Cefadroxil and Cephalexin Drug Levels and Dosing in Pediatric Musculoskeletal Infections
Condition: Osteomyelitis; Septic Arthritis; Pyomyositis
MeSH terms: Osteomyelitis; Arthritis, Infectious; Pyomyositis
Study type: Interventional
Phase: Phase 1

Summary: 
      The goal of this study is to figure out the best doses for two antibiotics (called cefadroxil
      and cephalexin) when they are used to treat bone, joint, or muscle infections in children. In
      order to do this, the study will collect data about children admitted to Children's Hospital
      Colorado who have these types of infections. During the study, these patients will receive
      doses by mouth of each of these antibiotics, in addition to an IV antibiotic (given through a
      vein) used to treat their infection. After the dose of the first antibiotic, blood samples
      will be drawn every few hours to measure how much of the drug is still in their body, until
      it is all gone. After the first antibiotic is out of the patient's body, the same will be
      done for the second antibiotic. Measurements, in the lab, of how much of these antibiotics
      are needed to kill the most common bacteria causing these infections, which is a type of
      "Staph" bacteria called "MSSA", will be taken. Finally, the blood levels of the antibiotics
      and the information from the lab tests about the Staph bacteria will be used to calculate how
      much and how often of the antibiotic should be given to children with bone, joint, or muscle
      infections. Currently, these types of infections are treated with an antibiotic that children
      have to take four times every day. The goal of this study is to find an antibiotic that
      children can take only two or three times per day.
    

Detailed description: 
      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.
    

Intervention name(s): Cefadroxil; Cephalexin
Intervention type(s): Drug; Drug
Intervention description(s): oral one-time dose of cefadroxil; oral one-time dose of cephalexin
Other intervention name(s): Duricef; Keflex
Intervention MeSH terms: Cephalexin; Cefadroxil
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science