media – initial therapy only 
• Uncomplicated community-acquired pneumonia 
  • Consider non-beta-lactam if not vaccinated against pneumococcus (e.g., levofloxacin, clindamycin) 
  • Cefpodoxime or cefuroxime are preferred. Avoid cefdinir. 
• Acute bacterial rhinosinusitis 
  • Consider in conjunction with clindamycin in select cases 

When should oral cephalosporins be avoided in pediatric respiratory infections? 

Given the PK and PD limitations of oral broad-spectrum cephalosporins, they should be avoided when treating^1,4: 

• Recurrent or refractory acute otitis media after failure of high-dose amoxicillin/clavulanate 
  • Alternative: ceftriaxone (intramuscular/intravenous) 
• Community-acquired pneumonia with concern for amoxicillin failure/resistant pneumococcus 
  • Alternatives: clindamycin, levofloxacin 
• Documented penicillin-resistant Streptococcus pneumoniae infections  
  • Alternatives: ceftriaxone (intramuscular/intravenous), levofloxacin, clindamycin 
    
    

What are the risks for inappropriate antibiotic prescribing? 

Beyond potential treatment failures, there are community- and patient-level risks with overuse of broad-spectrum oral cephalosporins. Patients receiving inappropriate antibiotics are more likely to have adverse drug events, including severe allergic reactions, as well as increased 30-day attributable health care expenditures.⁵ Additionally, observational data supports lower rates of methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae whenever oral broad-spectrum cephalosporin use is restricted.¹  

In conclusion, broad-spectrum oral cephalosporins are frequently misinterpreted as being the oral equivalent to parenteral third-generation cephalosporins. Given their unfavorable PK properties, oral broad-spectrum cephalosporins should not be used routinely to escalate therapy for patients who failed first-line therapy or who are concerning for resistant pneumococcal infections.   

References: 

1. Parker S, Mitchell, M, Child J. Cephem antibiotics: wise use today preserves cure for tomorrow. J Pediatr Rev. 2013;34(11):510-524. 
2. Wattles B, Vidwan N, Ghosal S, et al. Cefdinir use in the Kentucky Medicaid population: a priority for outpatient antimicrobial stewardship. J Pediatr Infect Dis Soc. 2021;10(2):157-160. 
3. Hersh AL, Fleming-Dutra KE, Shapiro DJ, Hyun DY, Hicks LA; Outpatient Antibiotic Use Target-Setting Workgroup. Frequency of first-line antibiotic selection among US ambulatory care visits for otitis media, sinusitis, and pharyngitis. JAMA Intern Med. 2016;176(12):1870-1872. doi:10.1001/jamainternmed.2016.6625   
4. Murphy ME, Powell E, Courter J, Mortensen JE. Predicting oral beta-lactam susceptibilities against Streptococcus pneumoniae. BMC Infect Dis. 2021;21(1):679. 
5. Butler AM, Brown DS, Durkin MJ, et al. Association of inappropriate outpatient pediatric antibiotic prescriptions with adverse drug events and health care expenditures. JAMA Netw Open. 2022;5(5):e2214253.