This study aims to shift the current treatment paradigm for the use of oral first-generation cephalosporins in pediatric musculoskeletal (MSK) infections. Optimizing treatment for MSK infections is particularly important, as osteomyelitis is one of the most common severe infections affecting children. Treatment for these infections has markedly improved over the last few decades, but significant morbidity is still seen, including the possibility of permanent disability due to pathologic fracture, growth arrest, and joint destruction. To avoid these long term sequelae and recrudescent infection, early diagnosis, appropriate therapy, and prolonged treatment courses (typically 4-6 weeks, or longer) are essential.
The most commonly used antibiotic for MSK infections is cephalexin, a first-generation cephalosporin. It is well tolerated, provides good tissue penetration, and has a preferred spectrum of activity for typical MSK pathogens, including methicillin susceptible Staphylococcus aureus (MSSA). Despite cephalexin's widespread use, its most significant disadvantage is its short plasma half-life. Because of this, cephalexin is traditionally dosed four times daily (QID) for serious infections like osteomyelitis. However, this dosing frequency, especially for prolonged treatment courses, proves difficult for both patients and their families. Concern about poor adherence drives some providers to prolong IV therapy or dose cephalexin three times daily (TID), though there are insufficient pharmacokinetic/pharmacodynamic (PK/PD) or outcome data to support TID dosing.
Cefadroxil, another first-generation cephalosporin, is an appealing alternative to cephalexin due to its longer half-life. Because of this, the investigators hypothesize that cefadroxil could be used effectively in pediatric patients with MSK infections with a more convenient dosing schedule than cephalexin. While cephalexin is typically dosed 3-4 times per day, cefadroxil could likely be dosed 2-3 times per day, even for serious infections like osteomyelitis. However, cefadroxil is rarely prescribed to children due to a lack of pediatric PK/PD data to guide dosing. Our study aims to address this unmet need and help physicians use these existing drugs in smarter and more effective ways in pediatric MSK infections.
The specific aims of this study are to:
1. Use a Population PK approach to define comparative PK parameters of cefadroxil and cephalexin in pediatric patients with MSK infections (osteomyelitis, septic arthritis, pyomyositis).
2. Establish reference MIC ranges for both cefadroxil and cephalexin against MSSA isolates.
3. Perform pharmacodynamic modeling (Monte Carlo simulation) based on the above PK parameters and MIC data to evaluate the expected PK/PD target attainment of cefadroxil and cephalexin at different dosing intervals: cephalexin given as 3 vs. 4 divided doses per day; cefadroxil given as 2 vs. 3 doses against a range of MICs.
To answer these questions, patients with MSK infections admitted to Children's Hospital Colorado (CHCO) will be enrolled in this study and sequentially given doses of both cefadroxil and cephalexin. After each oral dose, serum levels of the antibiotic will be measured at set time points until the drug is expected to be fully cleared. They will then receive the second antibiotic after a 24-hour washout period. MIC ranges will be measured based on banked MSSA isolates. Based on these study-derived PK and MIC data, adequacy of the studied cephalexin and cefadroxil dosing regimens will be analyzed.
If the study is able to confirm a favorable PK/PD profile for twice daily (BID) and/or three times daily (TID) cefadroxil dosing in children, even for severe infections, it could have an immediate impact on prescribing habits. Less frequent dosing would be an improvement over the current standard of care, allowing for easier medication administration, improved adherence, and increased provider confidence for early transition to oral therapy, which are all essential for optimal treatment of pediatric MSK infections.
