Cefadroxil and Cephalexin Drug Levels and Dosing in Pediatric Musculoskeletal Infections
| Status: | Not yet recruiting |
|---|---|
| Conditions: | Arthritis, Orthopedic |
| Therapuetic Areas: | Rheumatology, Orthopedics / Podiatry |
| Healthy: | No |
| Age Range: | Any - 18 |
| Updated: | 1/16/2019 |
| Start Date: | June 1, 2019 |
| End Date: | June 1, 2021 |
| Contact: | Andrew Haynes, MD |
| Email: | ANDREW.HAYNES@UCDENVER.EDU |
| Phone: | 720-777-6783 |
Comparative Pharmacokinetics and Pharmacodynamics (PK/PD) of Cefadroxil and Cephalexin for Pediatric Musculoskeletal (MSK) Infections
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.
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.
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.
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.
Inclusion Criteria:
Children who are admitted to Children's Hospital Colorado and:
- Are to be treated for a deep musculoskeletal infection (osteomyelitis, septic
arthritis, pyomyositis), as determined by their primary medical team
- Are aged 6 months to 18 years
- Clinically likely to be admitted for 48-72 hours
Exclusion Criteria:
Patients will be excluded if they:
- Are less than 6 months of age or greater than 18 years of age
- Weigh less than 5.5 kg
- Weigh greater than the 95%ile for age
- Have underlying current renal disease based on medical history
- Have an underlying chronic medical condition—examples include cystic fibrosis, sickle
cell anemia, inflammatory bowel disease, pancreatitis, hepatitis, immunodeficiency,
cancer, spina bifida, chromosomal abnormalities, cerebral palsy, or metabolic
disorders.
- Have a history of significant drug allergy to any beta-lactam antibiotic (e.g.
anaphylaxis and/or angioedema)
- Are on an oral antimicrobial at time of enrollment
- Are started on an oral antimicrobial during the study
o Note: If an enrolled patient is started on an oral antimicrobial prior to completion
of the study, they will be removed from the study. However, data obtained prior to
their receipt of an oral antimicrobial will still be included in the analysis.
- Are planned to be discharged within 48 hours
- Are known to be pregnant
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